%0 Journal Article %J Genome Med %D 2019 %T Copy number variant and runs of homozygosity detection by microarrays enabled more precise molecular diagnoses in 11,020 clinical exome cases. %A Dharmadhikari, Avinash V %A Ghosh, Rajarshi %A Bo Yuan %A Liu, Pengfei %A Dai, Hongzheng %A Al Masri, Sami %A Scull, Jennifer %A Posey, Jennifer E %A Jiang, Allen H %A He, Weimin %A Vetrini, Francesco %A Braxton, Alicia A %A Ward, Patricia %A Chiang, Theodore %A Qu, Chunjing %A Gu, Shen %A Shaw, Chad A %A Smith, Janice L %A Lalani, Seema %A Stankiewicz, Pawel %A Cheung, Sau-Wai %A Bacino, Carlos A %A Patel, Ankita %A Breman, Amy M %A Wang, Xia %A Meng, Linyan %A Xiao, Rui %A Xia, Fan %A Donna M Muzny %A Richard A Gibbs %A Beaudet, Arthur L %A Eng, Christine M %A James R Lupski %A Yang, Yaping %A Bi, Weimin %K Chromosome Aberrations %K DNA Copy Number Variations %K Exome Sequencing %K Female %K Genetic Testing %K Homozygote %K Humans %K Limit of Detection %K Male %K Microarray Analysis %X

BACKGROUND: Exome sequencing (ES) has been successfully applied in clinical detection of single nucleotide variants (SNVs) and small indels. However, identification of copy number variants (CNVs) using ES data remains challenging. The purpose of this study is to understand the contribution of CNVs and copy neutral runs of homozygosity (ROH) in molecular diagnosis of patients referred for ES.

METHODS: In a cohort of 11,020 consecutive ES patients, an Illumina SNP array analysis interrogating mostly coding SNPs was performed as a quality control (QC) measurement and for CNV/ROH detection. Among these patients, clinical chromosomal microarray analysis (CMA) was performed at Baylor Genetics (BG) on 3229 patients, either before, concurrently, or after ES. We retrospectively analyzed the findings from CMA and the QC array.

RESULTS: The QC array can detect ~ 70% of pathogenic/likely pathogenic CNVs (PCNVs) detectable by CMA. Out of the 11,020 ES cases, the QC array identified PCNVs in 327 patients and uniparental disomy (UPD) disorder-related ROH in 10 patients. The overall PCNV/UPD detection rate was 5.9% in the 3229 ES patients who also had CMA at BG; PCNV/UPD detection rate was higher in concurrent ES and CMA than in ES with prior CMA (7.2% vs 4.6%). The PCNVs/UPD contributed to the molecular diagnoses in 17.4% (189/1089) of molecularly diagnosed ES cases with CMA and were estimated to contribute in 10.6% of all molecularly diagnosed ES cases. Dual diagnoses with both PCNVs and SNVs were detected in 38 patients. PCNVs affecting single recessive disorder genes in a compound heterozygous state with SNVs were detected in 4 patients, and homozygous deletions (mostly exonic deletions) were detected in 17 patients. A higher PCNV detection rate was observed for patients with syndromic phenotypes and/or cardiovascular abnormalities.

CONCLUSIONS: Our clinical genomics study demonstrates that detection of PCNV/UPD through the QC array or CMA increases ES diagnostic rate, provides more precise molecular diagnosis for dominant as well as recessive traits, and enables more complete genetic diagnoses in patients with dual or multiple molecular diagnoses. Concurrent ES and CMA using an array with exonic coverage for disease genes enables most effective detection of both CNVs and SNVs and therefore is recommended especially in time-sensitive clinical situations.

%B Genome Med %V 11 %P 30 %8 2019 May 17 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31101064?dopt=Abstract %R 10.1186/s13073-019-0639-5 %0 Journal Article %J Genome Med %D 2019 %T De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome. %A Vetrini, Francesco %A McKee, Shane %A Rosenfeld, Jill A %A Suri, Mohnish %A Lewis, Andrea M %A Nugent, Kimberly Margaret %A Roeder, Elizabeth %A Littlejohn, Rebecca O %A Holder, Sue %A Zhu, Wenmiao %A Alaimo, Joseph T %A Graham, Brett %A Harris, Jill M %A Gibson, James B %A Pastore, Matthew %A McBride, Kim L %A Komara, Makanko %A Al-Gazali, Lihadh %A Al Shamsi, Aisha %A Fanning, Elizabeth A %A Wierenga, Klaas J %A Scott, Daryl A %A Ben-Neriah, Ziva %A Meiner, Vardiella %A Cassuto, Hanoch %A Elpeleg, Orly %A Holder, J Lloyd %A Burrage, Lindsay C %A Seaver, Laurie H %A Van Maldergem, Lionel %A Mahida, Sonal %A Soul, Janet S %A Marlatt, Margaret %A Matyakhina, Ludmila %A Vogt, Julie %A Gold, June-Anne %A Park, Soo-Mi %A Varghese, Vinod %A Lampe, Anne K %A Kumar, Ajith %A Lees, Melissa %A Holder-Espinasse, Muriel %A McConnell, Vivienne %A Bernhard, Birgitta %A Blair, Ed %A Harrison, Victoria %A Donna M Muzny %A Richard A Gibbs %A Sarah H Elsea %A Posey, Jennifer E %A Bi, Weimin %A Lalani, Seema %A Xia, Fan %A Yang, Yaping %A Eng, Christine M %A James R Lupski %A Liu, Pengfei %K Adolescent %K Child %K Child, Preschool %K Craniofacial Abnormalities %K Developmental Disabilities %K Female %K Humans %K INDEL Mutation %K Infant %K Intellectual Disability %K Male %K Muscle Hypotonia %K Smith-Magenis Syndrome %K Transcription Factors %K Young Adult %X

BACKGROUND: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity).

