%0 Journal Article %J Brain %D 2022 %T Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy. %A Marafi, Dana %A Fatih, Jawid M %A Kaiyrzhanov, Rauan %A Ferla, Matteo P %A Gijavanekar, Charul %A Al-Maraghi, Aljazi %A Liu, Ning %A Sites, Emily %A Alsaif, Hessa S %A Al-Owain, Mohammad %A Zakkariah, Mohamed %A El-Anany, Ehab %A Guliyeva, Ulviyya %A Guliyeva, Sughra %A Gaba, Colette %A Haseeb, Ateeq %A Alhashem, Amal M %A Danish, Enam %A Karageorgou, Vasiliki %A Beetz, Christian %A Subhi, Alaa A %A Mullegama, Sureni V %A Torti, Erin %A Sebastin, Monisha %A Breilyn, Margo Sheck %A Duberstein, Susan %A Abdel-Hamid, Mohamed S %A Mitani, Tadahiro %A Du, Haowei %A Rosenfeld, Jill A %A Jhangiani, Shalini N %A Coban Akdemir, Zeynep %A Richard A Gibbs %A Taylor, Jenny C %A Fakhro, Khalid A %A Hunter, Jill V %A Pehlivan, Davut %A Zaki, Maha S %A Gleeson, Joseph G %A Maroofian, Reza %A Houlden, Henry %A Posey, Jennifer E %A Sutton, V Reid %A Alkuraya, Fowzan S %A Sarah H Elsea %A James R Lupski %K Epilepsy, Generalized %K Glutamine %K Histidine %K Humans %K Metabolome %K Nitrogen %K Sodium-Calcium Exchanger %X

The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy and severe neurodevelopmental disorders. Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental disorders identified two siblings with developmental and epileptic encephalopathy and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar developmental and epileptic encephalopathy phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and CSF of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis.

%B Brain %V 145 %P 909-924 %8 2022 Apr 29 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/34605855?dopt=Abstract %R 10.1093/brain/awab369 %0 Journal Article %J Am J Med Genet A %D 2021 %T Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome. %A Dyment, David A %A O'Donnell-Luria, Anne %A Agrawal, Pankaj B %A Coban Akdemir, Zeynep %A Aleck, Kyrieckos A %A Antaki, Danny %A Al Sharhan, Hind %A Au, Ping-Yee B %A Aydin, Hatip %A Beggs, Alan H %A Bilguvar, Kaya %A Eric Boerwinkle %A Brand, Harrison %A Brownstein, Catherine A %A Buyske, Steve %A Chodirker, Bernard %A Choi, Jungmin %A Chudley, Albert E %A Clericuzio, Carol L %A Cox, Gerald F %A Curry, Cynthia %A de Boer, Elke %A de Vries, Bert B A %A Dunn, Kathryn %A Dutmer, Cullen M %A England, Eleina M %A Fahrner, Jill A %A Geckinli, Bilgen B %A Genetti, Casie A %A Gezdirici, Alper %A Gibson, William T %A Gleeson, Joseph G %A Greenberg, Cheryl R %A Hall, April %A Hamosh, Ada %A Hartley, Taila %A Jhangiani, Shalini N %A Karaca, Ender %A Kernohan, Kristin %A Lauzon, Julie L %A Lewis, M E Suzanne %A Lowry, R Brian %A López-Giráldez, Francesc %A Matise, Tara C %A McEvoy-Venneri, Jennifer %A McInnes, Brenda %A Mhanni, Aziz %A Garcia Minaur, Sixto %A Moilanen, Jukka %A Nguyen, An %A Nowaczyk, Malgorzata J M %A Posey, Jennifer E %A Õunap, Katrin %A Pehlivan, Davut %A Pajusalu, Sander %A Penney, Lynette S %A Poterba, Timothy %A Prontera, Paolo %A Doriqui, Maria Juliana Rodovalho %A Sawyer, Sarah L %A Sobreira, Nara %A Stanley, Valentina %A Torun, Deniz %A Wargowski, David %A Witmer, P Dane %A Wong, Isaac %A Xing, Jinchuan %A Zaki, Maha S %A Zhang, Yeting %A Boycott, Kym M %A Bamshad, Michael J %A Nickerson, Deborah A %A Blue, Elizabeth E %A Innes, A Micheil %K Adolescent %K Child %K Child, Preschool %K DNA Copy Number Variations %K Eczema %K Exome %K Exome Sequencing %K Facies %K Female %K Genetic Predisposition to Disease %K Genome, Human %K Genomics %K Growth Disorders %K Histone Deacetylases %K Humans %K Infant %K Intellectual Disability %K Male %K Microcephaly %K Phenotype %K Repressor Proteins %X

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.

%B Am J Med Genet A %V 185 %P 119-133 %8 2021 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33098347?dopt=Abstract %R 10.1002/ajmg.a.61926 %0 Journal Article %J Brain %D 2020 %T Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability. %A Van Bergen, Nicole J %A Guo, Yiran %A Al-Deri, Noraldin %A Lipatova, Zhanna %A Stanga, Daniela %A Zhao, Sarah %A Murtazina, Rakhilya %A Gyurkovska, Valeriya %A Pehlivan, Davut %A Mitani, Tadahiro %A Gezdirici, Alper %A Antony, Jayne %A Collins, Felicity %A Willis, Mary J H %A Coban Akdemir, Zeynep H %A Liu, Pengfei %A Punetha, Jaya %A Hunter, Jill V %A Jhangiani, Shalini N %A Fatih, Jawid M %A Rosenfeld, Jill A %A Posey, Jennifer E %A Richard A Gibbs %A Karaca, Ender %A Massey, Sean %A Ranasinghe, Thisara G %A Sleiman, Patrick %A Troedson, Chris %A James R Lupski %A Sacher, Michael %A Segev, Nava %A Hakonarson, Hakon %A Christodoulou, John %K Atrophy %K Autophagy %K Cerebellum %K Cerebral Cortex %K Child %K Child, Preschool %K Craniofacial Abnormalities %K Deafness %K Developmental Disabilities %K Epilepsy %K Female %K Fibroblasts %K Hearing Loss, Sensorineural %K Humans %K Infant %K Infant, Newborn %K Intellectual Disability %K Male %K Microcephaly %K Microscopy, Fluorescence %K Muscle Spasticity %K Nerve Tissue Proteins %K Neurodevelopmental Disorders %K Pedigree %K Quadriplegia %K RNA Splice Sites %K Syndrome %K Vesicular Transport Proteins %X

The conserved transport protein particle (TRAPP) complexes regulate key trafficking events and are required for autophagy. TRAPPC4, like its yeast Trs23 orthologue, is a core component of the TRAPP complexes and one of the essential subunits for guanine nucleotide exchange factor activity for Rab1 GTPase. Pathogenic variants in specific TRAPP subunits are associated with neurological disorders. We undertook exome sequencing in three unrelated families of Caucasian, Turkish and French-Canadian ethnicities with seven affected children that showed features of early-onset seizures, developmental delay, microcephaly, sensorineural deafness, spastic quadriparesis and progressive cortical and cerebellar atrophy in an effort to determine the genetic aetiology underlying neurodevelopmental disorders. All seven affected subjects shared the same identical rare, homozygous, potentially pathogenic variant in a non-canonical, well-conserved splice site within TRAPPC4 (hg19:chr11:g.118890966A>G; TRAPPC4: NM_016146.5; c.454+3A>G). Single nucleotide polymorphism array analysis revealed there was no haplotype shared between the tested Turkish and Caucasian families suggestive of a variant hotspot region rather than a founder effect. In silico analysis predicted the variant to cause aberrant splicing. Consistent with this, experimental evidence showed both a reduction in full-length transcript levels and an increase in levels of a shorter transcript missing exon 3, suggestive of an incompletely penetrant splice defect. TRAPPC4 protein levels were significantly reduced whilst levels of other TRAPP complex subunits remained unaffected. Native polyacrylamide gel electrophoresis and size exclusion chromatography demonstrated a defect in TRAPP complex assembly and/or stability. Intracellular trafficking through the Golgi using the marker protein VSVG-GFP-ts045 demonstrated significantly delayed entry into and exit from the Golgi in fibroblasts derived from one of the affected subjects. Lentiviral expression of wild-type TRAPPC4 in these fibroblasts restored trafficking, suggesting that the trafficking defect was due to reduced TRAPPC4 levels. Consistent with the recent association of the TRAPP complex with autophagy, we found that the fibroblasts had a basal autophagy defect and a delay in autophagic flux, possibly due to unsealed autophagosomes. These results were validated using a yeast trs23 temperature sensitive variant that exhibits constitutive and stress-induced autophagic defects at permissive temperature and a secretory defect at restrictive temperature. In summary we provide strong evidence for pathogenicity of this variant in a member of the core TRAPP subunit, TRAPPC4 that associates with vesicular trafficking and autophagy defects. This is the first report of a TRAPPC4 variant, and our findings add to the growing number of TRAPP-associated neurological disorders.

%B Brain %V 143 %P 112-130 %8 2020 Jan 01 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31794024?dopt=Abstract %R 10.1093/brain/awz374 %0 Journal Article %J Mol Genet Genomic Med %D 2020 %T Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1. %A Lin, Mao %A Liu, Zhenlei %A Liu, Gang %A Zhao, Sen %A Li, Chao %A Chen, Weisheng %A Coban Akdemir, Zeynep %A Lin, Jiachen %A Song, Xiaofei %A Wang, Shengru %A Xu, Qiming %A Zhao, Yanxue %A Wang, Lianlei %A Zhang, Yuanqiang %A Yan, Zihui %A Liu, Sen %A Liu, Jiaqi %A Chen, Yixin %A Zuo, Yuzhi %A Yang, Xu %A Sun, Tianshu %A Yang, Xin-Zhuang %A Niu, Yuchen %A Li, Xiaoxin %A You, Wesley %A Qiu, Bintao %A Ding, Chen %A Liu, Pengfei %A Zhang, Shuyang %A Carvalho, Claudia M B %A Posey, Jennifer E %A Qiu, Guixing %A James R Lupski %A Wu, Zhihong %A Zhang, Jianguo %A Wu, Nan %K Adolescent %K Adult %K Child %K Female %K Fibrillin-1 %K HEK293 Cells %K Humans %K Lipodystrophy %K Marfan Syndrome %K Mutation %K Phenotype %K Progeria %K Protein Domains %K Smad2 Protein %X

BACKGROUND: The molecular and genetic mechanisms by which different single nucleotide variant alleles in specific genes, or at the same genetic locus, cause distinct disease phenotypes often remain unclear. Allelic truncating mutations of FBN1 could cause either classical Marfan syndrome (MFS) or a more complicated phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS).

METHODS: We investigated a small cohort, encompassing two classical MFS and one MPLS subjects from China, whose clinical presentation included scoliosis potentially requiring surgical intervention. Targeted next generation sequencing was performed on all the participants. We analyzed the molecular diagnosis, clinical features, and the potential molecular mechanism involved in the MPLS subject in our cohort.

