@article {782, title = {CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 10}, pages = {1633-1641}, abstract = {

PURPOSE: Improved resolution of molecular diagnostic technologies enabled detection of smaller sized exonic level copy-number variants (CNVs). The contribution of CNVs to autosomal recessive (AR) conditions may be better recognized using a large clinical cohort.

METHODS: We retrospectively investigated the CNVs{\textquoteright} contribution to AR conditions in cases subjected to chromosomal microarray analysis (CMA, N = ~70,000) and/or clinical exome sequencing (ES, N = ~12,000) at Baylor Genetics; most had pediatric onset neurodevelopmental disorders.

RESULTS: CNVs contributed to biallelic variations in 87 cases, including 81 singletons and three affected sibling pairs. Seventy cases had CNVs affecting both alleles, and 17 had a CNV and a single-nucleotide variant (SNV)/indel in trans. In total, 94.3\% of AR-CNVs affected one gene; among these 41.4\% were single-exon and 35.0\% were multiexon partial-gene events. Sixty-nine percent of homozygous AR-CNVs were embedded in homozygous genomic intervals. Five cases had large deletions unmasking an SNV/indel on the intact allele for a recessive condition, resulting in multiple molecular diagnoses.

CONCLUSIONS: AR-CNVs are often smaller in size, transmitted through generations, and underrecognized due to limitations in clinical CNV detection methods. Our findings from a large clinical cohort emphasized integrated CNV and SNV/indel analyses for precise clinical and molecular diagnosis especially in the context of genomic disorders.

}, keywords = {Child, DNA Copy Number Variations, Exons, Humans, INDEL Mutation, Retrospective Studies, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-020-0864-8}, author = {Yuan, Bo and Wang, Lei and Liu, Pengfei and Shaw, Chad and Dai, Hongzheng and Cooper, Lance and Zhu, Wenmiao and Anderson, Stephanie A and Meng, Linyan and Wang, Xia and Wang, Yue and Xia, Fan and Xiao, Rui and Braxton, Alicia and Peacock, Sandra and Schmitt, Eric and Ward, Patricia A and Vetrini, Francesco and He, Weimin and Chiang, Theodore and Muzny, Donna and Gibbs, Richard A and Beaudet, Arthur L and Breman, Amy M and Smith, Janice and Cheung, Sau Wai and Bacino, Carlos A and Eng, Christine M and Yang, Yaping and Lupski, James R and Bi, Weimin} } @article {691, title = {Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle-opathies with Microcephaly, Dwarfism and Skeletal Abnormalities.}, journal = {Am J Med Genet A}, volume = {179}, year = {2019}, month = {2019 Oct}, pages = {2056-2066}, abstract = {

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

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61315}, author = {Karaca, Ender and Posey, Jennifer E and Bostwick, Bret and Liu, Pengfei and Gezdirici, Alper and Yesil, G{\"o}zde and Coban Akdemir, Zeynep and Bayram, Yavuz and Harms, Frederike L and Meinecke, Peter and Alawi, Malik and Bacino, Carlos A and Sutton, V Reid and Kort{\"u}m, Fanny and Lupski, James R} } @article {593, title = {Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 03 07}, pages = {422-438}, abstract = {

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive~inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.01.007}, author = {Burrage, Lindsay C and Reynolds, John J and Baratang, Nissan Vida and Phillips, Jennifer B and Wegner, Jeremy and McFarquhar, Ashley and Higgs, Martin R and Christiansen, Audrey E and Lanza, Denise G and Seavitt, John R and Jain, Mahim and Li, Xiaohui and Parry, David A and Raman, Vandana and Chitayat, David and Chinn, Ivan K and Bertuch, Alison A and Karaviti, Lefkothea and Schlesinger, Alan E and Earl, Dawn and Bamshad, Michael and Savarirayan, Ravi and Doddapaneni, Harsha and Muzny, Donna and Jhangiani, Shalini N and Eng, Christine M and Gibbs, Richard A and Bi, Weimin and Emrick, Lisa and Rosenfeld, Jill A and Postlethwait, John and Westerfield, Monte and Dickinson, Mary E and Beaudet, Arthur L and Ranza, Emmanuelle and Huber, Celine and Cormier-Daire, Val{\'e}rie and Shen, Wei and Mao, Rong and Heaney, Jason D and Orange, Jordan S and Bertola, D{\'e}bora and Yamamoto, Guilherme L and Baratela, Wagner A R and Butler, Merlin G and Ali, Asim and Adeli, Mehdi and Cohn, Daniel H and Krakow, Deborah and Jackson, Andrew P and Lees, Melissa and Offiah, Amaka C and Carlston, Colleen M and Carey, John C and Stewart, Grant S and Bacino, Carlos A and Campeau, Philippe M and Lee, Brendan} } @article {663, title = {Copy number variant and runs of homozygosity detection by microarrays enabled more precise molecular diagnoses in 11,020 clinical exome cases.}, journal = {Genome Med}, volume = {11}, year = {2019}, month = {2019 05 17}, pages = {30}, abstract = {

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.

}, issn = {1756-994X}, doi = {10.1186/s13073-019-0639-5}, author = {Dharmadhikari, Avinash V and Ghosh, Rajarshi and Yuan, Bo and Liu, Pengfei and Dai, Hongzheng and Al Masri, Sami and Scull, Jennifer and Posey, Jennifer E and Jiang, Allen H and He, Weimin and Vetrini, Francesco and Braxton, Alicia A and Ward, Patricia and Chiang, Theodore and Qu, Chunjing and Gu, Shen and Shaw, Chad A and Smith, Janice L and Lalani, Seema and Stankiewicz, Pawel and Cheung, Sau-Wai and Bacino, Carlos A and Patel, Ankita and Breman, Amy M and Wang, Xia and Meng, Linyan and Xiao, Rui and Xia, Fan and Muzny, Donna and Gibbs, Richard A and Beaudet, Arthur L and Eng, Christine M and Lupski, James R and Yang, Yaping and Bi, Weimin} } @article {577, title = {ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 02 07}, pages = {319-330}, abstract = {

ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de~novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In~vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In~vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.

}, keywords = {Alleles, Animals, Child, Child, Preschool, Developmental Disabilities, Female, Humans, Infant, Intellectual Disability, Male, Mice, Point Mutation, Syndrome, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.12.007}, author = {Carapito, Raphael and Ivanova, Ekaterina L and Morlon, Aurore and Meng, Linyan and Molitor, Anne and Erdmann, Eva and Kieffer, Bruno and Pichot, Ang{\'e}lique and Naegely, Lydie and Kolmer, Aline and Paul, Nicod{\`e}me and Hanauer, Antoine and Tran Mau-Them, Fr{\'e}d{\'e}ric and Jean-Mar{\c c}ais, Nolwenn and Hiatt, Susan M and Cooper, Gregory M and Tvrdik, Tatiana and Muir, Alison M and Dimartino, Cl{\'e}mantine and Chopra, Maya and Amiel, Jeanne and Gordon, Christopher T and Dutreux, Fabien and Garde, Aurore and Thauvin-Robinet, Christel and Wang, Xia and Leduc, Magalie S and Phillips, Meredith and Crawford, Heather P and Kukolich, Mary K and Hunt, David and Harrison, Victoria and Kharbanda, Mira and Smigiel, Robert and Gold, Nina and Hung, Christina Y and Viskochil, David H and Dugan, Sarah L and Bayrak-Toydemir, Pinar and Joly-Helas, G{\'e}raldine and Guerrot, Anne-Marie and Schluth-Bolard, Caroline and Rio, Marl{\`e}ne and Wentzensen, Ingrid M and McWalter, Kirsty and Schnur, Rhonda E and Lewis, Andrea M and Lalani, Seema R and Mensah-Bonsu, No{\"e}l and C{\'e}raline, Jocelyn and Sun, Zijie and Ploski, Rafal and Bacino, Carlos A and Mefford, Heather C and Faivre, Laurence and Bodamer, Olaf and Chelly, Jamel and Isidor, Bertrand and Bahram, Seiamak} } @article {506, title = {Phenotypic expansion in - a common cause of intellectual disability in females.}, journal = {Ann Clin Transl Neurol}, volume = {5}, year = {2018}, month = {2018 Oct}, pages = {1277-1285}, abstract = {

De variants in account for 1-3\% of unexplained intellectual disability (ID) cases and are amongst the most common causes of ID especially in females. Forty-seven patients (44 females, 3 males) have been described. We identified 31 additional individuals carrying 29 unique variants, including 30 postnatal individuals with complex clinical presentations of developmental delay or ID, and one fetus with abnormal ultrasound findings. Rare or novel phenotypes observed include respiratory problems, congenital heart disease, skeletal muscle mitochondrial DNA depletion, and late-onset neurologic decline. Our findings expand the spectrum of DNA variants and phenotypes associated with disorders.

}, issn = {2328-9503}, doi = {10.1002/acn3.622}, author = {Wang, Xia and Posey, Jennifer E and Rosenfeld, Jill A and Bacino, Carlos A and Scaglia, Fernando and Immken, LaDonna and Harris, Jill M and Hickey, Scott E and Mosher, Theresa M and Slavotinek, Anne and Zhang, Jing and Beuten, Joke and Leduc, Magalie S and He, Weimin and Vetrini, Francesco and Walkiewicz, Magdalena A and Bi, Weimin and Xiao, Rui and Liu, Pengfei and Shao, Yunru and Gezdirici, Alper and Gulec, Elif Y and Jiang, Yunyun and Darilek, Sandra A and Hansen, Adam W and Khayat, Michael M and Pehlivan, Davut and Piard, Juliette and Muzny, Donna M and Hanchard, Neil and Belmont, John W and Van Maldergem, Lionel and Gibbs, Richard A and Eldomery, Mohammad K and Akdemir, Zeynep C and Adesina, Adekunle M and Chen, Shan and Lee, Yi-Chien and Lee, Brendan and Lupski, James R and Eng, Christine M and Xia, Fan and Yang, Yaping and Graham, Brett H and Moretti, Paolo} } @article {637, title = {Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.}, journal = {PLoS Genet}, volume = {13}, year = {2017}, month = {2017 Jul}, pages = {e1006905}, abstract = {

Dominant mutations in CACNA1A, encoding the α-1A subunit of the neuronal P/Q type voltage-dependent Ca2+ channel, can cause diverse neurological phenotypes. Rare cases of markedly severe early onset developmental delay and congenital ataxia can be due to de novo CACNA1A missense alleles, with variants affecting the S4 transmembrane segments of the channel, some of which are reported to be loss-of-function. Exome sequencing in five individuals with severe early onset ataxia identified one novel variant (p.R1673P), in a girl with global developmental delay and progressive cerebellar atrophy, and a recurrent, de novo p.R1664Q variant, in four individuals with global developmental delay, hypotonia, and ophthalmologic abnormalities. Given the severity of these phenotypes we explored their functional impact in Drosophila. We previously generated null and partial loss-of-function alleles of cac, the homolog of CACNA1A in Drosophila. Here, we created transgenic wild type and mutant genomic rescue constructs with the two noted conserved point mutations. The p.R1673P mutant failed to rescue cac lethality, displayed a gain-of-function phenotype in electroretinograms (ERG) recorded from mutant clones, and evolved a neurodegenerative phenotype in aging flies, based on ERGs and transmission electron microscopy. In contrast, the p.R1664Q variant exhibited loss of function and failed to develop a neurodegenerative phenotype. Hence, the novel R1673P allele produces neurodegenerative phenotypes in flies and human, likely due to a toxic gain of function.

}, keywords = {Alleles, Animals, Animals, Genetically Modified, Calcium Channels, Cerebellar Ataxia, Child, Child, Preschool, Drosophila melanogaster, Female, Genome, Human, Genome-Wide Association Study, Humans, Male, Microscopy, Electron, Transmission, Mutation, Missense, Neurodegenerative Diseases, Neuroimaging, Phenotype, Point Mutation}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006905}, author = {Luo, Xi and Rosenfeld, Jill A and Yamamoto, Shinya and Harel, Tamar and Zuo, Zhongyuan and Hall, Melissa and Wierenga, Klaas J and Pastore, Matthew T and Bartholomew, Dennis and Delgado, Mauricio R and Rotenberg, Joshua and Lewis, Richard Alan and Emrick, Lisa and Bacino, Carlos A and Eldomery, Mohammad K and Coban Akdemir, Zeynep and Xia, Fan and Yang, Yaping and Lalani, Seema R and Lotze, Timothy and Lupski, James R and Lee, Brendan and Bellen, Hugo J and Wangler, Michael F} } @article {335, title = {De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Feb 02}, pages = {352-363}, abstract = {

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.

}, keywords = {Adolescent, Animals, Child, Child, Preschool, Disease Models, Animal, DNA Copy Number Variations, Down-Regulation, Female, Gene Deletion, Humans, Infant, Intellectual Disability, Male, Microcephaly, Neurodevelopmental Disorders, Polymorphism, Single Nucleotide, Proteasome Endopeptidase Complex, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.01.003}, author = {K{\"u}ry, S{\'e}bastien and Besnard, Thomas and Ebstein, Fr{\'e}d{\'e}ric and Khan, Tahir N and Gambin, Tomasz and Douglas, Jessica and Bacino, Carlos A and Craigen, William J and Sanders, Stephan J and Lehmann, Andrea and Latypova, X{\'e}nia and Khan, Kamal and Pacault, Mathilde and Sacharow, Stephanie and Glaser, Kimberly and Bieth, Eric and Perrin-Sabourin, Laurence and Jacquemont, Marie-Line and Cho, Megan T and Roeder, Elizabeth and Denomm{\'e}-Pichon, Anne-Sophie and Monaghan, Kristin G and Yuan, Bo and Xia, Fan and Simon, Sylvain and Bonneau, Dominique and Parent, Philippe and Gilbert-Dussardier, Brigitte and Odent, Sylvie and Toutain, Annick and Pasquier, Laurent and Barbouth, Deborah and Shaw, Chad A and Patel, Ankita and Smith, Janice L and Bi, Weimin and Schmitt, S{\'e}bastien and Deb, Wallid and Nizon, Mathilde and Mercier, Sandra and Vincent, Marie and Rooryck, Caroline and Malan, Val{\'e}rie and Brice{\~n}o, Ignacio and G{\'o}mez, Alberto and Nugent, Kimberly M and Gibson, James B and Cogn{\'e}, Benjamin and Lupski, James R and Stessman, Holly A F and Eichler, Evan E and Retterer, Kyle and Yang, Yaping and Redon, Richard and Katsanis, Nicholas and Rosenfeld, Jill A and Kloetzel, Peter-Michael and Golzio, Christelle and B{\'e}zieau, St{\'e}phane and Stankiewicz, Pawe{\l} and Isidor, Bertrand} } @article {453, title = {High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {664-685}, abstract = {

Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32\%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.

}, keywords = {Brain Diseases, Child, Child, Preschool, Epilepsy, Female, Genome, Human, Genome-Wide Association Study, Humans, Intellectual Disability, Male, Mutation, Recurrence, Seizures}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.008}, author = {Hamdan, Fadi F and Myers, Candace T and Cossette, Patrick and Lemay, Philippe and Spiegelman, Dan and Laporte, Alexandre Dionne and Nassif, Christina and Diallo, Ousmane and Monlong, Jean and Cadieux-Dion, Maxime and Dobrzeniecka, Sylvia and Meloche, Caroline and Retterer, Kyle and Cho, Megan T and Rosenfeld, Jill A and Bi, Weimin and Massicotte, Christine and Miguet, Marguerite and Brunga, Ledia and Regan, Brigid M and Mo, Kelly and Tam, Cory and Schneider, Amy and Hollingsworth, Georgie and FitzPatrick, David R and Donaldson, Alan and Canham, Natalie and Blair, Edward and Kerr, Bronwyn and Fry, Andrew E and Thomas, Rhys H and Shelagh, Joss and Hurst, Jane A and Brittain, Helen and Blyth, Moira and Lebel, Robert Roger and Gerkes, Erica H and Davis-Keppen, Laura and Stein, Quinn and Chung, Wendy K and Dorison, Sara J and Benke, Paul J and Fassi, Emily and Corsten-Janssen, Nicole and Kamsteeg, Erik-Jan and Mau-Them, Frederic T and Bruel, Ange-Line and Verloes, Alain and {\~O}unap, Katrin and Wojcik, Monica H and Albert, Dara V F and Venkateswaran, Sunita and Ware, Tyson and Jones, Dean and Liu, Yu-Chi and Mohammad, Shekeeb S and Bizargity, Peyman and Bacino, Carlos A and Leuzzi, Vincenzo and Martinelli, Simone and Dallapiccola, Bruno and Tartaglia, Marco and Blumkin, Lubov and Wierenga, Klaas J and Purcarin, Gabriela and O{\textquoteright}Byrne, James J and Stockler, Sylvia and Lehman, Anna and Keren, Boris and Nougues, Marie-Christine and Mignot, Cyril and Auvin, St{\'e}phane and Nava, Caroline and Hiatt, Susan M and Bebin, Martina and Shao, Yunru and Scaglia, Fernando and Lalani, Seema R and Frye, Richard E and Jarjour, Imad T and Jacques, St{\'e}phanie and Boucher, Renee-Myriam and Riou, Emilie and Srour, Myriam and Carmant, Lionel and Lortie, Anne and Major, Philippe and Diadori, Paola and Dubeau, Fran{\c c}ois and D{\textquoteright}Anjou, Guy and Bourque, Guillaume and Berkovic, Samuel F and Sadleir, Lynette G and Campeau, Philippe M and Kibar, Zoha and Lafreni{\`e}re, Ronald G and Girard, Simon L and Mercimek-Mahmutoglu, Saadet and Boelman, Cyrus and Rouleau, Guy A and Scheffer, Ingrid E and Mefford, Heather C and Andrade, Danielle M and Rossignol, Elsa and Minassian, Berge A and Michaud, Jacques L} } @article {376, title = {Identification of novel candidate disease genes from de novo exonic copy number variants.}, journal = {Genome Med}, volume = {9}, year = {2017}, month = {2017 09 21}, pages = {83}, abstract = {

BACKGROUND: Exon-targeted microarrays can detect small (<1000~bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery.

METHODS: We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association.

RESULTS: In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11\%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224~bp to 1.6~Mb in size) were compared to those in individuals with larger-sized deletions (up to 5~Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses.

CONCLUSIONS: Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.

}, keywords = {Cohort Studies, DNA Copy Number Variations, Exons, Genetic Diseases, Inborn, Genome, Human, Homeodomain Proteins, Humans, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Neurodevelopmental Disorders, Protein-Serine-Threonine Kinases, Retrospective Studies, Transcription Factors, Whole Genome Sequencing}, issn = {1756-994X}, doi = {10.1186/s13073-017-0472-7}, author = {Gambin, Tomasz and Yuan, Bo and Bi, Weimin and Liu, Pengfei and Rosenfeld, Jill A and Coban-Akdemir, Zeynep and Pursley, Amber N and Nagamani, Sandesh C S and Marom, Ronit and Golla, Sailaja and Dengle, Lauren and Petrie, Heather G and Matalon, Reuben and Emrick, Lisa and Proud, Monica B and Treadwell-Deering, Diane and Chao, Hsiao-Tuan and Koillinen, Hannele and Brown, Chester and Urraca, Nora and Mostafavi, Roya and Bernes, Saunder and Roeder, Elizabeth R and Nugent, Kimberly M and Bader, Patricia I and Bellus, Gary and Cummings, Michael and Northrup, Hope and Ashfaq, Myla and Westman, Rachel and Wildin, Robert and Beck, Anita E and Immken, LaDonna and Elton, Lindsay and Varghese, Shaun and Buchanan, Edward and Faivre, Laurence and Lefebvre, Mathilde and Schaaf, Christian P and Walkiewicz, Magdalena and Yang, Yaping and Kang, Sung-Hae L and Lalani, Seema R and Bacino, Carlos A and Beaudet, Arthur L and Breman, Amy M and Smith, Janice L and Cheung, Sau Wai and Lupski, James R and Patel, Ankita and Shaw, Chad A and Stankiewicz, Pawe{\l}} } @article {357, title = {Lessons learned from additional research analyses of unsolved clinical exome cases.}, journal = {Genome Med}, volume = {9}, year = {2017}, month = {2017 03 21}, pages = {26}, abstract = {

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.

}, keywords = {Adenosine Triphosphatases, ATPases Associated with Diverse Cellular Activities, Computational Biology, DNA Copy Number Variations, DNA-Binding Proteins, Exome, Female, Genetic Diseases, Inborn, Genomics, GTP-Binding Protein beta Subunits, Humans, Male, Membrane Proteins, Metalloendopeptidases, Mitochondrial Proteins, Pilot Projects, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Transcription Factors}, issn = {1756-994X}, doi = {10.1186/s13073-017-0412-6}, author = {Eldomery, Mohammad K and Coban-Akdemir, Zeynep and Harel, Tamar and Rosenfeld, Jill A and Gambin, Tomasz and Stray-Pedersen, Asbj{\o}rg and K{\"u}ry, S{\'e}bastien and Mercier, Sandra and Lessel, Davor and Denecke, Jonas and Wiszniewski, Wojciech and Penney, Samantha and Liu, Pengfei and Bi, Weimin and Lalani, Seema R and Schaaf, Christian P and Wangler, Michael F and Bacino, Carlos A and Lewis, Richard Alan and Potocki, Lorraine and Graham, Brett H and Belmont, John W and Scaglia, Fernando and Orange, Jordan S and Jhangiani, Shalini N and Chiang, Theodore and Doddapaneni, Harsha and Hu, Jianhong and Muzny, Donna M and Xia, Fan and Beaudet, Arthur L and Boerwinkle, Eric and Eng, Christine M and Plon, Sharon E and Sutton, V Reid and Gibbs, Richard A and Posey, Jennifer E and Yang, Yaping and Lupski, James R} } @article {348, title = {An Organismal CNV Mutator Phenotype Restricted to Early Human Development.}, journal = {Cell}, volume = {168}, year = {2017}, month = {2017 02 23}, pages = {830-842.e7}, abstract = {

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

}, keywords = {Chromosome Aberrations, Chromosome Breakpoints, Chromosome Duplication, DNA Copy Number Variations, DNA Replication, Embryonic Development, Female, Gametogenesis, Genetic Diseases, Inborn, Genomic Instability, Humans, Male, Mutation}, issn = {1097-4172}, doi = {10.1016/j.cell.2017.01.037}, author = {Liu, Pengfei and Yuan, Bo and Carvalho, Claudia M B and Wuster, Arthur and Walter, Klaudia and Zhang, Ling and Gambin, Tomasz and Chong, Zechen and Campbell, Ian M and Coban Akdemir, Zeynep and Gelowani, Violet and Writzl, Karin and Bacino, Carlos A and Lindsay, Sarah J and Withers, Marjorie and Gonzaga-Jauregui, Claudia and Wiszniewska, Joanna and Scull, Jennifer and Stankiewicz, Pawe{\l} and Jhangiani, Shalini N and Muzny, Donna M and Zhang, Feng and Chen, Ken and Gibbs, Richard A and Rautenstrauss, Bernd and Cheung, Sau Wai and Smith, Janice and Breman, Amy and Shaw, Chad A and Patel, Ankita and Hurles, Matthew E and Lupski, James R} } @article {540, title = {Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management.}, journal = {JAMA Pediatr}, volume = {171}, year = {2017}, month = {2017 12 04}, pages = {e173438}, abstract = {

Importance: While congenital malformations and genetic diseases are a leading cause of early infant death, to our knowledge, the contribution of single-gene disorders in this group is undetermined.

Objective: To determine the diagnostic yield and use of clinical exome sequencing in critically ill infants.

Design, Setting, and Participants: Clinical exome sequencing was performed for 278 unrelated infants within the first 100 days of life who were admitted to Texas Children{\textquoteright}s Hospital in Houston, