%0 Journal Article %J Am J Hum Genet %D 2021 %T COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay. %A Marom, Ronit %A Burrage, Lindsay C %A Venditti, Rossella %A Clément, Aurélie %A Blanco-Sánchez, Bernardo %A Jain, Mahim %A Scott, Daryl A %A Rosenfeld, Jill A %A Sutton, V Reid %A Shinawi, Marwan %A Mirzaa, Ghayda %A DeVile, Catherine %A Roberts, Rowenna %A Calder, Alistair D %A Allgrove, Jeremy %A Grafe, Ingo %A Lanza, Denise G %A Li, Xiaohui %A Joeng, Kyu Sang %A Lee, Yi-Chien %A Song, I-Wen %A Sliepka, Joseph M %A Batkovskyte, Dominyka %A Washington, Megan %A Dawson, Brian C %A Jin, Zixue %A Jiang, Ming-Ming %A Chen, Shan %A Chen, Yuqing %A Tran, Alyssa A %A Emrick, Lisa T %A David R Murdock %A Hanchard, Neil A %A Zapata, Gladys E %A Mehta, Nitesh R %A Weis, Mary Ann %A Scott, Abbey A %A Tremp, Brenna A %A Phillips, Jennifer B %A Wegner, Jeremy %A Taylor-Miller, Tashunka %A Richard A Gibbs %A Donna M Muzny %A Jhangiani, Shalini N %A Hicks, John %A Stottmann, Rolf W %A Dickinson, Mary E %A Seavitt, John R %A Heaney, Jason D %A Eyre, David R %A Westerfield, Monte %A De Matteis, Maria Antonietta %A Lee, Brendan %K Animals %K Ascorbic Acid %K Bone and Bones %K Brain %K Child %K Child, Preschool %K Coat Protein Complex I %K Coatomer Protein %K Collagen Type I %K Developmental Disabilities %K Embryo, Nonmammalian %K Endoplasmic Reticulum %K Female %K Fibroblasts %K Gene Expression Regulation, Developmental %K Golgi Apparatus %K Haploinsufficiency %K Humans %K Intellectual Disability %K Male %K Mice %K Osteoporosis %K RNA, Small Interfering %K Severity of Illness Index %K Zebrafish %X

Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects' fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2 mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2 mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2 mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis.

%B Am J Hum Genet %V 108 %P 1710-1724 %8 2021 Sep 02 %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/34450031?dopt=Abstract %R 10.1016/j.ajhg.2021.08.002 %0 Journal Article %J Nature %D 2020 %T High-depth African genomes inform human migration and health. %A Choudhury, Ananyo %A Aron, Shaun %A Botigué, Laura R %A Sengupta, Dhriti %A Botha, Gerrit %A Bensellak, Taoufik %A Wells, Gordon %A Kumuthini, Judit %A Shriner, Daniel %A Fakim, Yasmina J %A Ghoorah, Anisah W %A Dareng, Eileen %A Odia, Trust %A Falola, Oluwadamilare %A Adebiyi, Ezekiel %A Hazelhurst, Scott %A Mazandu, Gaston %A Nyangiri, Oscar A %A Mbiyavanga, Mamana %A Benkahla, Alia %A Kassim, Samar K %A Mulder, Nicola %A Adebamowo, Sally N %A Chimusa, Emile R %A Donna M Muzny %A Ginger A Metcalf %A Richard A Gibbs %A Rotimi, Charles %A Ramsay, Michèle %A Adeyemo, Adebowale A %A Lombard, Zané %A Hanchard, Neil A %K Africa %K Datasets as Topic %K DNA Repair %K Female %K Gene Flow %K Genetic Variation %K Genetics, Medical %K Genetics, Population %K Genome, Human %K Genomics %K Health %K History, Ancient %K Human Migration %K Humans %K Immunity %K Language %K Male %K Metabolism %K Selection, Genetic %K Whole Genome Sequencing %X

The African continent is regarded as the cradle of modern humans and African genomes contain more genetic variation than those from any other continent, yet only a fraction of the genetic diversity among African individuals has been surveyed. Here we performed whole-genome sequencing analyses of 426 individuals-comprising 50 ethnolinguistic groups, including previously unsampled populations-to explore the breadth of genomic diversity across Africa. We uncovered more than 3 million previously undescribed variants, most of which were found among individuals from newly sampled ethnolinguistic groups, as well as 62 previously unreported loci that are under strong selection, which were predominantly found in genes that are involved in viral immunity, DNA repair and metabolism. We observed complex patterns of ancestral admixture and putative-damaging and novel variation, both within and between populations, alongside evidence that Zambia was a likely intermediate site along the routes of expansion of Bantu-speaking populations. Pathogenic variants in genes that are currently characterized as medically relevant were uncommon-but in other genes, variants denoted as 'likely pathogenic' in the ClinVar database were commonly observed. Collectively, these findings refine our current understanding of continental migration, identify gene flow and the response to human disease as strong drivers of genome-level population variation, and underscore the scientific imperative for a broader characterization of the genomic diversity of African individuals to understand human ancestry and improve health.

%B Nature %V 586 %P 741-748 %8 2020 Oct %G eng %N 7831 %1 https://www.ncbi.nlm.nih.gov/pubmed/33116287?dopt=Abstract %R 10.1038/s41586-020-2859-7 %0 Journal Article %J Eur J Hum Genet %D 2019 %T Genetic architecture of laterality defects revealed by whole exome sequencing. %A Li, Alexander H %A Hanchard, Neil A %A Azamian, Mahshid %A D'Alessandro, Lisa C A %A Coban-Akdemir, Zeynep %A Lopez, Keila N %A Hall, Nancy J %A Dickerson, Heather %A Nicosia, Annarita %A Fernbach, Susan %A Boone, Philip M %A Gambin, Tomaz %A Karaca, Ender %A Gu, Shen %A Bo Yuan %A Jhangiani, Shalini N %A Harshavardhan Doddapaneni %A Jianhong Hu %A Dinh, Huyen %A Jayaseelan, Joy %A Donna M Muzny %A Lalani, Seema %A Towbin, Jeffrey %A Penny, Daniel %A Fraser, Charles %A Martin, James %A James R Lupski %A Richard A Gibbs %A Eric Boerwinkle %A Ware, Stephanie M %A Belmont, John W %K Animals %K Body Patterning %K Embryonic Development %K Exome Sequencing %K Female %K Genetic Association Studies %K Genome, Human %K Genomics %K GTP Phosphohydrolases %K Heart Defects, Congenital %K Heterotaxy Syndrome %K Humans %K Male %K Peroxidases %K Zebrafish %K Zebrafish Proteins %X

Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for <20% of cases. We sought to characterize the genetic spectrum of these conditions by performing whole-exome sequencing of 323 unrelated laterality cases. We investigated the role of rare, predicted-damaging variation in 1726 putative laterality candidate genes derived from model organisms, pathway analyses, and human phenotypes. We also evaluated the contribution of homo/hemizygous exon deletions and gene-based burden of rare variation. A total of 28 candidate variants (26 rare predicted-damaging variants and 2 hemizygous deletions) were identified, including variants in genes known to cause heterotaxy and primary ciliary dyskinesia (ACVR2B, NODAL, ZIC3, DNAI1, DNAH5, HYDIN, MMP21), and genes without a human phenotype association, but with prior evidence for a role in embryonic laterality or cardiac development. Sanger validation of the latter variants in probands and their parents revealed no de novo variants, but apparent transmitted heterozygous (ROCK2, ISL1, SMAD2), and hemizygous (RAI2, RIPPLY1) variant patterns. Collectively, these variants account for 7.1% of our study subjects. We also observe evidence for an excess burden of rare, predicted loss-of-function variation in PXDNL and BMS1- two genes relevant to the broader laterality phenotype. These findings highlight potential new genes in the development of laterality defects, and suggest extensive locus heterogeneity and complex genetic models in this class of birth defects.

%B Eur J Hum Genet %V 27 %P 563-573 %8 2019 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/30622330?dopt=Abstract %R 10.1038/s41431-018-0307-z %0 Journal Article %J Genome Med %D 2019 %T Interchromosomal template-switching as a novel molecular mechanism for imprinting perturbations associated with Temple syndrome. %A Carvalho, Claudia M B %A Coban-Akdemir, Zeynep %A Hijazi, Hadia %A Bo Yuan %A Pendleton, Matthew %A Harrington, Eoghan %A Beaulaurier, John %A Juul, Sissel %A Turner, Daniel J %A Kanchi, Rupa S %A Jhangiani, Shalini N %A Donna M Muzny %A Richard A Gibbs %A Stankiewicz, Pawel %A Belmont, John W %A Shaw, Chad A %A Cheung, Sau Wai %A Hanchard, Neil A %A Sutton, V Reid %A Bader, Patricia I %A James R Lupski %K Chromosome Aberrations %K Chromosome Disorders %K Chromosomes, Human, Pair 14 %K DNA Methylation %K DNA Replication %K Genomic Imprinting %K Humans %K Male %K Pedigree %K Phenotype %K Polymorphism, Single Nucleotide %K Young Adult %X

BACKGROUND: Intrachromosomal triplications (TRP) can contribute to disease etiology via gene dosage effects, gene disruption, position effects, or fusion gene formation. Recently, post-zygotic de novo triplications adjacent to copy-number neutral genomic intervals with runs of homozygosity (ROH) have been shown to result in uniparental isodisomy (UPD). The genomic structure of these complex genomic rearrangements (CGRs) shows a consistent pattern of an inverted triplication flanked by duplications (DUP-TRP/INV-DUP) formed by an iterative DNA replisome template-switching mechanism during replicative repair of a single-ended, double-stranded DNA (seDNA), the ROH results from an interhomolog or nonsister chromatid template switch. It has been postulated that these CGRs may lead to genetic abnormalities in carriers due to dosage-sensitive genes mapping within the copy-number variant regions, homozygosity for alleles at a locus causing an autosomal recessive (AR) disease trait within the ROH region, or imprinting-associated diseases.

METHODS: Here, we report a family wherein the affected subject carries a de novo 2.2-Mb TRP followed by 42.2 Mb of ROH and manifests clinical features overlapping with those observed in association with chromosome 14 maternal UPD (UPD(14)mat). UPD(14)mat can cause clinical phenotypic features enabling a diagnosis of Temple syndrome. This CGR was then molecularly characterized by high-density custom aCGH, genome-wide single-nucleotide polymorphism (SNP) and methylation arrays, exome sequencing (ES), and the Oxford Nanopore long-read sequencing technology.

RESULTS: We confirmed the postulated DUP-TRP/INV-DUP structure by multiple orthogonal genomic technologies in the proband. The methylation status of known differentially methylated regions (DMRs) on chromosome 14 revealed that the subject shows the typical methylation pattern of UPD(14)mat. Consistent with these molecular findings, the clinical features overlap with those observed in Temple syndrome, including speech delay.

CONCLUSIONS: These data provide experimental evidence that, in humans, triplication can lead to segmental UPD and imprinting disease. Importantly, genotype/phenotype analyses further reveal how a post-zygotically generated complex structural variant, resulting from a replication-based mutational mechanism, contributes to expanding the clinical phenotype of known genetic syndromes. Mechanistically, such events can distort transmission genetics resulting in homozygosity at a locus for which only one parent is a carrier as well as cause imprinting diseases.

%B Genome Med %V 11 %P 25 %8 2019 Apr 23 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31014393?dopt=Abstract %R 10.1186/s13073-019-0633-y %0 Journal Article %J Genome Med %D 2017 %T Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns. %A Li, Alexander H %A Hanchard, Neil A %A Furthner, Dieter %A Fernbach, Susan %A Azamian, Mahshid %A Nicosia, Annarita %A Rosenfeld, Jill %A Muzny, Donna %A D'Alessandro, Lisa C A %A Morris, Shaine %A Jhangiani, Shalini %A Parekh, Dhaval R %A Franklin, Wayne J %A Lewin, Mark %A Towbin, Jeffrey A %A Penny, Daniel J %A Fraser, Charles D %A Martin, James F %A Eng, Christine %A Lupski, James R %A Gibbs, Richard A %A Boerwinkle, Eric %A Belmont, John W %K Exome Sequencing %K Female %K Genetic Heterogeneity %K Heart Defects, Congenital %K Humans %K Inheritance Patterns %K Male %X

BACKGROUND: Left-sided lesions (LSLs) account for an important fraction of severe congenital cardiovascular malformations (CVMs). The genetic contributions to LSLs are complex, and the mutations that cause these malformations span several diverse biological signaling pathways: TGFB, NOTCH, SHH, and more. Here, we use whole exome sequence data generated in 342 LSL cases to identify likely damaging variants in putative candidate CVM genes.

METHODS: Using a series of bioinformatics filters, we focused on genes harboring population-rare, putative loss-of-function (LOF), and predicted damaging variants in 1760 CVM candidate genes constructed a priori from the literature and model organism databases. Gene variants that were not observed in a comparably sequenced control dataset of 5492 samples without severe CVM were then subjected to targeted validation in cases and parents. Whole exome sequencing data from 4593 individuals referred for clinical sequencing were used to bolster evidence for the role of candidate genes in CVMs and LSLs.

RESULTS: Our analyses revealed 28 candidate variants in 27 genes, including 17 genes not previously associated with a human CVM disorder, and revealed diverse patterns of inheritance among LOF carriers, including 9 confirmed de novo variants in both novel and newly described human CVM candidate genes (ACVR1, JARID2, NR2F2, PLRG1, SMURF1) as well as established syndromic CVM genes (KMT2D, NF1, TBX20, ZEB2). We also identified two genes (DNAH5, OFD1) with evidence of recessive and hemizygous inheritance patterns, respectively. Within our clinical cohort, we also observed heterozygous LOF variants in JARID2 and SMAD1 in individuals with cardiac phenotypes, and collectively, carriers of LOF variants in our candidate genes had a four times higher odds of having CVM (odds ratio = 4.0, 95% confidence interval 2.5-6.5).

CONCLUSIONS: Our analytical strategy highlights the utility of bioinformatic resources, including human disease records and model organism phenotyping, in novel gene discovery for rare human disease. The results underscore the extensive genetic heterogeneity underlying non-syndromic LSLs, and posit potential novel candidate genes and complex modes of inheritance in this important group of birth defects.

%B Genome Med %V 9 %P 95 %8 2017 Oct 31 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/29089047?dopt=Abstract %R 10.1186/s13073-017-0482-5 %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 Am J Hum Genet %D 2016 %T Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in Humans. %A Vetrini, Francesco %A D'Alessandro, Lisa C A %A Akdemir, Zeynep C %A Braxton, Alicia %A Azamian, Mahshid S %A Eldomery, Mohammad K %A Miller, Kathryn %A Kois, Chelsea %A Sack, Virginia %A Shur, Natasha %A Rijhsinghani, Asha %A Chandarana, Jignesh %A Ding, Yan %A Holtzman, Judy %A Jhangiani, Shalini N %A Muzny, Donna M %A Gibbs, Richard A %A Eng, Christine M %A Hanchard, Neil A %A Harel, Tamar %A Rosenfeld, Jill A %A Belmont, John W %A Lupski, James R %A Yang, Yaping %K Alleles %K Amino Acid Motifs %K Amino Acid Sequence %K Animals %K Caenorhabditis elegans %K Cysteine %K Exome %K Female %K Fetal Diseases %K Functional Laterality %K Heart Defects, Congenital %K Heterotaxy Syndrome %K Homozygote %K Humans %K Infant, Newborn %K Introns %K Male %K Membrane Proteins %K Mice %K Middle Aged %K Models, Molecular %K Mutation %K Mutation, Missense %K Oryzias %K Pedigree %K RNA Splicing %K Situs Inversus %X

Disruption of the establishment of left-right (L-R) asymmetry leads to situs anomalies ranging from situs inversus totalis (SIT) to situs ambiguus (heterotaxy). The genetic causes of laterality defects in humans are highly heterogeneous. Via whole-exome sequencing (WES), we identified homozygous mutations in PKD1L1 from three affected individuals in two unrelated families. PKD1L1 encodes a polycystin-1-like protein and its loss of function is known to cause laterality defects in mouse and medaka fish models. Family 1 had one fetus and one deceased child with heterotaxy and complex congenital heart malformations. WES identified a homozygous splicing mutation, c.6473+2_6473+3delTG, which disrupts the invariant splice donor site in intron 42, in both affected individuals. In the second family, a homozygous c.5072G>C (p.Cys1691Ser) missense mutation was detected in an individual with SIT and congenital heart disease. The p.Cys1691Ser substitution affects a highly conserved cysteine residue and is predicted by molecular modeling to disrupt a disulfide bridge essential for the proper folding of the G protein-coupled receptor proteolytic site (GPS) motif. Damaging effects associated with substitutions of this conserved cysteine residue in the GPS motif have also been reported in other genes, namely GPR56, BAI3, and PKD1 in human and lat-1 in C. elegans, further supporting the likely pathogenicity of p.Cys1691Ser in PKD1L1. The identification of bi-allelic PKD1L1 mutations recapitulates previous findings regarding phenotypic consequences of loss of function of the orthologous genes in mice and medaka fish and further expands our understanding of genetic contributions to laterality defects in humans.

%B Am J Hum Genet %V 99 %P 886-893 %8 2016 Oct 06 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/27616478?dopt=Abstract %R 10.1016/j.ajhg.2016.07.011 %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 Clin Genet %D 2013 %T Exploring the utility of whole-exome sequencing as a diagnostic tool in a child with atypical episodic muscle weakness. %A Hanchard, Neil A %A David R Murdock %A Magoulas, Pilar L %A Matthew N Bainbridge %A Donna M Muzny %A Wu, Yuanqing %A Wang, Min %A James R Lupski %A Richard A Gibbs %A Brown, Chester W %K Base Sequence %K Calcium Channels %K Child, Preschool %K Exome %K Exons %K Female %K Genotype %K High-Throughput Nucleotide Sequencing %K Humans %K Male %K Muscle Weakness %K Mutation %K NAV1.4 Voltage-Gated Sodium Channel %K Pedigree %K Phenotype %X

The advent of whole-exome next-generation sequencing (WES) has been pivotal for the molecular characterization of Mendelian disease; however, the clinical applicability of WES has remained relatively unexplored. We describe our exploration of WES as a diagnostic tool in a 3½-year old female patient with a 2-year history of episodic muscle weakness and paroxysmal dystonia who presented following a previous extensive but unrevealing diagnostic work-up. WES was performed on the proband and her two parents. Parental exome data was used to filter potential de novo genomic events in the proband and suspected variants were confirmed using di-deoxy sequencing. WES revealed a de novo non-synonymous mutation in exon 21 of the calcium channel gene CACNA1S that has been previously reported in a single patient as a rare cause of atypical hypokalemic periodic paralysis. This was unexpected, as the proband's original differential diagnosis had included hypokalemic periodic paralysis, but clinical and laboratory features were equivocal, and standard clinical molecular testing for hypokalemic periodic paralysis and related disorders was negative. This report highlights the potential diagnostic utility of WES in clinical practice, with implications for the approach to similar diagnostic dilemmas in the future.

%B Clin Genet %V 83 %P 457-461 %8 2013 May %G eng %N 5 %R 10.1111/j.1399-0004.2012.01951.x %0 Journal Article %J Am J Hum Genet %D 2013 %T TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities. %A Wiszniewski, Wojciech %A Hunter, Jill V %A Hanchard, Neil A %A Willer, Jason R %A Shaw, Chad %A Tian, Qi %A Illner, Anna %A Wang, Xueqing %A Cheung, Sau W %A Patel, Ankita %A Campbell, Ian M %A Gelowani, Violet %A Hixson, Patricia %A Ester, Audrey R %A Azamian, Mahshid S %A Potocki, Lorraine %A Zapata, Gladys %A Hernandez, Patricia P %A Ramocki, Melissa B %A Santos-Cortez, Regie L P %A Wang, Gao %A York, Michele K %A Justice, Monica J %A Chu, Zili D %A Bader, Patricia I %A Omo-Griffith, Lisa %A Madduri, Nirupama S %A Scharer, Gunter %A Crawford, Heather P %A Yanatatsaneejit, Pattamawadee %A Eifert, Anna %A Kerr, Jeffery %A Bacino, Carlos A %A Franklin, Adiaha I A %A Goin-Kochel, Robin P %A Simpson, Gayle %A Immken, Ladonna %A Haque, Muhammad E %A Stosic, Marija %A Williams, Misti D %A Morgan, Thomas M %A Pruthi, Sumit %A Omary, Reed %A Boyadjiev, Simeon A %A Win, Kay K %A Thida, Aye %A Hurles, Matthew %A Hibberd, Martin Lloyd %A Khor, Chiea Chuen %A Van Vinh Chau, Nguyen %A Gallagher, Thomas E %A Mutirangura, Apiwat %A Stankiewicz, Pawel %A Beaudet, Arthur L %A Maletic-Savatic, Mirjana %A Rosenfeld, Jill A %A Shaffer, Lisa G %A Davis, Erica E %A Belmont, John W %A Dunstan, Sarah %A Simmons, Cameron P %A Bonnen, Penelope E %A Leal, Suzanne M %A Katsanis, Nicholas %A Lupski, James R %A Lalani, Seema R %K Age of Onset %K Aging, Premature %K Asian People %K Base Sequence %K Brain %K Child %K Child, Preschool %K Chromosomes, Human, Pair 2 %K Exons %K Female %K Genetic Predisposition to Disease %K Humans %K Language Development Disorders %K Leukoencephalopathies %K Magnetic Resonance Imaging %K Male %K Molecular Sequence Data %K Pedigree %K Sequence Analysis, DNA %K Sequence Deletion %K Tetraspanins %X

White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ~70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.

%B Am J Hum Genet %V 93 %P 197-210 %8 2013 Aug 08 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/23810381?dopt=Abstract %R 10.1016/j.ajhg.2013.05.027