RESULTS: We report a novel de novo FBN1 mutation for the first Chinese subject with MPLS, a more complicated fibrillinopathy, and two subjects with more classical MFS. We further predict that the MPLS truncating mutation, and others previously reported, is prone to escape the nonsense-mediated decay (NMD), while MFS mutations are predicted to be subjected to NMD. Also, the MPLS mutation occurs within the glucogenic hormone asprosin domain of FBN1. In vitro experiments showed that the single MPLS mutation p.Glu2759Cysfs*9 appears to perturb proper FBN1 protein aggregation as compared with the classical MFS mutation p.Tyr2596Thrfs*86. Both mutations appear to upregulate SMAD2 phosphorylation in vitro.

CONCLUSION: We provide direct evidence that a dominant-negative interaction of FBN1 potentially explains the complex MPLS phenotypes through genetic and functional analysis. Our study expands the mutation spectrum of FBN1 and highlights the potential molecular mechanism for MPLS.

%B Mol Genet Genomic Med %V 8 %P e1023 %8 2020 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31774634?dopt=Abstract %R 10.1002/mgg3.1023 %0 Journal Article %J Neurol Genet %D 2020 %T Integrated sequencing and array comparative genomic hybridization in familial Parkinson disease. %A Robak, Laurie A %A Du, Renqian %A Bo Yuan %A Gu, Shen %A Alfradique-Dunham, Isabel %A Kondapalli, Vismaya %A Hinojosa, Evelyn %A Stillwell, Amanda %A Young, Emily %A Zhang, Chaofan %A Song, Xiaofei %A Du, Haowei %A Gambin, Tomasz %A Jhangiani, Shalini N %A Coban Akdemir, Zeynep %A Donna M Muzny %A Tejomurtula, Anusha %A Ross, Owen A %A Shaw, Chad %A Jankovic, Joseph %A Bi, Weimin %A Posey, Jennifer E %A James R Lupski %A Shulman, Joshua M %X

OBJECTIVE: To determine how single nucleotide variants (SNVs) and copy number variants (CNVs) contribute to molecular diagnosis in familial Parkinson disease (PD), we integrated exome sequencing (ES) and genome-wide array-based comparative genomic hybridization (aCGH) and further probed CNV structure to reveal mutational mechanisms.

METHODS: We performed ES on 110 subjects with PD and a positive family history; 99 subjects were also evaluated using genome-wide aCGH. We interrogated ES and aCGH data for pathogenic SNVs and CNVs at Mendelian PD gene loci. We confirmed SNVs via Sanger sequencing and further characterized CNVs with custom-designed high-density aCGH, droplet digital PCR, and breakpoint sequencing.

RESULTS: Using ES, we discovered individuals with known pathogenic SNVs in (p.Glu365Lys, p.Thr408Met, p.Asn409Ser, and p.Leu483Pro) and (p.Arg1441Gly and p.Gly2019Ser). Two subjects were each double heterozygotes for variants in and . Based on aCGH, we additionally discovered cases with an duplication and heterozygous intragenic deletion. Five additional subjects harbored both SNVs (p.Asn52Metfs*29, p.Thr240Met, p.Pro437Leu, and p.Trp453*) and likely disrupting CNVs at the locus, consistent with compound heterozygosity. In nearly all cases, breakpoint sequencing revealed microhomology, a mutational signature consistent with CNV formation due to DNA replication errors.

CONCLUSIONS: Integrated ES and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for and CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.

%B Neurol Genet %V 6 %P e498 %8 2020 Oct %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/32802956?dopt=Abstract %R 10.1212/NXG.0000000000000498 %0 Journal Article %J Genet Med %D 2020 %T Low-level parental somatic mosaic SNVs in exomes from a large cohort of trios with diverse suspected Mendelian conditions. %A Gambin, Tomasz %A Liu, Qian %A Karolak, Justyna A %A Grochowski, Christopher M %A Xie, Nina G %A Wu, Lucia R %A Yan, Yan Helen %A Cao, Ye %A Coban Akdemir, Zeynep H %A Wilson, Theresa A %A Jhangiani, Shalini N %A Chen, Ed %A Eng, Christine M %A Donna M Muzny %A Posey, Jennifer E %A Yang, Yaping %A Zhang, David Y %A Shaw, Chad %A Liu, Pengfei %A James R Lupski %A Stankiewicz, Paweł %K Exome %K Exome Sequencing %K High-Throughput Nucleotide Sequencing %K Humans %K Mosaicism %K Parents %X

PURPOSE: The goal of this study was to assess the scale of low-level parental mosaicism in exome sequencing (ES) databases.

METHODS: We analyzed approximately 2000 family trio ES data sets from the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) and Baylor Genetics (BG). Among apparent de novo single-nucleotide variants identified in the affected probands, we selected rare unique variants with variant allele fraction (VAF) between 30% and 70% in the probands and lower than 10% in one of the parents.

RESULTS: Of 102 candidate mosaic variants validated using amplicon-based next-generation sequencing, droplet digital polymerase chain reaction, or blocker displacement amplification, 27 (26.4%) were confirmed to be low- (VAF between 1% and 10%) or very low (VAF <1%) level mosaic. Detection precision in parental samples with two or more alternate reads was 63.6% (BHCMG) and 43.6% (BG). In nine investigated individuals, we observed variability of mosaic ratios among blood, saliva, fibroblast, buccal, hair, and urine samples.

CONCLUSION: Our computational pipeline enables robust discrimination between true and false positive candidate mosaic variants and efficient detection of low-level mosaicism in ES samples. We confirm that the presence of two or more alternate reads in the parental sample is a reliable predictor of low-level parental somatic mosaicism.

%B Genet Med %V 22 %P 1768-1776 %8 2020 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/32655138?dopt=Abstract %R 10.1038/s41436-020-0897-z %0 Journal Article %J Hum Mutat %D 2020 %T Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy. %A Assia Batzir, Nurit %A Kishor Bhagwat, Pranjali %A Larson, Austin %A Coban Akdemir, Zeynep %A Bagłaj, Maciej %A Bofferding, Leon %A Bosanko, Katherine B %A Bouassida, Skander %A Callewaert, Bert %A Cannon, Ashley %A Enchautegui Colon, Yazmin %A Garnica, Adolfo D %A Harr, Margaret H %A Heck, Sandra %A Hurst, Anna C E %A Jhangiani, Shalini N %A Isidor, Bertrand %A Littlejohn, Rebecca O %A Liu, Pengfei %A Magoulas, Pilar %A Mar Fan, Helen %A Marom, Ronit %A McLean, Scott %A Nezarati, Marjan M %A Nugent, Kimberly M %A Petersen, Michael B %A Rocha, Maria L %A Roeder, Elizabeth %A Smigiel, Robert %A Tully, Ian %A Weisfeld-Adams, James %A Wells, Katerina O %A Posey, Jennifer E %A James R Lupski %A Beaudet, Arthur L %A Wangler, Michael F %K Abnormalities, Multiple %K Actins %K Adult %K Amino Acid Substitution %K Arginine %K Colon %K DNA Mutational Analysis %K Exome Sequencing %K Female %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genotype %K Humans %K Intestinal Pseudo-Obstruction %K Male %K Molecular Diagnostic Techniques %K Mutation %K Phenotype %K Urinary Bladder %K Young Adult %X

Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with megacystis-microcolon intestinal hypoperistalsis syndrome and chronic intestinal pseudo-obstruction. The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction, or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64% (34/53), of which 97% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides accounted for 49% (26/53) of disease in the cohort. As a group, the ACTG2-negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death, or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178>p.Arg257>p.Arg40 along with other less-frequently reported sites p.Arg63 and p.Arg211. These results provide genotype-phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy.

%B Hum Mutat %V 41 %P 641-654 %8 2020 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/31769566?dopt=Abstract %R 10.1002/humu.23960 %0 Journal Article %J Am J Med Genet A %D 2019 %T Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle-opathies with Microcephaly, Dwarfism and Skeletal Abnormalities. %A Karaca, Ender %A Posey, Jennifer E %A Bostwick, Bret %A Liu, Pengfei %A Gezdirici, Alper %A Yesil, Gozde %A Coban Akdemir, Zeynep %A Bayram, Yavuz %A Harms, Frederike L %A Meinecke, Peter %A Alawi, Malik %A Bacino, Carlos A %A Sutton, V Reid %A Kortüm, Fanny %A James R Lupski %K Alleles %K Bone and Bones %K Cell Cycle %K Cell Cycle Proteins %K Child %K Child, Preschool %K Dwarfism %K Family %K Female %K Humans %K Infant %K Infant, Newborn %K Male %K Microcephaly %K Nuclear Proteins %K Pedigree %K Phenotype %X

Co-occurrence of primordial dwarfism and microcephaly together with particular skeletal findings are seen in a wide range of Mendelian syndromes including microcephaly micromelia syndrome (MMS, OMIM 251230), microcephaly, short stature, and limb abnormalities (MISSLA, OMIM 617604), and microcephalic primordial dwarfisms (MPDs). Genes associated with these syndromes encode proteins that have crucial roles in DNA replication or in other critical steps of the cell cycle that link DNA replication to cell division. We identified four unrelated families with five affected individuals having biallelic or de novo variants in DONSON presenting with a core phenotype of severe short stature (z score < -3 SD), additional skeletal abnormalities, and microcephaly. Two apparently unrelated families with identical homozygous c.631C > T p.(Arg211Cys) variant had clinical features typical of Meier-Gorlin syndrome (MGS), while two siblings with compound heterozygous c.346delG p.(Asp116Ile*62) and c.1349A > G p.(Lys450Arg) variants presented with Seckel-like phenotype. We also identified a de novo c.683G > T p.(Trp228Leu) variant in DONSON in a patient with prominent micrognathia, short stature and hypoplastic femur and tibia, clinically diagnosed with Femoral-Facial syndrome (FFS, OMIM 134780). Biallelic variants in DONSON have been recently described in individuals with microcephalic dwarfism. These studies also demonstrated that DONSON has an essential conserved role in the cell cycle. Here we describe novel biallelic and de novo variants that are associated with MGS, Seckel-like phenotype and FFS, the last of which has not been associated with any disease gene to date.

%B Am J Med Genet A %V 179 %P 2056-2066 %8 2019 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/31407851?dopt=Abstract %R 10.1002/ajmg.a.61315 %0 Journal Article %J Am J Hum Genet %D 2019 %T Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders. %A Mitani, Tadahiro %A Punetha, Jaya %A Akalin, Ibrahim %A Pehlivan, Davut %A Dawidziuk, Mateusz %A Coban Akdemir, Zeynep %A Yilmaz, Sarenur %A Aslan, Ezgi %A Hunter, Jill V %A Hijazi, Hadia %A Grochowski, Christopher M %A Jhangiani, Shalini N %A Karaca, Ender %A Fatih, Jawid M %A Iwanowski, Piotr %A Gambin, Tomasz %A Wlasienko, Pawel %A Goszczanska-Ciuchta, Alicja %A Bekiesinska-Figatowska, Monika %A Hosseini, Masoumeh %A Arzhangi, Sanaz %A Najmabadi, Hossein %A Rosenfeld, Jill A %A Du, Haowei %A Marafi, Dana %A Blaser, Susan %A Teitelbaum, Ronni %A Silver, Rachel %A Posey, Jennifer E %A Ropers, Hans-Hilger %A Richard A Gibbs %A Wiszniewski, Wojciech %A James R Lupski %A Chitayat, David %A Kahrizi, Kimia %A Gawlinski, Pawel %K Alleles %K Brain %K Cell Movement %K Child %K Exome %K Female %K Genetic Variation %K Homozygote %K Humans %K Lissencephaly %K Male %K Microcephaly %K Microtubule-Associated Proteins %K Microtubules %K Nervous System Malformations %K Neurons %K Phenotype %K Tubulin %X

Lissencephaly comprises a spectrum of malformations of cortical development. This spectrum includes agyria, pachygyria, and subcortical band heterotopia; each represents anatomical malformations of brain cortical development caused by neuronal migration defects. The molecular etiologies of neuronal migration anomalies are highly enriched for genes encoding microtubules and microtubule-associated proteins, and this enrichment highlights the critical role for these genes in cortical growth and gyrification. Using exome sequencing and family based rare variant analyses, we identified a homozygous variant (c.997C>T [p.Arg333Cys]) in TUBGCP2, encoding gamma-tubulin complex protein 2 (GCP2), in two individuals from a consanguineous family; both individuals presented with microcephaly and developmental delay. GCP2 forms the multiprotein γ-tubulin ring complex (γ-TuRC) together with γ-tubulin and other GCPs to regulate the assembly of microtubules. By querying clinical exome sequencing cases and through GeneMatcher-facilitated collaborations, we found three additional families with bi-allelic variation and similarly affected phenotypes including a homozygous variant (c.1843G>C [p.Ala615Pro]) in two families and compound heterozygous variants consisting of one missense variant (c.889C>T [p.Arg297Cys]) and one splice variant (c.2025-2A>G) in another family. Brain imaging from all five affected individuals revealed varying degrees of cortical malformations including pachygyria and subcortical band heterotopia, presumably caused by disruption of neuronal migration. Our data demonstrate that pathogenic variants in TUBGCP2 cause an autosomal recessive neurodevelopmental trait consisting of a neuronal migration disorder, and our data implicate GCP2 as a core component of γ-TuRC in neuronal migrating cells.

%B Am J Hum Genet %V 105 %P 1005-1015 %8 2019 Nov 07 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/31630790?dopt=Abstract %R 10.1016/j.ajhg.2019.09.017 %0 Journal Article %J Am J Hum Genet %D 2019 %T Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway. %A Karolak, Justyna A %A Vincent, Marie %A Deutsch, Gail %A Gambin, Tomasz %A Cogné, Benjamin %A Pichon, Olivier %A Vetrini, Francesco %A Mefford, Heather C %A Dines, Jennifer N %A Golden-Grant, Katie %A Dipple, Katrina %A Freed, Amanda S %A Leppig, Kathleen A %A Dishop, Megan %A Mowat, David %A Bennetts, Bruce %A Gifford, Andrew J %A Weber, Martin A %A Lee, Anna F %A Boerkoel, Cornelius F %A Bartell, Tina M %A Ward-Melver, Catherine %A Besnard, Thomas %A Petit, Florence %A Bache, Iben %A Tümer, Zeynep %A Denis-Musquer, Marie %A Joubert, Madeleine %A Martinovic, Jelena %A Bénéteau, Claire %A Molin, Arnaud %A Carles, Dominique %A André, Gwenaelle %A Bieth, Eric %A Chassaing, Nicolas %A Devisme, Louise %A Chalabreysse, Lara %A Pasquier, Laurent %A Secq, Véronique %A Don, Massimiliano %A Orsaria, Maria %A Missirian, Chantal %A Mortreux, Jérémie %A Sanlaville, Damien %A Pons, Linda %A Küry, Sébastien %A Bézieau, Stéphane %A Liet, Jean-Michel %A Joram, Nicolas %A Bihouée, Tiphaine %A Scott, Daryl A %A Brown, Chester W %A Scaglia, Fernando %A Tsai, Anne Chun-Hui %A Grange, Dorothy K %A Phillips, John A %A Pfotenhauer, Jean P %A Jhangiani, Shalini N %A Gonzaga-Jauregui, Claudia G %A Chung, Wendy K %A Schauer, Galen M %A Lipson, Mark H %A Mercer, Catherine L %A van Haeringen, Arie %A Liu, Qian %A Popek, Edwina %A Coban Akdemir, Zeynep H %A James R Lupski %A Szafranski, Przemyslaw %A Isidor, Bertrand %A Le Caignec, Cedric %A Stankiewicz, Paweł %K DNA Copy Number Variations %K Female %K Fibroblast Growth Factor 10 %K Gene Expression Regulation %K Gestational Age %K Humans %K Infant, Newborn %K Infant, Newborn, Diseases %K Lung %K Lung Diseases %K Male %K Maternal Inheritance %K Organogenesis %K Paternal Inheritance %K Pedigree %K Polymorphism, Single Nucleotide %K Receptor, Fibroblast Growth Factor, Type 2 %K Signal Transduction %K T-Box Domain Proteins %X

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

%B Am J Hum Genet %V 104 %P 213-228 %8 2019 Feb 07 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/30639323?dopt=Abstract %R 10.1016/j.ajhg.2018.12.010 %0 Journal Article %J J Clin Endocrinol Metab %D 2019 %T Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease. %A Jolly, Angad %A Bayram, Yavuz %A Turan, Serap %A Aycan, Zehra %A Tos, Tulay %A Abali, Zehra Yavas %A Hacihamdioglu, Bulent %A Coban Akdemir, Zeynep Hande %A Hijazi, Hadia %A Bas, Serpil %A Atay, Zeynep %A Guran, Tulay %A Abali, Saygin %A Bas, Firdevs %A Darendeliler, Feyza %A Colombo, Roberto %A Barakat, Tahsin Stefan %A Rinne, Tuula %A White, Janson J %A Yesil, Gozde %A Gezdirici, Alper %A Gulec, Elif Yilmaz %A Karaca, Ender %A Pehlivan, Davut %A Jhangiani, Shalini N %A Donna M Muzny %A Poyrazoglu, Sukran %A Bereket, Abdullah %A Richard A Gibbs %A Posey, Jennifer E %A James R Lupski %K Cell Cycle Proteins %K Cohort Studies %K DNA Helicases %K DNA-Binding Proteins %K Exome Sequencing %K Female %K Gene Frequency %K Humans %K Hypogonadism %K Immunoglobulins %K Minichromosome Maintenance Proteins %K Primary Ovarian Insufficiency %X

CONTEXT: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hypergonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait.

OBJECTIVE: To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI.

DESIGN, SETTING, AND PARTICIPANTS: We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity.

RESULTS: This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds.

CONCLUSIONS: ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI.

%B J Clin Endocrinol Metab %V 104 %P 3049-3067 %8 2019 Aug 01 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/31042289?dopt=Abstract %R 10.1210/jc.2019-00248 %0 Journal Article %J Am J Hum Genet %D 2019 %T A Genocentric Approach to Discovery of Mendelian Disorders. %A Hansen, Adam W %A Mullai Murugan %A Li, He %A Khayat, Michael M %A Wang, Liwen %A Rosenfeld, Jill %A B. Kim Andrews %A Jhangiani, Shalini N %A Coban Akdemir, Zeynep H %A Fritz J Sedlazeck %A Ashley-Koch, Allison E %A Liu, Pengfei %A Donna M Muzny %A Davis, Erica E %A Katsanis, Nicholas %A Aniko Sabo %A Posey, Jennifer E %A Yang, Yaping %A Wangler, Michael F %A Eng, Christine M %A Sutton, V Reid %A James R Lupski %A Eric Boerwinkle %A Richard A Gibbs %K Databases, Genetic %K Exome %K Exome Sequencing %K Genetic Diseases, Inborn %K Genetic Predisposition to Disease %K Genetic Variation %K Genomics %K Humans %K Pedigree %K Phenotype %X

The advent of inexpensive, clinical exome sequencing (ES) has led to the accumulation of genetic data from thousands of samples from individuals affected with a wide range of diseases, but for whom the underlying genetic and molecular etiology of their clinical phenotype remains unknown. In many cases, detailed phenotypes are unavailable or poorly recorded and there is little family history to guide study. To accelerate discovery, we integrated ES data from 18,696 individuals referred for suspected Mendelian disease, together with relatives, in an Apache Hadoop data lake (Hadoop Architecture Lake of Exomes [HARLEE]) and implemented a genocentric analysis that rapidly identified 154 genes harboring variants suspected to cause Mendelian disorders. The approach did not rely on case-specific phenotypic classifications but was driven by optimization of gene- and variant-level filter parameters utilizing historical Mendelian disease-gene association discovery data. Variants in 19 of the 154 candidate genes were subsequently reported as causative of a Mendelian trait and additional data support the association of all other candidate genes with disease endpoints.

%B Am J Hum Genet %V 105 %P 974-986 %8 2019 Nov 07 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/31668702?dopt=Abstract %R 10.1016/j.ajhg.2019.09.027 %0 Journal Article %J Am J Hum Genet %D 2019 %T The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance. %A Pehlivan, Davut %A Bayram, Yavuz %A Gunes, Nilay %A Coban Akdemir, Zeynep %A Shukla, Anju %A Bierhals, Tatjana %A Tabakci, Burcu %A Sahin, Yavuz %A Gezdirici, Alper %A Fatih, Jawid M %A Gulec, Elif Yilmaz %A Yesil, Gozde %A Punetha, Jaya %A Ocak, Zeynep %A Grochowski, Christopher M %A Karaca, Ender %A Albayrak, Hatice Mutlu %A Radhakrishnan, Periyasamy %A Erdem, Haktan Bagis %A Sahin, Ibrahim %A Yildirim, Timur %A Bayhan, Ilhan A %A Bursali, Aysegul %A Elmas, Muhsin %A Yuksel, Zafer %A Ozdemir, Ozturk %A Silan, Fatma %A Yildiz, Onur %A Yesilbas, Osman %A Isikay, Sedat %A Balta, Burhan %A Gu, Shen %A Jhangiani, Shalini N %A Harshavardhan Doddapaneni %A Jianhong Hu %A Donna M Muzny %A Eric Boerwinkle %A Richard A Gibbs %A Tsiakas, Konstantinos %A Hempel, Maja %A Girisha, Katta Mohan %A Gul, Davut %A Posey, Jennifer E %A Elcioglu, Nursel H %A Tuysuz, Beyhan %A James R Lupski %K Adolescent %K Adult %K Arthrogryposis %K Child %K Child, Preschool %K Cohort Studies %K Connectin %K DNA Copy Number Variations %K Exome Sequencing %K Female %K Genetic Markers %K Genomics %K Gestational Age %K Humans %K Infant %K Infant, Newborn %K Male %K Mosaicism %K Multifactorial Inheritance %K Mutation %K Pedigree %K Ryanodine Receptor Calcium Release Channel %K Vesicular Transport Proteins %K Young Adult %X

Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.

%B Am J Hum Genet %V 105 %P 132-150 %8 2019 Jul 03 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31230720?dopt=Abstract %R 10.1016/j.ajhg.2019.05.015 %0 Journal Article %J Clin Genet %D 2019 %T Heterozygous CTNNB1 and TBX4 variants in a patient with abnormal lung growth, pulmonary hypertension, microcephaly, and spasticity. %A Karolak, Justyna A %A Szafranski, Przemyslaw %A Kilner, David %A Patel, Chirag %A Scurry, Bonnie %A Kinning, Esther %A Chandler, Kate %A Jhangiani, Shalini N %A Coban Akdemir, Zeynep H %A James R Lupski %A Popek, Edwina %A Stankiewicz, Paweł %K Alleles %K beta Catenin %K DNA Mutational Analysis %K Exome Sequencing %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genetic Variation %K Heterozygote %K Humans %K Hypertension, Pulmonary %K Immunohistochemistry %K Microcephaly %K Muscle Spasticity %K Mutation %K Phenotype %K T-Box Domain Proteins %X

The canonical wingless (Wnt) and fibroblast growth factor (FGF) signaling pathways involving CTNNB1 and TBX4, respectively, are crucial for the regulation of human development. Perturbations of these pathways and disruptions from biological homeostasis have been associated with abnormal morphogenesis of multiple organs, including the lung. The aim of this study was to identify the underlying genetic cause of abnormal lung growth, pulmonary hypertension (PAH), severe microcephaly, and muscle spasticity in a full-term newborn, who died at 4 months of age due to progressively worsening PAH and respiratory failure. Family trio exome sequencing showed a de novo heterozygous nonsense c.1603C>T (p.Arg535*) variant in CTNNB1 and a paternally inherited heterozygous missense c.1198G>A (p.Glu400Lys) variant in TBX4, both predicted to be likely deleterious. We expand the phenotypic spectrum associated with CTNNB1 and TBX4 variants and indicate that they could act synergistically to produce a distinct more severe phenotype. Our findings further support a recently proposed complex compound inheritance model in lethal lung developmental diseases and the contention that dual molecular diagnoses can parsimoniously explain blended phenotypes.

%B Clin Genet %V 96 %P 366-370 %8 2019 Oct %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/31309540?dopt=Abstract %R 10.1111/cge.13605 %0 Journal Article %J Genet Med %D 2019 %T Insights into genetics, human biology and disease gleaned from family based genomic studies. %A Posey, Jennifer E %A O'Donnell-Luria, Anne H %A Chong, Jessica X %A Harel, Tamar %A Jhangiani, Shalini N %A Coban Akdemir, Zeynep H %A Buyske, Steven %A Pehlivan, Davut %A Carvalho, Claudia M B %A Baxter, Samantha %A Sobreira, Nara %A Liu, Pengfei %A Wu, Nan %A Rosenfeld, Jill A %A Kumar, Sushant %A Avramopoulos, Dimitri %A White, Janson J %A Doheny, Kimberly F %A Witmer, P Dane %A Boehm, Corinne %A Sutton, V Reid %A Donna M Muzny %A Eric Boerwinkle %A Gunel, Murat %A Nickerson, Deborah A %A Mane, Shrikant %A MacArthur, Daniel G %A Richard A Gibbs %A Hamosh, Ada %A Lifton, Richard P %A Matise, Tara C %A Rehm, Heidi L %A Gerstein, Mark %A Bamshad, Michael J %A Valle, David %A Lupski, James R %K Databases, Genetic %K Exome Sequencing %K Genetic Diseases, Inborn %K Genetic Heterogeneity %K Genetic Predisposition to Disease %K Genome, Human %K Genomics %K Humans %K National Institutes of Health (U.S.) %K Pedigree %K United States %X

Identifying genes and variants contributing to rare disease phenotypes and Mendelian conditions informs biology and medicine, yet potential phenotypic consequences for variation of >75% of the ~20,000 annotated genes in the human genome are lacking. Technical advances to assess rare variation genome-wide, particularly exome sequencing (ES), enabled establishment in the United States of the National Institutes of Health (NIH)-supported Centers for Mendelian Genomics (CMGs) and have facilitated collaborative studies resulting in novel "disease gene" discoveries. Pedigree-based genomic studies and rare variant analyses in families with suspected Mendelian conditions have led to the elucidation of hundreds of novel disease genes and highlighted the impact of de novo mutational events, somatic variation underlying nononcologic traits, incompletely penetrant alleles, phenotypes with high locus heterogeneity, and multilocus pathogenic variation. Herein, we highlight CMG collaborative discoveries that have contributed to understanding both rare and common diseases and discuss opportunities for future discovery in single-locus Mendelian disorder genomics. Phenotypic annotation of all human genes; development of bioinformatic tools and analytic methods; exploration of non-Mendelian modes of inheritance including reduced penetrance, multilocus variation, and oligogenic inheritance; construction of allelic series at a locus; enhanced data sharing worldwide; and integration with clinical genomics are explored. Realizing the full contribution of rare disease research to functional annotation of the human genome, and further illuminating human biology and health, will lay the foundation for the Precision Medicine Initiative.

%B Genet Med %V 21 %P 798-812 %8 2019 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/30655598?dopt=Abstract %R 10.1038/s41436-018-0408-7 %0 Journal Article %J Am J Hum Genet %D 2019 %T Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability. %A Cogné, Benjamin %A Ehresmann, Sophie %A Beauregard-Lacroix, Eliane %A Rousseau, Justine %A Besnard, Thomas %A Garcia, Thomas %A Petrovski, Slavé %A Avni, Shiri %A McWalter, Kirsty %A Blackburn, Patrick R %A Sanders, Stephan J %A Uguen, Kévin %A Harris, Jacqueline %A Cohen, Julie S %A Blyth, Moira %A Lehman, Anna %A Berg, Jonathan %A Li, Mindy H %A Kini, Usha %A Joss, Shelagh %A von der Lippe, Charlotte %A Gordon, Christopher T %A Humberson, Jennifer B %A Robak, Laurie %A Scott, Daryl A %A Sutton, Vernon R %A Skraban, Cara M %A Johnston, Jennifer J %A Poduri, Annapurna %A Nordenskjöld, Magnus %A Shashi, Vandana %A Gerkes, Erica H %A Bongers, Ernie M H F %A Gilissen, Christian %A Zarate, Yuri A %A Kvarnung, Malin %A Lally, Kevin P %A Kulch, Peggy A %A Daniels, Brina %A Hernandez-Garcia, Andres %A Stong, Nicholas %A McGaughran, Julie %A Retterer, Kyle %A Tveten, Kristian %A Sullivan, Jennifer %A Geisheker, Madeleine R %A Stray-Pedersen, Asbjorg %A Tarpinian, Jennifer M %A Klee, Eric W %A Sapp, Julie C %A Zyskind, Jacob %A Holla, Øystein L %A Bedoukian, Emma %A Filippini, Francesca %A Guimier, Anne %A Picard, Arnaud %A Busk, Øyvind L %A Punetha, Jaya %A Pfundt, Rolph %A Lindstrand, Anna %A Nordgren, Ann %A Kalb, Fayth %A Desai, Megha %A Ebanks, Ashley Harmon %A Jhangiani, Shalini N %A Dewan, Tammie %A Coban Akdemir, Zeynep H %A Telegrafi, Aida %A Zackai, Elaine H %A Begtrup, Amber %A Song, Xiaofei %A Toutain, Annick %A Wentzensen, Ingrid M %A Odent, Sylvie %A Bonneau, Dominique %A Latypova, Xénia %A Deb, Wallid %A Redon, Sylvia %A Bilan, Frédéric %A Legendre, Marine %A Troyer, Caitlin %A Whitlock, Kerri %A Caluseriu, Oana %A Murphree, Marine I %A Pichurin, Pavel N %A Agre, Katherine %A Gavrilova, Ralitza %A Rinne, Tuula %A Park, Meredith %A Shain, Catherine %A Heinzen, Erin L %A Xiao, Rui %A Amiel, Jeanne %A Lyonnet, Stanislas %A Isidor, Bertrand %A Biesecker, Leslie G %A Lowenstein, Dan %A Posey, Jennifer E %A Denommé-Pichon, Anne-Sophie %A Férec, Claude %A Yang, Xiang-Jiao %A Rosenfeld, Jill A %A Gilbert-Dussardier, Brigitte %A Audebert-Bellanger, Séverine %A Redon, Richard %A Stessman, Holly A F %A Nellaker, Christoffer %A Yang, Yaping %A James R Lupski %A Goldstein, David B %A Eichler, Evan E %A Bolduc, Francois %A Bézieau, Stéphane %A Küry, Sébastien %A Campeau, Philippe M %K Adaptor Proteins, Signal Transducing %K Adolescent %K Adult %K Amino Acid Sequence %K Autistic Disorder %K Child %K Child, Preschool %K Female %K Genetic Association Studies %K Humans %K Infant %K Intellectual Disability %K Male %K Mutation, Missense %K Nuclear Proteins %K Prognosis %K Sequence Homology %K Syndrome %K Young Adult %X

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

%B Am J Hum Genet %V 104 %P 530-541 %8 2019 Mar 07 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/30827496?dopt=Abstract %R 10.1016/j.ajhg.2019.01.010 %0 Journal Article %J Am J Hum Genet %D 2019 %T Paralog Studies Augment Gene Discovery: DDX and DHX Genes. %A Paine, Ingrid %A Posey, Jennifer E %A Grochowski, Christopher M %A Jhangiani, Shalini N %A Rosenheck, Sarah %A Kleyner, Robert %A Marmorale, Taylor %A Yoon, Margaret %A Wang, Kai %A Robison, Reid %A Cappuccio, Gerarda %A Pinelli, Michele %A Magli, Adriano %A Coban Akdemir, Zeynep %A Hui, Joannie %A Yeung, Wai Lan %A Wong, Bibiana K Y %A Ortega, Lucia %A Bekheirnia, Mir Reza %A Bierhals, Tatjana %A Hempel, Maja %A Johannsen, Jessika %A Santer, René %A Aktas, Dilek %A Alikaşifoğlu, Mehmet %A Bozdogan, Sevcan %A Aydin, Hatip %A Karaca, Ender %A Bayram, Yavuz %A Ityel, Hadas %A Dorschner, Michael %A White, Janson J %A Wilichowski, Ekkehard %A Wortmann, Saskia B %A Casella, Erasmo B %A Kitajima, Joao Paulo %A Kok, Fernando %A Monteiro, Fabiola %A Donna M Muzny %A Bamshad, Michael %A Richard A Gibbs %A Sutton, V Reid %A Van Esch, Hilde %A Brunetti-Pierri, Nicola %A Hildebrandt, Friedhelm %A Brautbar, Ariel %A Van den Veyver, Ignatia B %A Glass, Ian %A Lessel, Davor %A Lyon, Gholson J %A James R Lupski %K DEAD-box RNA Helicases %K Exome Sequencing %K Female %K Genetic Association Studies %K Humans %K Infant %K Infant, Newborn %K Male %K Mutation, Missense %K Neoplasm Proteins %K Neurodevelopmental Disorders %K Pedigree %K RNA Helicases %X

Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.

%B Am J Hum Genet %V 105 %P 302-316 %8 2019 Aug 01 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/31256877?dopt=Abstract %R 10.1016/j.ajhg.2019.06.001 %0 Journal Article %J Eur J Hum Genet %D 2018 %T Biallelic variants in KIF14 cause intellectual disability with microcephaly. %A Makrythanasis, Periklis %A Maroofian, Reza %A Stray-Pedersen, Asbjørg %A Musaev, Damir %A Zaki, Maha S %A Mahmoud, Iman G %A Selim, Laila %A Elbadawy, Amera %A Jhangiani, Shalini N %A Coban Akdemir, Zeynep H %A Gambin, Tomasz %A Sorte, Hanne S %A Heiberg, Arvid %A McEvoy-Venneri, Jennifer %A James, Kiely N %A Stanley, Valentina %A Belandres, Denice %A Guipponi, Michel %A Santoni, Federico A %A Ahangari, Najmeh %A Tara, Fatemeh %A Doosti, Mohammad %A Iwaszkiewicz, Justyna %A Zoete, Vincent %A Backe, Paul Hoff %A Hamamy, Hanan %A Gleeson, Joseph G %A Lupski, James R %A Karimiani, Ehsan Ghayoor %A Antonarakis, Stylianos E %K Child %K Child, Preschool %K Female %K Humans %K Intellectual Disability %K Kinesins %K Loss of Function Mutation %K Microcephaly %K Mutation, Missense %K Oncogene Proteins %K Pedigree %K Phenotype %K Protein Domains %K Syndrome %X

Kinesin proteins are critical for various cellular functions such as intracellular transport and cell division, and many members of the family have been linked to monogenic disorders and cancer. We report eight individuals with intellectual disability and microcephaly from four unrelated families with parental consanguinity. In the affected individuals of each family, homozygosity for likely pathogenic variants in KIF14 were detected; two loss-of-function (p.Asn83Ilefs*3 and p.Ser1478fs), and two missense substitutions (p.Ser841Phe and p.Gly459Arg). KIF14 is a mitotic motor protein that is required for spindle localization of the mitotic citron rho-interacting kinase, CIT, also mutated in microcephaly. Our results demonstrate the involvement of KIF14 in development and reveal a wide phenotypic variability ranging from fetal lethality to moderate developmental delay and microcephaly.

%B Eur J Hum Genet %V 26 %P 330-339 %8 2018 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/29343805?dopt=Abstract %R 10.1038/s41431-017-0088-9 %0 Journal Article %J Eur J Hum Genet %D 2018 %T Comprehensive genomic analysis of patients with disorders of cerebral cortical development. %A Wiszniewski, Wojciech %A Gawlinski, Pawel %A Gambin, Tomasz %A Bekiesinska-Figatowska, Monika %A Obersztyn, Ewa %A Antczak-Marach, Dorota %A Akdemir, Zeynep Hande Coban %A Harel, Tamar %A Karaca, Ender %A Jurek, Marta %A Sobecka, Katarzyna %A Nowakowska, Beata %A Kruk, Malgorzata %A Terczynska, Iwona %A Goszczanska-Ciuchta, Alicja %A Rudzka-Dybala, Mariola %A Jamroz, Ewa %A Pyrkosz, Antoni %A Jakubiuk-Tomaszuk, Anna %A Iwanowski, Piotr %A Gieruszczak-Bialek, Dorota %A Piotrowicz, Malgorzata %A Sasiadek, Maria %A Kochanowska, Iwona %A Gurda, Barbara %A Steinborn, Barbara %A Dawidziuk, Mateusz %A Castaneda, Jennifer %A Wlasienko, Pawel %A Bezniakow, Natalia %A Jhangiani, Shalini N %A Hoffman-Zacharska, Dorota %A Bal, Jerzy %A Szczepanik, Elzbieta %A Boerwinkle, Eric %A Gibbs, Richard A %A Lupski, James R %K Cadherins %K DNA Copy Number Variations %K Exome %K Female %K Genetic Heterogeneity %K Humans %K Male %K Malformations of Cortical Development %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Receptors, Cell Surface %X

Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes  and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.

%B Eur J Hum Genet %V 26 %P 1121-1131 %8 2018 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/29706646?dopt=Abstract %R 10.1038/s41431-018-0137-z %0 Journal Article %J PLoS Genet %D 2018 %T Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa. %A Li, Lin %A Jiao, Xiaodong %A D'Atri, Ilaria %A Ono, Fumihito %A Nelson, Ralph %A Chan, Chi-Chao %A Nakaya, Naoki %A Ma, Zhiwei %A Ma, Yan %A Cai, Xiaoying %A Zhang, Longhua %A Lin, Siying %A Hameed, Abdul %A Chioza, Barry A %A Hardy, Holly %A Arno, Gavin %A Hull, Sarah %A Khan, Muhammad Imran %A Fasham, James %A Harlalka, Gaurav V %A Michaelides, Michel %A Moore, Anthony T %A Coban Akdemir, Zeynep Hande %A Jhangiani, Shalini %A James R Lupski %A Cremers, Frans P M %A Qamar, Raheel %A Salman, Ahmed %A Chilton, John %A Self, Jay %A Ayyagari, Radha %A Kabir, Firoz %A Naeem, Muhammad Asif %A Ali, Muhammad %A Akram, Javed %A Sieving, Paul A %A Riazuddin, Sheikh %A Baple, Emma L %A Riazuddin, S Amer %A Crosby, Andrew H %A Hejtmancik, J Fielding %K Animals %K Asian People %K Cell Line %K Chloride Channels %K Cytoplasm %K Eye Proteins %K HEK293 Cells %K Homozygote %K Humans %K Mice %K Mice, Knockout %K Mutation, Missense %K Pakistan %K Retina %K Retinal Cone Photoreceptor Cells %K Retinal Rod Photoreceptor Cells %K Retinitis Pigmentosa %K Zebrafish %X

We identified a homozygous missense alteration (c.75C>A, p.D25E) in CLCC1, encoding a presumptive intracellular chloride channel highly expressed in the retina, associated with autosomal recessive retinitis pigmentosa (arRP) in eight consanguineous families of Pakistani descent. The p.D25E alteration decreased CLCC1 channel function accompanied by accumulation of mutant protein in granules within the ER lumen, while siRNA knockdown of CLCC1 mRNA induced apoptosis in cultured ARPE-19 cells. TALEN KO in zebrafish was lethal 11 days post fertilization. The depressed electroretinogram (ERG) cone response and cone spectral sensitivity of 5 dpf KO zebrafish and reduced eye size, retinal thickness, and expression of rod and cone opsins could be rescued by injection of wild type CLCC1 mRNA. Clcc1+/- KO mice showed decreased ERGs and photoreceptor number. Together these results strongly suggest that intracellular chloride transport by CLCC1 is a critical process in maintaining retinal integrity, and CLCC1 is crucial for survival and function of retinal cells.

%B PLoS Genet %V 14 %P e1007504 %8 2018 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/30157172?dopt=Abstract %R 10.1371/journal.pgen.1007504 %0 Journal Article %J Genet Med %D 2018 %T Phenotypic expansion illuminates multilocus pathogenic variation. %A Karaca, Ender %A Posey, Jennifer E %A Coban Akdemir, Zeynep %A Pehlivan, Davut %A Harel, Tamar %A Jhangiani, Shalini N %A Bayram, Yavuz %A Song, Xiaofei %A Bahrambeigi, Vahid %A Yuregir, Ozge Ozalp %A Bozdogan, Sevcan %A Yesil, Gozde %A Isikay, Sedat %A Muzny, Donna %A Gibbs, Richard A %A Lupski, James R %K Child, Preschool %K Exome %K Exome Sequencing %K Female %K Genetic Association Studies %K Genetic Diseases, Inborn %K Genetic Variation %K Genotype %K Heterozygote %K High-Throughput Nucleotide Sequencing %K Humans %K Infant %K Infant, Newborn %K Male %K Mutation %K Pathology, Molecular %K Pedigree %K Phenotype %X

PURPOSE: Multilocus variation-pathogenic variants in two or more disease genes-can potentially explain the underlying genetic basis for apparent phenotypic expansion in cases for which the observed clinical features extend beyond those reported in association with a "known" disease gene.

METHODS: Analyses focused on 106 patients, 19 for whom apparent phenotypic expansion was previously attributed to variation at known disease genes. We performed a retrospective computational reanalysis of whole-exome sequencing data using stringent Variant Call File filtering criteria to determine whether molecular diagnoses involving additional disease loci might explain the observed expanded phenotypes.

RESULTS: Multilocus variation was identified in 31.6% (6/19) of families with phenotypic expansion and 2.3% (2/87) without phenotypic expansion. Intrafamilial clinical variability within two families was explained by multilocus variation identified in the more severely affected sibling.

CONCLUSION: Our findings underscore the role of multiple rare variants at different loci in the etiology of genetically and clinically heterogeneous cohorts. Intrafamilial phenotypic and genotypic variability allowed a dissection of genotype-phenotype relationships in two families. Our data emphasize the critical role of the clinician in diagnostic genomic analyses and demonstrate that apparent phenotypic expansion may represent blended phenotypes resulting from pathogenic variation at more than one locus.

%B Genet Med %V 20 %P 1528-1537 %8 2018 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/29790871?dopt=Abstract %R 10.1038/gim.2018.33 %0 Journal Article %J Cell %D 2017 %T An Organismal CNV Mutator Phenotype Restricted to Early Human Development. %A Liu, Pengfei %A Yuan, Bo %A Carvalho, Claudia M B %A Wuster, Arthur %A Walter, Klaudia %A Zhang, Ling %A Gambin, Tomasz %A Chong, Zechen %A Campbell, Ian M %A Coban Akdemir, Zeynep %A Gelowani, Violet %A Writzl, Karin %A Bacino, Carlos A %A Lindsay, Sarah J %A Withers, Marjorie %A Gonzaga-Jauregui, Claudia %A Wiszniewska, Joanna %A Scull, Jennifer %A Stankiewicz, Paweł %A Jhangiani, Shalini N %A Muzny, Donna M %A Zhang, Feng %A Chen, Ken %A Gibbs, Richard A %A Rautenstrauss, Bernd %A Cheung, Sau Wai %A Smith, Janice %A Breman, Amy %A Shaw, Chad A %A Patel, Ankita %A Hurles, Matthew E %A Lupski, James R %K Chromosome Aberrations %K Chromosome Breakpoints %K Chromosome Duplication %K DNA Copy Number Variations %K DNA Replication %K Embryonic Development %K Female %K Gametogenesis %K Genetic Diseases, Inborn %K Genomic Instability %K Humans %K Male %K Mutation %X

De novo copy number variants (dnCNVs) arising at multiple loci in a personal genome have usually been considered to reflect cancer somatic genomic instabilities. We describe a multiple dnCNV (MdnCNV) phenomenon in which individuals with genomic disorders carry five to ten constitutional dnCNVs. These CNVs originate from independent formation incidences, are predominantly tandem duplications or complex gains, exhibit breakpoint junction features reminiscent of replicative repair, and show increased de novo point mutations flanking the rearrangement junctions. The active CNV mutation shower appears to be restricted to a transient perizygotic period. We propose that a defect in the CNV formation process is responsible for the "CNV-mutator state," and this state is dampened after early embryogenesis. The constitutional MdnCNV phenomenon resembles chromosomal instability in various cancers. Investigations of this phenomenon may provide unique access to understanding genomic disorders, structural variant mutagenesis, human evolution, and cancer biology.

%B Cell %V 168 %P 830-842.e7 %8 2017 Feb 23 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/28235197?dopt=Abstract %R 10.1016/j.cell.2017.01.037 %0 Journal Article %J J Allergy Clin Immunol %D 2017 %T Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders. %A Stray-Pedersen, Asbjørg %A Sorte, Hanne Sørmo %A Samarakoon, Pubudu %A Gambin, Tomasz %A Chinn, Ivan K %A Coban Akdemir, Zeynep H %A Erichsen, Hans Christian %A Forbes, Lisa R %A Gu, Shen %A Yuan, Bo %A Jhangiani, Shalini N %A Muzny, Donna M %A Rødningen, Olaug Kristin %A Sheng, Ying %A Nicholas, Sarah K %A Noroski, Lenora M %A Seeborg, Filiz O %A Davis, Carla M %A Canter, Debra L %A Mace, Emily M %A Vece, Timothy J %A Allen, Carl E %A Abhyankar, Harshal A %A Boone, Philip M %A Beck, Christine R %A Wiszniewski, Wojciech %A Fevang, Børre %A Aukrust, Pål %A Tjønnfjord, Geir E %A Gedde-Dahl, Tobias %A Hjorth-Hansen, Henrik %A Dybedal, Ingunn %A Nordøy, Ingvild %A Jørgensen, Silje F %A Abrahamsen, Tore G %A Øverland, Torstein %A Bechensteen, Anne Grete %A Skogen, Vegard %A Osnes, Liv T N %A Kulseth, Mari Ann %A Prescott, Trine E %A Rustad, Cecilie F %A Heimdal, Ketil R %A Belmont, John W %A Rider, Nicholas L %A Chinen, Javier %A Cao, Tram N %A Smith, Eric A %A Caldirola, Maria Soledad %A Bezrodnik, Liliana %A Lugo Reyes, Saul Oswaldo %A Espinosa Rosales, Francisco J %A Guerrero-Cursaru, Nina Denisse %A Pedroza, Luis Alberto %A Poli, Cecilia M %A Franco, Jose L %A Trujillo Vargas, Claudia M %A Aldave Becerra, Juan Carlos %A Wright, Nicola %A Issekutz, Thomas B %A Issekutz, Andrew C %A Abbott, Jordan %A Caldwell, Jason W %A Bayer, Diana K %A Chan, Alice Y %A Aiuti, Alessandro %A Cancrini, Caterina %A Holmberg, Eva %A West, Christina %A Burstedt, Magnus %A Karaca, Ender %A Yesil, Gozde %A Artac, Hasibe %A Bayram, Yavuz %A Atik, Mehmed Musa %A Eldomery, Mohammad K %A Ehlayel, Mohammad S %A Jolles, Stephen %A Flatø, Berit %A Bertuch, Alison A %A Hanson, I Celine %A Zhang, Victor W %A Wong, Lee-Jun %A Hu, Jianhong %A Walkiewicz, Magdalena %A Yang, Yaping %A Eng, Christine M %A Boerwinkle, Eric %A Gibbs, Richard A %A Shearer, William T %A Lyle, Robert %A Orange, Jordan S %A Lupski, James R %K Adolescent %K Adult %K Aged %K Child %K Child, Preschool %K DNA Copy Number Variations %K Female %K Genomics %K High-Throughput Nucleotide Sequencing %K Humans %K Immunologic Deficiency Syndromes %K Infant %K Male %K Middle Aged %K Young Adult %X

BACKGROUND: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions.

OBJECTIVE: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs.

METHODS: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping.

RESULTS: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays.

CONCLUSION: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

%B J Allergy Clin Immunol %V 139 %P 232-245 %8 2017 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/27577878?dopt=Abstract %R 10.1016/j.jaci.2016.05.042 %0 Journal Article %J N Engl J Med %D 2017 %T Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. %A Posey, Jennifer E %A Harel, Tamar %A Liu, Pengfei %A Rosenfeld, Jill A %A James, Regis A %A Coban Akdemir, Zeynep H %A Walkiewicz, Magdalena %A Bi, Weimin %A Xiao, Rui %A Ding, Yan %A Xia, Fan %A Beaudet, Arthur L %A Muzny, Donna M %A Gibbs, Richard A %A Boerwinkle, Eric %A Eng, Christine M %A Sutton, V Reid %A Shaw, Chad A %A Plon, Sharon E %A Yang, Yaping %A Lupski, James R %K Exome %K Genetic Diseases, Inborn %K Genetic Variation %K Genotyping Techniques %K High-Throughput Nucleotide Sequencing %K Humans %K Phenotype %K Retrospective Studies %K Sequence Analysis, DNA %X

BACKGROUND: Whole-exome sequencing can provide insight into the relationship between observed clinical phenotypes and underlying genotypes.

METHODS: We conducted a retrospective analysis of data from a series of 7374 consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing; our goal was to determine the frequency and clinical characteristics of patients for whom more than one molecular diagnosis was reported. The phenotypic similarity between molecularly diagnosed pairs of diseases was calculated with the use of terms from the Human Phenotype Ontology.

RESULTS: A molecular diagnosis was rendered for 2076 of 7374 patients (28.2%); among these patients, 101 (4.9%) had diagnoses that involved two or more disease loci. We also analyzed parental samples, when available, and found that de novo variants accounted for 67.8% (61 of 90) of pathogenic variants in autosomal dominant disease genes and 51.7% (15 of 29) of pathogenic variants in X-linked disease genes; both variants were de novo in 44.7% (17 of 38) of patients with two monoallelic variants. Causal copy-number variants were found in 12 patients (11.9%) with multiple diagnoses. Phenotypic similarity scores were significantly lower among patients in whom the phenotype resulted from two distinct mendelian disorders that affected different organ systems (50 patients) than among patients with disorders that had overlapping phenotypic features (30 patients) (median score, 0.21 vs. 0.36; P=1.77×10).

CONCLUSIONS: In our study, we found multiple molecular diagnoses in 4.9% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. (Funded by the National Institutes of Health and the Ting Tsung and Wei Fong Chao Foundation.).

%B N Engl J Med %V 376 %P 21-31 %8 2017 Jan 05 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/27959697?dopt=Abstract %R 10.1056/NEJMoa1516767 %0 Journal Article %J Am J Hum Genet %D 2017 %T REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis. %A Bayram, Yavuz %A White, Janson J %A Elcioglu, Nursel %A Cho, Megan T %A Zadeh, Neda %A Gedikbasi, Asuman %A Palanduz, Sukru %A Ozturk, Sukru %A Cefle, Kivanc %A Kasapcopur, Ozgur %A Coban Akdemir, Zeynep %A Pehlivan, Davut %A Begtrup, Amber %A Carvalho, Claudia M B %A Paine, Ingrid Sophie %A Mentes, Ali %A Bektas-Kayhan, Kivanc %A Karaca, Ender %A Jhangiani, Shalini N %A Muzny, Donna M %A Gibbs, Richard A %A Lupski, James R %K Adolescent %K Base Sequence %K Chromosome Segregation %K Exons %K Family %K Female %K Fibromatosis, Gingival %K Genetic Predisposition to Disease %K Humans %K Male %K Middle Aged %K Mutation %K Pedigree %K Repressor Proteins %X

Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis that develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. HGF is a genetically heterogeneous disorder and can be transmitted either as an autosomal-dominant or autosomal-recessive trait or appear sporadically. To date, four loci (2p22.1, 2p23.3-p22.3, 5q13-q22, and 11p15) have been mapped to autosomes and one gene (SOS1) has been associated with the HGF trait observed to segregate in a dominant inheritance pattern. Here we report 11 individuals with HGF from three unrelated families. Whole-exome sequencing (WES) revealed three different truncating mutations including two frameshifts and one nonsense variant in RE1-silencing transcription factor (REST) in the probands from all families and further genetic and genomic analyses confirmed the WES-identified findings. REST is a transcriptional repressor that is expressed throughout the body; it has different roles in different cellular contexts, such as oncogenic and tumor-suppressor functions and hematopoietic and cardiac differentiation. Here we show the consequences of germline final-exon-truncating mutations in REST for organismal development and the association with the HGF phenotype.

%B Am J Hum Genet %V 101 %P 149-156 %8 2017 Jul 06 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/28686854?dopt=Abstract %R 10.1016/j.ajhg.2017.06.006 %0 Journal Article %J Genet Med %D 2017 %T Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene. %A Bekheirnia, Mir Reza %A Bekheirnia, Nasim %A Bainbridge, Matthew N %A Gu, Shen %A Coban Akdemir, Zeynep Hande %A Gambin, Tomek %A Janzen, Nicolette K %A Jhangiani, Shalini N %A Muzny, Donna M %A Michael, Mini %A Brewer, Eileen D %A Elenberg, Ewa %A Kale, Arundhati S %A Riley, Alyssa A %A Swartz, Sarah J %A Scott, Daryl A %A Yang, Yaping %A Srivaths, Poyyapakkam R %A Wenderfer, Scott E %A Bodurtha, Joann %A Applegate, Carolyn D %A Velinov, Milen %A Myers, Angela %A Borovik, Lior %A Craigen, William J %A Hanchard, Neil A %A Rosenfeld, Jill A %A Lewis, Richard Alan %A Gonzales, Edmond T %A Gibbs, Richard A %A Belmont, John W %A Roth, David R %A Eng, Christine %A Braun, Michael C %A Lupski, James R %A Lamb, Dolores J %K Adolescent %K Child %K Child, Preschool %K DNA Copy Number Variations %K Exome Sequencing %K Female %K Forkhead Transcription Factors %K Genetic Predisposition to Disease %K Hepatocyte Nuclear Factor 1-beta %K Humans %K Infant %K Intracellular Signaling Peptides and Proteins %K Male %K Nuclear Proteins %K PAX2 Transcription Factor %K Pedigree %K Polymorphism, Single Nucleotide %K Protein Tyrosine Phosphatases %K Repressor Proteins %K Urogenital Abnormalities %K Vesico-Ureteral Reflux %K Young Adult %X

PURPOSE: To investigate the utility of whole-exome sequencing (WES) to define a molecular diagnosis for patients clinically diagnosed with congenital anomalies of kidney and urinary tract (CAKUT).

METHODS: WES was performed in 62 families with CAKUT. WES data were analyzed for single-nucleotide variants (SNVs) in 35 known CAKUT genes, putatively deleterious sequence changes in new candidate genes, and potentially disease-associated copy-number variants (CNVs).

RESULTS: In approximately 5% of families, pathogenic SNVs were identified in PAX2, HNF1B, and EYA1. Observed phenotypes in these families expand the current understanding about the role of these genes in CAKUT. Four pathogenic CNVs were also identified using two CNV detection tools. In addition, we found one deleterious de novo SNV in FOXP1 among the 62 families with CAKUT. The clinical database of the Baylor Miraca Genetics laboratory was queried and seven additional unrelated individuals with novel de novo SNVs in FOXP1 were identified. Six of these eight individuals with FOXP1 SNVs have syndromic urinary tract defects, implicating this gene in urinary tract development.

CONCLUSION: We conclude that WES can be used to identify molecular etiology (SNVs, CNVs) in a subset of individuals with CAKUT. WES can also help identify novel CAKUT genes.Genet Med 19 4, 412-420.

%B Genet Med %V 19 %P 412-420 %8 2017 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/27657687?dopt=Abstract %R 10.1038/gim.2016.131 %0 Journal Article %J BMC Med Genomics %D 2016 %T Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate. %A Charng, Wu-Lin %A Karaca, Ender %A Coban Akdemir, Zeynep %A Gambin, Tomasz %A Atik, Mehmed M %A Gu, Shen %A Posey, Jennifer E %A Jhangiani, Shalini N %A Muzny, Donna M %A Doddapaneni, Harsha %A Hu, Jianhong %A Boerwinkle, Eric %A Gibbs, Richard A %A Rosenfeld, Jill A %A Cui, Hong %A Xia, Fan %A Manickam, Kandamurugu %A Yang, Yaping %A Faqeih, Eissa A %A Al Asmari, Ali %A Saleh, Mohammed A M %A El-Hattab, Ayman W %A Lupski, James R %K Arabs %K Cohort Studies %K Consanguinity %K Data Mining %K Databases, Genetic %K DNA Copy Number Variations %K Exome %K Female %K High-Throughput Nucleotide Sequencing %K Humans %K Male %K Molecular Diagnostic Techniques %K Nervous System Diseases %K Pedigree %K Phenotype %K Polymorphism, Single Nucleotide %K Sequence Analysis, DNA %X

BACKGROUND: Neurodevelopment is orchestrated by a wide range of genes, and the genetic causes of neurodevelopmental disorders are thus heterogeneous. We applied whole exome sequencing (WES) for molecular diagnosis and in silico analysis to identify novel disease gene candidates in a cohort from Saudi Arabia with primarily Mendelian neurologic diseases.

METHODS: We performed WES in 31 mostly consanguineous Arab families and analyzed both single nucleotide and copy number variants (CNVs) from WES data. Interaction/expression network and pathway analyses, as well as paralog studies were utilized to investigate potential pathogenicity and disease association of novel candidate genes. Additional cases for candidate genes were identified through the clinical WES database at Baylor Miraca Genetics Laboratories and GeneMatcher.

RESULTS: We found known pathogenic or novel variants in known disease genes with phenotypic expansion in 6 families, disease-associated CNVs in 2 families, and 12 novel disease gene candidates in 11 families, including KIF5B, GRM7, FOXP4, MLLT1, and KDM2B. Overall, a potential molecular diagnosis was provided by variants in known disease genes in 17 families (54.8 %) and by novel candidate disease genes in an additional 11 families, making the potential molecular diagnostic rate ~90 %.

CONCLUSIONS: Molecular diagnostic rate from WES is improved by exome-predicted CNVs. Novel candidate disease gene discovery is facilitated by paralog studies and through the use of informatics tools and available databases to identify additional evidence for pathogenicity.

TRIAL REGISTRATION: Not applicable.

%B BMC Med Genomics %V 9 %P 42 %8 2016 Jul 19 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/27435318?dopt=Abstract %R 10.1186/s12920-016-0208-3 %0 Journal Article %J Genet Med %D 2016 %T Molecular diagnostic experience of whole-exome sequencing in adult patients. %A Posey, Jennifer E %A Rosenfeld, Jill A %A James, Regis A %A Bainbridge, Matthew %A Niu, Zhiyv %A Wang, Xia %A Dhar, Shweta %A Wiszniewski, Wojciech %A Akdemir, Zeynep H C %A Gambin, Tomasz %A Xia, Fan %A Person, Richard E %A Walkiewicz, Magdalena %A Shaw, Chad A %A Sutton, V Reid %A Beaudet, Arthur L %A Muzny, Donna %A Eng, Christine M %A Yang, Yaping %A Gibbs, Richard A %A Lupski, James R %A Boerwinkle, Eric %A Plon, Sharon E %K Adult %K Exome %K Female %K Genetic Diseases, Inborn %K Genetic Predisposition to Disease %K Genetic Testing %K Genome, Human %K High-Throughput Nucleotide Sequencing %K Humans %K Male %K Pathology, Molecular %X

PURPOSE: Whole-exome sequencing (WES) is increasingly used as a diagnostic tool in medicine, but prior reports focus on predominantly pediatric cohorts with neurologic or developmental disorders. We describe the diagnostic yield and characteristics of WES in adults.

METHODS: We performed a retrospective analysis of consecutive WES reports for adults from a diagnostic laboratory. Phenotype composition was determined using Human Phenotype Ontology terms.

RESULTS: Molecular diagnoses were reported for 17.5% (85/486) of adults, which is lower than that for a primarily pediatric population (25.2%; P = 0.0003); the diagnostic rate was higher (23.9%) for those 18-30 years of age compared to patients older than 30 years (10.4%; P = 0.0001). Dual Mendelian diagnoses contributed to 7% of diagnoses, revealing blended phenotypes. Diagnoses were more frequent among individuals with abnormalities of the nervous system, skeletal system, head/neck, and growth. Diagnostic rate was independent of family history information, and de novo mutations contributed to 61.4% of autosomal dominant diagnoses.

CONCLUSION: Early WES experience in adults demonstrates molecular diagnoses in a substantial proportion of patients, informing clinical management, recurrence risk, and recommendations for relatives. A positive family history was not predictive, consistent with molecular diagnoses often revealed by de novo events, informing the Mendelian basis of genetic disease in adults.Genet Med 18 7, 678-685.

%B Genet Med %V 18 %P 678-85 %8 2016 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/26633545?dopt=Abstract %R 10.1038/gim.2015.142 %0 Journal Article %J Mol Genet Genomic Med %D 2016 %T A potential founder variant in in three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction. %A Sorte, Hanne S %A Osnes, Liv T %A Fevang, Børre %A Aukrust, Pål %A Erichsen, Hans C %A Backe, Paul H %A Abrahamsen, Tore G %A Kittang, Ole B %A Øverland, Torstein %A Jhangiani, Shalini N %A Muzny, Donna M %A Vigeland, Magnus D %A Samarakoon, Pubudu %A Gambin, Tomasz %A Akdemir, Zeynep H C %A Gibbs, Richard A %A Rødningen, Olaug K %A Lyle, Robert %A Lupski, James R %A Stray-Pedersen, Asbjørg %X

BACKGROUND: Four patients from three Norwegian families presented with a common skin phenotype of warts, molluscum contagiosum, and dermatitis since early childhood, and various other immunological features. Warts are a common manifestation of (HPV), but when they are overwhelming, disseminated and/or persistent, and presenting together with other immunological features, a primary immunodeficiency disease (PIDD) may be suspected.

METHODS AND RESULTS: The four patients were exome sequenced as part of a larger study for detecting genetic causes of primary immunodeficiencies. No disease-causing variants were identified in known primary immunodeficiency genes or in other disease-related OMIM genes. However, the same homozygous missense variant in (also known as ) was identified in all four patients. In each family, the variant was located within a narrow region of homozygosity, representing a potential region of autozygosity. is a protein of undetermined function. A role in T-cell activation has been suggested and the mouse protein homolog (Rltpr) is essential for costimulation of T-cell activation via CD28, and for the development of regulatory T cells. Immunophenotyping demonstrated reduced regulatory, CD4+ memory, and CD4+ follicular T cells in all four patients. In addition, they all seem to have a deficiency in IFN -synthesis in CD4+ T cells and NK cells.

CONCLUSIONS: We report a novel primary immunodeficiency, and a differential molecular diagnosis to ,,,,,,, and related diseases. The specific variant may represent a Norwegian founder variant segregating on a population-specific haplotype.

%B Mol Genet Genomic Med %V 4 %P 604-616 %8 2016 Nov %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/27896283?dopt=Abstract %R 10.1002/mgg3.237 %0 Journal Article %J Am J Hum Genet %D 2016 %T Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations. %A Lalani, Seema R %A Liu, Pengfei %A Rosenfeld, Jill A %A Watkin, Levi B %A Chiang, Theodore %A Leduc, Magalie S %A Zhu, Wenmiao %A Ding, Yan %A Pan, Shujuan %A Vetrini, Francesco %A Miyake, Christina Y %A Shinawi, Marwan %A Gambin, Tomasz %A Eldomery, Mohammad K %A Akdemir, Zeynep Hande Coban %A Emrick, Lisa %A Wilnai, Yael %A Schelley, Susan %A Koenig, Mary Kay %A Memon, Nada %A Farach, Laura S %A Coe, Bradley P %A Azamian, Mahshid %A Hernandez, Patricia %A Zapata, Gladys %A Jhangiani, Shalini N %A Muzny, Donna M %A Lotze, Timothy %A Clark, Gary %A Wilfong, Angus %A Northrup, Hope %A Adesina, Adekunle %A Bacino, Carlos A %A Scaglia, Fernando %A Bonnen, Penelope E %A Crosson, Jane %A Duis, Jessica %A Maegawa, Gustavo H B %A Coman, David %A Inwood, Anita %A McGill, Jim %A Boerwinkle, Eric %A Graham, Brett %A Beaudet, Art %A Eng, Christine M %A Hanchard, Neil A %A Xia, Fan %A Orange, Jordan S %A Gibbs, Richard A %A Lupski, James R %A Yang, Yaping %K Alleles %K Arabs %K Arrhythmias, Cardiac %K Base Sequence %K Child %K Child, Preschool %K Endoplasmic Reticulum Stress %K Exome %K Exons %K Female %K Gene Deletion %K Golgi Apparatus %K Hispanic or Latino %K Homozygote %K Humans %K Infant %K Male %K Molecular Sequence Data %K Muscle Weakness %K Pedigree %K Rhabdomyolysis %K White People %X

The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ∼34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.

%B Am J Hum Genet %V 98 %P 347-57 %8 2016 Feb 04 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/26805781?dopt=Abstract %R 10.1016/j.ajhg.2015.12.008 %0 Journal Article %J Genet Med %D 2016 %T The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy. %A Pehlivan, Davut %A Beck, Christine R %A Okamoto, Yuji %A Harel, Tamar %A Akdemir, Zeynep H C %A Jhangiani, Shalini N %A Withers, Marjorie A %A Goksungur, Meryem Tuba %A Carvalho, Claudia M B %A Czesnik, Dirk %A Gonzaga-Jauregui, Claudia %A Wiszniewski, Wojciech %A Muzny, Donna M %A Gibbs, Richard A %A Rautenstrauss, Bernd %A Sereda, Michael W %A Lupski, James R %K Adult %K Age of Onset %K Charcot-Marie-Tooth Disease %K Child, Preschool %K Comparative Genomic Hybridization %K DNA Copy Number Variations %K Exome %K Female %K Genetic Predisposition to Disease %K GTP Phosphohydrolases %K High-Throughput Nucleotide Sequencing %K Humans %K Male %K Mitochondrial Proteins %K Motor Neurons %K Myelin P0 Protein %K Myelin Proteins %K Neural Conduction %K Polymorphism, Single Nucleotide %K Polyneuropathies %X

PURPOSE: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders of the peripheral nervous system. Copy-number variants (CNVs) contribute significantly to CMT, as duplication of PMP22 underlies the majority of CMT1 cases. We hypothesized that CNVs and/or single-nucleotide variants (SNVs) might exist in patients with CMT with an unknown molecular genetic etiology.

METHODS: Two hundred patients with CMT, negative for both SNV mutations in several CMT genes and for CNVs involving PMP22, were screened for CNVs by high-resolution oligonucleotide array comparative genomic hybridization. Whole-exome sequencing was conducted on individuals with rare, potentially pathogenic CNVs.

RESULTS: Putatively causative CNVs were identified in five subjects (~2.5%); four of the five map to known neuropathy genes. Breakpoint sequencing revealed Alu-Alu-mediated junctions as a predominant contributor. Exome sequencing identified MFN2 SNVs in two of the individuals.

CONCLUSION: Neuropathy-associated CNV outside of the PMP22 locus is rare in CMT. Nevertheless, there is potential clinical utility in testing for CNVs and exome sequencing in CMT cases negative for the CMT1A duplication. These findings suggest that complex phenotypes including neuropathy can potentially be caused by a combination of SNVs and CNVs affecting more than one disease-associated locus and contributing to a mutational burden.Genet Med 18 5, 443-451.

%B Genet Med %V 18 %P 443-51 %8 2016 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/26378787?dopt=Abstract %R 10.1038/gim.2015.124 %0 Journal Article %J Eur J Med Genet %D 2016 %T Two male sibs with severe micrognathia and a missense variant in MED12. %A Prescott, Trine E %A Kulseth, Mari Ann %A Heimdal, Ketil R %A Stadheim, Barbro %A Hopp, Einar %A Gambin, Tomasz %A Coban Akdemir, Zeynep H %A Jhangiani, Shalini N %A Donna M Muzny %A Richard A Gibbs %A Lupski, James R %A Stray-Pedersen, Asbjørg %K Exons %K Genes, X-Linked %K Genetic Association Studies %K Genotype %K Humans %K Infant %K Male %K Mediator Complex %K Micrognathism %K Mutation, Missense %K Pedigree %K Phenotype %K Polymorphism, Single Nucleotide %K Severity of Illness Index %K Siblings %K Tomography, X-Ray Computed %K X Chromosome Inactivation %X

Missense variants in MED12 cause three partially overlapping dysmorphic X-linked intellectual disability (XLID) syndromes: Lujan-Fryns syndrome (also known as Lujan syndrome), FG syndrome (also known as Opitz-Kaveggia syndrome) and X-linked Ohdo syndrome. We report a family with two severely micrognathic male sibs, a 10½ year old boy and a fetus, in which hemizygosity for a previously unreported missense variant in exon 13 of MED12 (NM_005120.2), c.1862G > A, p.(Arg621Gln) was detected by whole exome sequencing. The affected sibs shared no other rare variant with relevance to the phenotype. X-chromosome inactivation in blood was completely skewed (100:0) in the unaffected heterozygous mother, most likely as a result of preferential inactivation of the X-chromosome harbouring the missense variant in MED12. Neither the unaffected brother nor the unaffected maternal grandfather carried the missense variant in MED12. In the 10½ year old boy, upper airway obstruction secondary to Pierre Robin sequence necessitated a tracheostomy for the first 10 months of life. He has mild to moderate intellectual disability and some dysmorphic features seen in MED12-related syndromes. In addition, he has a horizontal gaze paresis, anomalies of the inner ear, and a cervical block vertebra. This report contributes to the expanding phenotypic range associated with MED12-mutations.

%B Eur J Med Genet %V 59 %P 367-72 %8 2016 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/27286923?dopt=Abstract %R 10.1016/j.ejmg.2016.06.001 %0 Journal Article %J Hum Genet %D 2015 %T Exome sequencing reveals homozygous TRIM2 mutation in a patient with early onset CMT and bilateral vocal cord paralysis. %A Pehlivan, Davut %A Coban Akdemir, Zeynep %A Karaca, Ender %A Bayram, Yavuz %A Jhangiani, Shalini %A Yildiz, Edibe Pembegul %A Muzny, Donna %A Uluc, Kayihan %A Gibbs, Richard A %A Elcioglu, Nursel %A Lupski, James R %A Harel, Tamar %K Adult %K Charcot-Marie-Tooth Disease %K Exome %K Female %K High-Throughput Nucleotide Sequencing %K Homozygote %K Humans %K Infant, Newborn %K Male %K Mutation, Missense %K Nuclear Proteins %K Vocal Cord Paralysis %X

Charcot-Marie-Tooth disease is a heterogeneous group of inherited distal symmetric polyneuropathies associated with mutations in genes encoding components essential for normal functioning of the Schwann cell and axon. TRIM2, encoding a ligase that ubiquitinates the neurofilament light chain, was recently associated with early-onset neuropathy in a single patient. We report a TRIM2 homozygous missense mutation (c.2000A>C; p.D667A) in a patient with peripheral neuropathy and bilateral vocal cord paralysis, allowing for further delineation of the associated phenotypic spectrum.

%B Hum Genet %V 134 %P 671-3 %8 2015 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/25893792?dopt=Abstract %R 10.1007/s00439-015-1548-3 %0 Journal Article %J Neuron %D 2015 %T Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. %A Karaca, Ender %A Harel, Tamar %A Pehlivan, Davut %A Jhangiani, Shalini N %A Gambin, Tomasz %A Coban Akdemir, Zeynep %A Gonzaga-Jauregui, Claudia %A Erdin, Serkan %A Bayram, Yavuz %A Campbell, Ian M %A Hunter, Jill V %A Atik, Mehmed M %A Van Esch, Hilde %A Yuan, Bo %A Wiszniewski, Wojciech %A Isikay, Sedat %A Yesil, Gozde %A Yuregir, Ozge O %A Tug Bozdogan, Sevcan %A Aslan, Huseyin %A Aydin, Hatip %A Tos, Tulay %A Aksoy, Ayse %A De Vivo, Darryl C %A Jain, Preti %A Geckinli, B Bilge %A Sezer, Ozlem %A Gul, Davut %A Durmaz, Burak %A Cogulu, Ozgur %A Ozkinay, Ferda %A Topcu, Vehap %A Candan, Sukru %A Cebi, Alper Han %A Ikbal, Mevlit %A Yilmaz Gulec, Elif %A Gezdirici, Alper %A Koparir, Erkan %A Ekici, Fatma %A Coskun, Salih %A Cicek, Salih %A Karaer, Kadri %A Koparir, Asuman %A Duz, Mehmet Bugrahan %A Kirat, Emre %A Fenercioglu, Elif %A Ulucan, Hakan %A Seven, Mehmet %A Guran, Tulay %A Elcioglu, Nursel %A Yildirim, Mahmut Selman %A Aktas, Dilek %A Alikaşifoğlu, Mehmet %A Ture, Mehmet %A Yakut, Tahsin %A Overton, John D %A Yuksel, Adnan %A Ozen, Mustafa %A Muzny, Donna M %A Adams, David R %A Boerwinkle, Eric %A Chung, Wendy K %A Gibbs, Richard A %A Lupski, James R %K Brain %K Cohort Studies %K Databases, Genetic %K Female %K Gene Regulatory Networks %K Genetic Association Studies %K Genetic Variation %K Humans %K Male %K Mendelian Randomization Analysis %K Nervous System Diseases %K Pedigree %X

Development of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations.

%B Neuron %V 88 %P 499-513 %8 2015 Nov 04 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/26539891?dopt=Abstract %R 10.1016/j.neuron.2015.09.048 %0 Journal Article %J Am J Hum Genet %D 2015 %T The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities. %A Chong, Jessica X %A Buckingham, Kati J %A Jhangiani, Shalini N %A Boehm, Corinne %A Sobreira, Nara %A Smith, Joshua D %A Harrell, Tanya M %A McMillin, Margaret J %A Wiszniewski, Wojciech %A Gambin, Tomasz %A Coban Akdemir, Zeynep H %A Doheny, Kimberly %A Scott, Alan F %A Avramopoulos, Dimitri %A Chakravarti, Aravinda %A Hoover-Fong, Julie %A Mathews, Debra %A Witmer, P Dane %A Ling, Hua %A Hetrick, Kurt %A Watkins, Lee %A Patterson, Karynne E %A Reinier, Frederic %A Blue, Elizabeth %A Muzny, Donna %A Kircher, Martin %A Bilguvar, Kaya %A López-Giráldez, Francesc %A Sutton, V Reid %A Tabor, Holly K %A Leal, Suzanne M %A Gunel, Murat %A Mane, Shrikant %A Gibbs, Richard A %A Boerwinkle, Eric %A Hamosh, Ada %A Shendure, Jay %A Lupski, James R %A Lifton, Richard P %A Valle, David %A Nickerson, Deborah A %A Bamshad, Michael J %K Genetic Diseases, Inborn %K Genetics, Medical %K Humans %K Phenotype %K Proteins %X

Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying ∼50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families.

%B Am J Hum Genet %V 97 %P 199-215 %8 2015 Aug 06 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/26166479?dopt=Abstract %R 10.1016/j.ajhg.2015.06.009