METHODS: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes.

RESULTS: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances.

CONCLUSIONS: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.

%B Genome Med %V 11 %P 12 %8 2019 Feb 28 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/30819258?dopt=Abstract %R 10.1186/s13073-019-0623-0 %0 Journal Article %J Am J Med Genet A %D 2018 %T The phenotypic spectrum of Xia-Gibbs syndrome. %A Jiang, Yunyun %A Wangler, Michael F %A McGuire, Amy L %A Lupski, James R %A Posey, Jennifer E %A Khayat, Michael M %A Murdock, David R %A Sanchez-Pulido, Luis %A Ponting, Chris P %A Xia, Fan %A Hunter, Jill V %A Meng, Qingchang %A Murugan, Mullai %A Gibbs, Richard A %K Autism Spectrum Disorder %K Child %K Cognition %K Corpus Callosum %K Developmental Disabilities %K DNA-Binding Proteins %K Face %K Female %K Humans %K Male %K Mutation %K Pedigree %K Phenotype %K Registries %K Seizures %K Syndrome %K Young Adult %X

Xia-Gibbs syndrome (XGS: OMIM # 615829) results from de novo truncating mutations within the AT-Hook DNA Binding Motif Containing 1 gene (AHDC1). To further define the phenotypic and molecular spectrum of this disorder, we established an XGS Registry and recruited patients from a worldwide pool of approximately 60 probands. Additional de novo truncating mutations were observed among 25 individuals, extending both the known number of mutation sites and the range of positions within the coding region that were sensitive to alteration. Detailed phenotypic examination of 20 of these patients via clinical records review and data collection from additional surveys showed a wider age range than previously described. Data from developmental milestones showed evidence for delayed speech and that males were more severely affected. Neuroimaging from six available patients showed an associated thinning of the corpus callosum and posterior fossa cysts. An increased risk of both scoliosis and seizures relative to the population burden was also observed. Data from a modified autism screening tool revealed that XGS shares significant overlap with autism spectrum disorders. These details of the phenotypic heterogeneity of XGS implicate specific genotype/phenotype correlations and suggest potential clinical management guidelines.

%B Am J Med Genet A %V 176 %P 1315-1326 %8 2018 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/29696776?dopt=Abstract %R 10.1002/ajmg.a.38699 %0 Journal Article %J Am J Hum Genet %D 2018 %T Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies. %A Cheng, Hanyin %A Dharmadhikari, Avinash V %A Varland, Sylvia %A Ma, Ning %A Domingo, Deepti %A Kleyner, Robert %A Rope, Alan F %A Yoon, Margaret %A Stray-Pedersen, Asbjørg %A Posey, Jennifer E %A Crews, Sarah R %A Eldomery, Mohammad K %A Akdemir, Zeynep Coban %A Lewis, Andrea M %A Sutton, Vernon R %A Rosenfeld, Jill A %A Conboy, Erin %A Agre, Katherine %A Xia, Fan %A Walkiewicz, Magdalena %A Longoni, Mauro %A High, Frances A %A van Slegtenhorst, Marjon A %A Mancini, Grazia M S %A Finnila, Candice R %A van Haeringen, Arie %A den Hollander, Nicolette %A Ruivenkamp, Claudia %A Naidu, Sakkubai %A Mahida, Sonal %A Palmer, Elizabeth E %A Murray, Lucinda %A Lim, Derek %A Jayakar, Parul %A Parker, Michael J %A Giusto, Stefania %A Stracuzzi, Emanuela %A Romano, Corrado %A Beighley, Jennifer S %A Bernier, Raphael A %A Küry, Sébastien %A Nizon, Mathilde %A Corbett, Mark A %A Shaw, Marie %A Gardner, Alison %A Barnett, Christopher %A Armstrong, Ruth %A Kassahn, Karin S %A Van Dijck, Anke %A Vandeweyer, Geert %A Kleefstra, Tjitske %A Schieving, Jolanda %A Jongmans, Marjolijn J %A de Vries, Bert B A %A Pfundt, Rolph %A Kerr, Bronwyn %A Rojas, Samantha K %A Boycott, Kym M %A Person, Richard %A Willaert, Rebecca %A Eichler, Evan E %A Kooy, R Frank %A Yang, Yaping %A Wu, Joseph C %A Lupski, James R %A Arnesen, Thomas %A Cooper, Gregory M %A Chung, Wendy K %A Gecz, Jozef %A Stessman, Holly A F %A Meng, Linyan %A Lyon, Gholson J %K Abnormalities, Multiple %K Adolescent %K Adult %K Autism Spectrum Disorder %K Cell Line %K Child %K Exons %K Female %K Gene Expression Regulation %K Genetic Predisposition to Disease %K Genetic Variation %K Humans %K Intellectual Disability %K Male %K Middle Aged %K Mutation %K N-Terminal Acetyltransferase A %K N-Terminal Acetyltransferase E %K Pedigree %K Phenotype %K RNA, Messenger %K Saccharomyces cerevisiae %X

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

%B Am J Hum Genet %V 102 %P 985-994 %8 2018 May 03 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/29656860?dopt=Abstract %R 10.1016/j.ajhg.2018.03.004 %0 Journal Article %J J Med Genet %D 2017 %T Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO. %A Scott, Daryl A %A Hernandez-Garcia, Andres %A Azamian, Mahshid S %A Jordan, Valerie K %A Kim, Bum Jun %A Starkovich, Molly %A Zhang, Jinglan %A Wong, Lee-Jun %A Darilek, Sandra A %A Breman, Amy M %A Yang, Yaping %A Lupski, James R %A Jiwani, Amyn K %A Das, Bibhuti %A Lalani, Seema R %A Iglesias, Alejandro D %A Rosenfeld, Jill A %A Xia, Fan %K Child %K Child, Preschool %K Developmental Disabilities %K DNA-Binding Proteins %K Exome %K Heart Defects, Congenital %K Heart Ventricles %K Humans %K Infant %K Male %K Nuclear Matrix-Associated Proteins %K Octamer Transcription Factors %K RNA-Binding Proteins %X

BACKGROUND: The non-POU domain containing octamer-binding gene (NONO) is located on chromosome Xq13.1 and encodes a member of a small family of RNA-binding and DNA-binding proteins that perform a variety of tasks involved in RNA synthesis, transcriptional regulation and DNA repair. Loss-of-function variants in NONO have been described as a cause of intellectual disability in males but have not been described in association with congenital heart defects or cardiomyopathy. In this article, we seek to further define the phenotypic consequences of NONO depletion in human subjects.

METHODS: We searched a clinical database of over 6000 individuals referred for exome sequencing and over 60 000 individuals referred for CNV analysis.

RESULTS: We identified two males with atrial and ventricular septal defects, left ventricular non-compaction (LVNC), developmental delay and intellectual disability, who harboured de novo, loss-of-function variants in NONO. We also identified a male infant with developmental delay, congenital brain anomalies and severe LVNC requiring cardiac transplantation, who inherited a single-gene deletion of NONO from his asymptomatic mother.

CONCLUSIONS: We conclude that in addition to global developmental delay and intellectual disability, males with loss-of-function variants in NONO may also be predisposed to developing congenital heart defects and LVNC with the penetrance of these cardiac-related problems being influenced by genetic, epigenetic, environmental or stochastic factors. Brain imaging of males with NONO deficiency may reveal structural defects with abnormalities of the corpus callosum being the most common. Although dysmorphic features vary between affected individuals, relative macrocephaly is a common feature.

%B J Med Genet %V 54 %P 47-53 %8 2017 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/27550220?dopt=Abstract %R 10.1136/jmedgenet-2016-104039 %0 Journal Article %J Am J Hum Genet %D 2017 %T De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder. %A Küry, Sébastien %A Besnard, Thomas %A Ebstein, Frédéric %A Khan, Tahir N %A Gambin, Tomasz %A Douglas, Jessica %A Bacino, Carlos A %A Craigen, William J %A Sanders, Stephan J %A Lehmann, Andrea %A Latypova, Xénia %A Khan, Kamal %A Pacault, Mathilde %A Sacharow, Stephanie %A Glaser, Kimberly %A Bieth, Eric %A Perrin-Sabourin, Laurence %A Jacquemont, Marie-Line %A Cho, Megan T %A Roeder, Elizabeth %A Denommé-Pichon, Anne-Sophie %A Monaghan, Kristin G %A Yuan, Bo %A Xia, Fan %A Simon, Sylvain %A Bonneau, Dominique %A Parent, Philippe %A Gilbert-Dussardier, Brigitte %A Odent, Sylvie %A Toutain, Annick %A Pasquier, Laurent %A Barbouth, Deborah %A Shaw, Chad A %A Patel, Ankita %A Smith, Janice L %A Bi, Weimin %A Schmitt, Sébastien %A Deb, Wallid %A Nizon, Mathilde %A Mercier, Sandra %A Vincent, Marie %A Rooryck, Caroline %A Malan, Valérie %A Briceño, Ignacio %A Gómez, Alberto %A Nugent, Kimberly M %A Gibson, James B %A Cogné, Benjamin %A Lupski, James R %A Stessman, Holly A F %A Eichler, Evan E %A Retterer, Kyle %A Yang, Yaping %A Redon, Richard %A Katsanis, Nicholas %A Rosenfeld, Jill A %A Kloetzel, Peter-Michael %A Golzio, Christelle %A Bézieau, Stéphane %A Stankiewicz, Paweł %A Isidor, Bertrand %K Adolescent %K Animals %K Child %K Child, Preschool %K Disease Models, Animal %K DNA Copy Number Variations %K Down-Regulation %K Female %K Gene Deletion %K Humans %K Infant %K Intellectual Disability %K Male %K Microcephaly %K Neurodevelopmental Disorders %K Polymorphism, Single Nucleotide %K Proteasome Endopeptidase Complex %K Zebrafish %X

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.

%B Am J Hum Genet %V 100 %P 352-363 %8 2017 Feb 02 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/28132691?dopt=Abstract %R 10.1016/j.ajhg.2017.01.003 %0 Journal Article %J Nat Genet %D 2017 %T Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations. %A Wang, Xia %A Charng, Wu-Lin %A Chen, Chun-An %A Rosenfeld, Jill A %A Al Shamsi, Aisha %A Al-Gazali, Lihadh %A McGuire, Marianne %A Mew, Nicholas Ah %A Arnold, Georgianne L %A Qu, Chunjing %A Ding, Yan %A Muzny, Donna M %A Gibbs, Richard A %A Eng, Christine M %A Walkiewicz, Magdalena %A Xia, Fan %A Plon, Sharon E %A Lupski, James R %A Schaaf, Christian P %A Yang, Yaping %K Abnormalities, Multiple %K Animals %K Bone Diseases, Developmental %K Cell Line %K Chromosome Disorders %K Craniofacial Abnormalities %K Feeding and Eating Disorders %K Female %K Fusion Proteins, bcr-abl %K Germ-Line Mutation %K Heart Defects, Congenital %K HEK293 Cells %K Humans %K Leukemia, Myelogenous, Chronic, BCR-ABL Positive %K Limb Deformities, Congenital %K Male %K Mice %K Mice, Knockout %K Philadelphia Chromosome %K Phosphorylation %K Proto-Oncogene Mas %K Signal Transduction %X

ABL1 is a proto-oncogene well known as part of the fusion gene BCR-ABL1 in the Philadelphia chromosome of leukemia cancer cells. Inherited germline ABL1 changes have not been associated with genetic disorders. Here we report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. The variant c.734A>G (p.Tyr245Cys) was found to occur de novo or cosegregate with disease in five individuals (families 1-3). Additionally, a de novo c.1066G>A (p.Ala356Thr) variant was identified in a sixth individual (family 4). We overexpressed the mutant constructs in HEK 293T cells and observed increased tyrosine phosphorylation, suggesting increased ABL1 kinase activities associated with both the p.Tyr245Cys and p.Ala356Thr substitutions. Our clinical and experimental findings, together with previously reported teratogenic effects of selective BCR-ABL inhibitors in humans and developmental defects in Abl1 knockout mice, suggest that ABL1 has an important role during organismal development.

%B Nat Genet %V 49 %P 613-617 %8 2017 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/28288113?dopt=Abstract %R 10.1038/ng.3815 %0 Journal Article %J Hum Genet %D 2017 %T Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features. %A Zhang, Jing %A Gambin, Tomasz %A Yuan, Bo %A Szafranski, Przemyslaw %A Rosenfeld, Jill A %A Balwi, Mohammed Al %A Alswaid, Abdulrahman %A Al-Gazali, Lihadh %A Shamsi, Aisha M Al %A Komara, Makanko %A Ali, Bassam R %A Roeder, Elizabeth %A McAuley, Laura %A Roy, Daniel S %A Manchester, David K %A Magoulas, Pilar %A King, Lauren E %A Hannig, Vickie %A Bonneau, Dominique %A Denommé-Pichon, Anne-Sophie %A Charif, Majida %A Besnard, Thomas %A Bézieau, Stéphane %A Cogné, Benjamin %A Andrieux, Joris %A Zhu, Wenmiao %A He, Weimin %A Vetrini, Francesco %A Ward, Patricia A %A Cheung, Sau Wai %A Bi, Weimin %A Eng, Christine M %A Lupski, James R %A Yang, Yaping %A Patel, Ankita %A Lalani, Seema R %A Xia, Fan %A Stankiewicz, Paweł %K Adolescent %K Autism Spectrum Disorder %K Carrier Proteins %K Child %K Child, Preschool %K Cohort Studies %K DNA Copy Number Variations %K Facies %K Female %K Haploinsufficiency %K Humans %K Infant %K Intellectual Disability %K Language Development Disorders %K Male %K Ubiquitin-Protein Ligases %X

Impairment of ubiquitin-proteasome system activity involving ubiquitin ligase genes UBE3A, UBE3B, and HUWE1 and deubiquitinating enzyme genes USP7 and USP9X has been reported in patients with neurodevelopmental delays. To date, only a handful of single-nucleotide variants (SNVs) and copy-number variants (CNVs) involving TRIP12, encoding a member of the HECT domain E3 ubiquitin ligases family on chromosome 2q36.3 have been reported. Using chromosomal microarray analysis and whole-exome sequencing (WES), we have identified, respectively, five deletion CNVs and four inactivating SNVs (two frameshifts, one missense, and one splicing) in TRIP12. Seven of these variants were found to be de novo; parental studies could not be completed in two families. Quantitative PCR analyses of the splicing mutation showed a dramatically decreased level of TRIP12 mRNA in the proband compared to the family controls, indicating a loss-of-function mechanism. The shared clinical features include intellectual disability with or without autistic spectrum disorders, speech delay, and facial dysmorphism. Our findings demonstrate that E3 ubiquitin ligase TRIP12 plays an important role in nervous system development and function. The nine presented pathogenic variants further document that TRIP12 haploinsufficiency causes a childhood-onset neurodevelopmental disorder. Finally, our data enable expansion of the phenotypic spectrum of ubiquitin-proteasome dependent disorders.

%B Hum Genet %V 136 %P 377-386 %8 2017 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/28251352?dopt=Abstract %R 10.1007/s00439-017-1763-1 %0 Journal Article %J Genome Med %D 2017 %T Lessons learned from additional research analyses of unsolved clinical exome cases. %A Eldomery, Mohammad K %A Coban-Akdemir, Zeynep %A Harel, Tamar %A Rosenfeld, Jill A %A Gambin, Tomasz %A Stray-Pedersen, Asbjørg %A Küry, Sébastien %A Mercier, Sandra %A Lessel, Davor %A Denecke, Jonas %A Wiszniewski, Wojciech %A Penney, Samantha %A Liu, Pengfei %A Bi, Weimin %A Lalani, Seema R %A Schaaf, Christian P %A Wangler, Michael F %A Bacino, Carlos A %A Lewis, Richard Alan %A Potocki, Lorraine %A Graham, Brett H %A Belmont, John W %A Scaglia, Fernando %A Orange, Jordan S %A Jhangiani, Shalini N %A Chiang, Theodore %A Doddapaneni, Harsha %A Hu, Jianhong %A Muzny, Donna M %A Xia, Fan %A Beaudet, Arthur L %A Boerwinkle, Eric %A Eng, Christine M %A Plon, Sharon E %A Sutton, V Reid %A Gibbs, Richard A %A Posey, Jennifer E %A Yang, Yaping %A Lupski, James R %K Adenosine Triphosphatases %K ATPases Associated with Diverse Cellular Activities %K Computational Biology %K DNA Copy Number Variations %K DNA-Binding Proteins %K Exome %K Female %K Genetic Diseases, Inborn %K Genomics %K GTP-Binding Protein beta Subunits %K Humans %K Male %K Membrane Proteins %K Metalloendopeptidases %K Mitochondrial Proteins %K Pilot Projects %K Polymorphism, Single Nucleotide %K Sequence Analysis, DNA %K Transcription Factors %X

BACKGROUND: Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery.

METHODS: We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent-offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols.

RESULTS: Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3).

CONCLUSION: An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts.

%B Genome Med %V 9 %P 26 %8 2017 Mar 21 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/28327206?dopt=Abstract %R 10.1186/s13073-017-0412-6 %0 Journal Article %J Genome Med %D 2017 %T Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders. %A Bostwick, Bret L %A McLean, Scott %A Posey, Jennifer E %A Streff, Haley E %A Gripp, Karen W %A Blesson, Alyssa %A Powell-Hamilton, Nina %A Tusi, Jessica %A Stevenson, David A %A Farrelly, Ellyn %A Hudgins, Louanne %A Yang, Yaping %A Xia, Fan %A Wang, Xia %A Liu, Pengfei %A Walkiewicz, Magdalena %A McGuire, Marianne %A Grange, Dorothy K %A Andrews, Marisa V %A Hummel, Marybeth %A Madan-Khetarpal, Suneeta %A Infante, Elena %A Coban-Akdemir, Zeynep %A Miszalski-Jamka, Karol %A Jefferies, John L %A Rosenfeld, Jill A %A Emrick, Lisa %A Nugent, Kimberly M %A Lupski, James R %A Belmont, John W %A Lee, Brendan %A Lalani, Seema R %K Adolescent %K Adult %K CDC2 Protein Kinase %K Child %K Child, Preschool %K Face %K Female %K Heart Defects, Congenital %K Humans %K Infant %K Intellectual Disability %K Male %K Mutation %K Phenotype %K Syndrome %X

BACKGROUND: De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder.

METHODS: To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review.

RESULTS: We demonstrate greater than expected phenotypic heterogeneity, including 33% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites.

CONCLUSIONS: Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified.

%B Genome Med %V 9 %P 73 %8 2017 Aug 14 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/28807008?dopt=Abstract %R 10.1186/s13073-017-0463-8 %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 Genome Med %D 2016 %T MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death. %A Eldomery, Mohammad K %A Akdemir, Zeynep C %A Vögtle, F-Nora %A Charng, Wu-Lin %A Mulica, Patrycja %A Rosenfeld, Jill A %A Gambin, Tomasz %A Gu, Shen %A Burrage, Lindsay C %A Al Shamsi, Aisha %A Penney, Samantha %A Jhangiani, Shalini N %A Zimmerman, Holly H %A Muzny, Donna M %A Wang, Xia %A Tang, Jia %A Medikonda, Ravi %A Ramachandran, Prasanna V %A Wong, Lee-Jun %A Boerwinkle, Eric %A Gibbs, Richard A %A Eng, Christine M %A Lalani, Seema R %A Hertecant, Jozef %A Rodenburg, Richard J %A Abdul-Rahman, Omar A %A Yang, Yaping %A Xia, Fan %A Wang, Meng C %A Lupski, James R %A Meisinger, Chris %A Sutton, V Reid %K Adult %K Amino Acid Sequence %K Female %K Genes, Recessive %K Heart Defects, Congenital %K Humans %K Infant %K Infant, Newborn %K Male %K Metalloendopeptidases %K Muscle Hypotonia %K Pedigree %K Phenotype %K Sequence Homology, Amino Acid %K Sudden Infant Death %K Syndrome %X

BACKGROUND: Mitochondrial presequence proteases perform fundamental functions as they process about 70 % of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease.

METHODS: Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia. Proposed pathogenic variants were confirmed by Sanger sequencing or array comparative genomic hybridization. Functional analysis of the identified MIP variants was performed using the model organism Saccharomyces cerevisiae as the protein and its functions are highly conserved from yeast to human.

RESULTS: Biallelic single nucleotide variants (SNVs) or copy number variants (CNVs) in MIPEP, which encodes MIP, were present in all four probands, three of whom had infantile/childhood death. Two patients had compound heterozygous SNVs (p.L582R/p.L71Q and p.E602*/p.L306F) and one patient from a consanguineous family had a homozygous SNV (p.K343E). The fourth patient, identified through the GeneMatcher tool, a part of the Matchmaker Exchange Project, was found to have inherited a paternal SNV (p.H512D) and a maternal CNV (1.4-Mb deletion of 13q12.12) that includes MIPEP. All amino acids affected in the patients' missense variants are highly conserved from yeast to human and therefore S. cerevisiae was employed for functional analysis (for p.L71Q, p.L306F, and p.K343E). The mutations p.L339F (human p.L306F) and p.K376E (human p.K343E) resulted in a severe decrease of Oct1 protease activity and accumulation of non-processed Oct1 substrates and consequently impaired viability under respiratory growth conditions. The p.L83Q (human p.L71Q) failed to localize to the mitochondria.

CONCLUSIONS: Our findings reveal for the first time the role of the mitochondrial intermediate peptidase in human disease. Loss of MIP function results in a syndrome which consists of LVNC, DD, seizures, hypotonia, and cataracts. Our approach highlights the power of data exchange and the importance of an interrelationship between clinical and research efforts for disease gene discovery.

%B Genome Med %V 8 %P 106 %8 2016 Nov 01 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/27799064?dopt=Abstract %R 10.1186/s13073-016-0360-6 %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 Nat Commun %D 2016 %T Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. %A Gomez-Ospina, Natalia %A Potter, Carol J %A Xiao, Rui %A Manickam, Kandamurugu %A Kim, Mi-Sun %A Kim, Kang Ho %A Shneider, Benjamin L %A Picarsic, Jennifer L %A Jacobson, Theodora A %A Zhang, Jing %A He, Weimin %A Liu, Pengfei %A Knisely, A S %A Finegold, Milton J %A Muzny, Donna M %A Boerwinkle, Eric %A Lupski, James R %A Plon, Sharon E %A Gibbs, Richard A %A Eng, Christine M %A Yang, Yaping %A Washington, Gabriel C %A Porteus, Matthew H %A Berquist, William E %A Kambham, Neeraja %A Singh, Ravinder J %A Xia, Fan %A Enns, Gregory M %A Moore, David D %K ATP Binding Cassette Transporter, Subfamily B, Member 11 %K ATP-Binding Cassette Transporters %K Bile Acids and Salts %K Cholestasis, Intrahepatic %K Female %K Humans %K Male %K Mutation %K Receptors, Cytoplasmic and Nuclear %K Young Adult %X

Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.

%B Nat Commun %V 7 %P 10713 %8 2016 Feb 18 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/26888176?dopt=Abstract %R 10.1038/ncomms10713 %0 Journal Article %J Genome Med %D 2016 %T POGZ truncating alleles cause syndromic intellectual disability. %A White, Janson %A Beck, Christine R %A Harel, Tamar %A Posey, Jennifer E %A Jhangiani, Shalini N %A Tang, Sha %A Farwell, Kelly D %A Powis, Zöe %A Mendelsohn, Nancy J %A Baker, Janice A %A Pollack, Lynda %A Mason, Kati J %A Wierenga, Klaas J %A Arrington, Daniel K %A Hall, Melissa %A Psychogios, Apostolos %A Fairbrother, Laura %A Walkiewicz, Magdalena %A Person, Richard E %A Niu, Zhiyv %A Zhang, Jing %A Rosenfeld, Jill A %A Muzny, Donna M %A Eng, Christine %A Beaudet, Arthur L %A Lupski, James R %A Boerwinkle, Eric %A Gibbs, Richard A %A Yang, Yaping %A Xia, Fan %A Sutton, V Reid %K Adolescent %K Adult %K Alleles %K Child, Preschool %K Exome %K Female %K Heterozygote %K Humans %K Infant %K Intellectual Disability %K Male %K Mutation %K Sequence Analysis, DNA %K Transposases %X

BACKGROUND: Large-scale cohort-based whole exome sequencing of individuals with neurodevelopmental disorders (NDDs) has identified numerous novel candidate disease genes; however, detailed phenotypic information is often lacking in such studies. De novo mutations in pogo transposable element with zinc finger domain (POGZ) have been identified in six independent and diverse cohorts of individuals with NDDs ranging from autism spectrum disorder to developmental delay.

METHODS: Whole exome sequencing was performed on five unrelated individuals. Sanger sequencing was used to validate variants and segregate mutations with the phenotype in available family members.

RESULTS: We identified heterozygous truncating mutations in POGZ in five unrelated individuals, which were confirmed to be de novo or not present in available parental samples. Careful review of the phenotypes revealed shared features that included developmental delay, intellectual disability, hypotonia, behavioral abnormalities, and similar facial characteristics. Variable features included short stature, microcephaly, strabismus and hearing loss.

CONCLUSIONS: While POGZ has been associated with neurodevelopmental disorders in large cohort studies, our data suggest that loss of function variants in POGZ lead to an identifiable syndrome of NDD with specific phenotypic traits. This study exemplifies the era of human reverse clinical genomics ushered in by large disease-directed cohort studies; first defining a new syndrome molecularly and, only subsequently, phenotypically.

%B Genome Med %V 8 %P 3 %8 2016 Jan 06 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/26739615?dopt=Abstract %R 10.1186/s13073-015-0253-0 %0 Journal Article %J Am J Hum Genet %D 2016 %T Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes. %A Harel, Tamar %A Yoon, Wan Hee %A Garone, Caterina %A Gu, Shen %A Coban-Akdemir, Zeynep %A Eldomery, Mohammad K %A Posey, Jennifer E %A Jhangiani, Shalini N %A Rosenfeld, Jill A %A Cho, Megan T %A Fox, Stephanie %A Withers, Marjorie %A Brooks, Stephanie M %A Chiang, Theodore %A Duraine, Lita %A Erdin, Serkan %A Yuan, Bo %A Shao, Yunru %A Moussallem, Elie %A Lamperti, Costanza %A Donati, Maria A %A Smith, Joshua D %A McLaughlin, Heather M %A Eng, Christine M %A Walkiewicz, Magdalena %A Xia, Fan %A Pippucci, Tommaso %A Magini, Pamela %A Seri, Marco %A Zeviani, Massimo %A Hirano, Michio %A Hunter, Jill V %A Srour, Myriam %A Zanigni, Stefano %A Lewis, Richard Alan %A Muzny, Donna M %A Lotze, Timothy E %A Boerwinkle, Eric %A Gibbs, Richard A %A Hickey, Scott E %A Graham, Brett H %A Yang, Yaping %A Buhas, Daniela %A Martin, Donna M %A Potocki, Lorraine %A Graziano, Claudio %A Bellen, Hugo J %A Lupski, James R %K Adenosine Triphosphatases %K Adult %K Alleles %K Animals %K ATPases Associated with Diverse Cellular Activities %K Axons %K Cardiomyopathies %K Child %K Child, Preschool %K Developmental Disabilities %K DNA Copy Number Variations %K Drosophila melanogaster %K Female %K Fibroblasts %K Homozygote %K Humans %K Infant %K Infant, Newborn %K Male %K Membrane Proteins %K Mitochondria %K Mitochondrial Proteins %K Muscle Hypotonia %K Muscles %K Mutation %K Nervous System Diseases %K Neurons %K Optic Atrophy %K Phenotype %K Polymorphism, Single Nucleotide %K Syndrome %K Young Adult %X

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of bor, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of bor resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

%B Am J Hum Genet %V 99 %P 831-845 %8 2016 Oct 06 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/27640307?dopt=Abstract %R 10.1016/j.ajhg.2016.08.007 %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 Am J Hum Genet %D 2015 %T De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome. %A Burrage, Lindsay C %A Charng, Wu-Lin %A Eldomery, Mohammad K %A Willer, Jason R %A Davis, Erica E %A Lugtenberg, Dorien %A Zhu, Wenmiao %A Leduc, Magalie S %A Akdemir, Zeynep C %A Azamian, Mahshid %A Zapata, Gladys %A Hernandez, Patricia P %A Schoots, Jeroen %A de Munnik, Sonja A %A Roepman, Ronald %A Pearring, Jillian N %A Jhangiani, Shalini %A Katsanis, Nicholas %A Vissers, Lisenka E L M %A Brunner, Han G %A Beaudet, Arthur L %A Rosenfeld, Jill A %A Muzny, Donna M %A Gibbs, Richard A %A Eng, Christine M %A Xia, Fan %A Lalani, Seema R %A Lupski, James R %A Bongers, Ernie M H F %A Yang, Yaping %K Adolescent %K Amino Acid Sequence %K Base Sequence %K Cell Cycle %K Child, Preschool %K Congenital Microtia %K Dwarfism %K Exons %K Female %K Geminin %K Gene Expression %K Genes, Dominant %K Growth Disorders %K Heterozygote %K High-Throughput Nucleotide Sequencing %K Humans %K Inheritance Patterns %K Male %K Micrognathism %K Molecular Sequence Data %K Mutation %K Patella %K Pedigree %K Protein Stability %K Proteolysis %K RNA Splicing %K Sequence Alignment %X

Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(∗)) and c.35_38delTCAA (p.Ile12Lysfs(∗)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.

%B Am J Hum Genet %V 97 %P 904-13 %8 2015 Dec 03 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/26637980?dopt=Abstract %R 10.1016/j.ajhg.2015.11.006 %0 Journal Article %J Am J Hum Genet %D 2014 %T De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea. %A Xia, Fan %A Bainbridge, Matthew N %A Tan, Tiong Yang %A Wangler, Michael F %A Scheuerle, Angela E %A Zackai, Elaine H %A Harr, Margaret H %A Sutton, V Reid %A Nalam, Roopa L %A Zhu, Wenmiao %A Nash, Margot %A Ryan, Monique M %A Yaplito-Lee, Joy %A Hunter, Jill V %A Deardorff, Matthew A %A Penney, Samantha J %A Beaudet, Arthur L %A Plon, Sharon E %A Boerwinkle, Eric A %A Lupski, James R %A Eng, Christine M %A Muzny, Donna M %A Yang, Yaping %A Gibbs, Richard A %K Child %K Child, Preschool %K DNA-Binding Proteins %K Exome %K Female %K Humans %K Infant %K Intellectual Disability %K Language Development Disorders %K Male %K Muscle Hypotonia %K Mutation %K Sleep Apnea Syndromes %K Syndrome %X

Clinical whole-exome sequencing (WES) for identification of mutations leading to Mendelian disease has been offered to the medical community since 2011. Clinically undiagnosed neurological disorders are the most frequent basis for test referral, and currently, approximately 25% of such cases are diagnosed at the molecular level. To date, there are approximately 4,000 "known" disease-associated loci, and many are associated with striking dysmorphic features, making genotype-phenotype correlations relatively straightforward. A significant fraction of cases, however, lack characteristic dysmorphism or clinical pathognomonic traits and are dependent upon molecular tests for definitive diagnoses. Further, many molecular diagnoses are guided by recent gene-disease association discoveries. Hence, there is a critical interplay between clinical testing and research leading to gene-disease association discovery. Here, we describe four probands, all of whom presented with hypotonia, intellectual disability, global developmental delay, and mildly dysmorphic facial features. Three of the four also had sleep apnea. Each was a simplex case without a remarkable family history. Using WES, we identified AHDC1 de novo truncating mutations that most likely cause this genetic syndrome.

%B Am J Hum Genet %V 94 %P 784-9 %8 2014 May 01 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/24791903?dopt=Abstract %R 10.1016/j.ajhg.2014.04.006 %0 Journal Article %J PLoS Genet %D 2014 %T Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome. %A Wangler, Michael F %A Gonzaga-Jauregui, Claudia %A Gambin, Tomasz %A Penney, Samantha %A Moss, Timothy %A Chopra, Atul %A Probst, Frank J %A Xia, Fan %A Yang, Yaping %A Werlin, Steven %A Eglite, Ieva %A Kornejeva, Liene %A Bacino, Carlos A %A Baldridge, Dustin %A Neul, Jeff %A Lehman, Efrat Lev %A Larson, Austin %A Beuten, Joke %A Muzny, Donna M %A Jhangiani, Shalini %A Gibbs, Richard A %A Lupski, James R %A Beaudet, Arthur %K Abnormalities, Multiple %K Actins %K Adolescent %K Adult %K Child %K Child, Preschool %K Colon %K Exome %K Female %K Heterozygote %K Humans %K Intestinal Pseudo-Obstruction %K Male %K Muscle, Smooth %K Mutation %K Urinary Bladder %X

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare disorder of enteric smooth muscle function affecting the intestine and bladder. Patients with this severe phenotype are dependent on total parenteral nutrition and urinary catheterization. The cause of this syndrome has remained a mystery since Berdon's initial description in 1976. No genes have been clearly linked to MMIHS. We used whole-exome sequencing for gene discovery followed by targeted Sanger sequencing in a cohort of patients with MMIHS and intestinal pseudo-obstruction. We identified heterozygous ACTG2 missense variants in 15 unrelated subjects, ten being apparent de novo mutations. Ten unique variants were detected, of which six affected CpG dinucleotides and resulted in missense mutations at arginine residues, perhaps related to biased usage of CpG containing codons within actin genes. We also found some of the same heterozygous mutations that we observed as apparent de novo mutations in MMIHS segregating in families with intestinal pseudo-obstruction, suggesting that ACTG2 is responsible for a spectrum of smooth muscle disease. ACTG2 encodes γ2 enteric actin and is the first gene to be clearly associated with MMIHS, suggesting an important role for contractile proteins in enteric smooth muscle disease.

%B PLoS Genet %V 10 %P e1004258 %8 2014 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/24676022?dopt=Abstract %R 10.1371/journal.pgen.1004258 %0 Journal Article %J JAMA %D 2014 %T Molecular findings among patients referred for clinical whole-exome sequencing. %A Yang, Yaping %A Muzny, Donna M %A Xia, Fan %A Niu, Zhiyv %A Person, Richard %A Ding, Yan %A Ward, Patricia %A Braxton, Alicia %A Wang, Min %A Buhay, Christian %A Veeraraghavan, Narayanan %A Hawes, Alicia %A Chiang, Theodore %A Leduc, Magalie %A Beuten, Joke %A Zhang, Jing %A He, Weimin %A Scull, Jennifer %A Willis, Alecia %A Landsverk, Megan %A Craigen, William J %A Bekheirnia, Mir Reza %A Stray-Pedersen, Asbjorg %A Liu, Pengfei %A Wen, Shu %A Alcaraz, Wendy %A Cui, Hong %A Walkiewicz, Magdalena %A Reid, Jeffrey %A Bainbridge, Matthew %A Patel, Ankita %A Boerwinkle, Eric %A Beaudet, Arthur L %A Lupski, James R %A Plon, Sharon E %A Gibbs, Richard A %A Eng, Christine M %K Adolescent %K Adult %K Child %K Child, Preschool %K Exome %K Female %K Fetus %K Genetic Diseases, Inborn %K Genetic Testing %K Genomics %K Humans %K Incidental Findings %K Infant %K Infant, Newborn %K Male %K Molecular Diagnostic Techniques %K Mutation %K Phenotype %K Referral and Consultation %K Sequence Analysis, DNA %X

IMPORTANCE: Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders.

OBJECTIVE: To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome.

DESIGN, SETTING, AND PATIENTS: Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient's physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay.

MAIN OUTCOMES AND MEASURES: Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings.

RESULTS: A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95% CI, 23.5%-31.2%) for the neurological group, 282/1147 (24.6%; 95% CI, 22.1%-27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95% CI, 26.1%-47.5%) for the specific neurological group, and 49/244 (20.1%; 95% CI, 15.6%-25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics.

CONCLUSIONS AND RELEVANCE: Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.

%B JAMA %V 312 %P 1870-9 %8 2014 Nov 12 %G eng %N 18 %1 https://www.ncbi.nlm.nih.gov/pubmed/25326635?dopt=Abstract %R 10.1001/jama.2014.14601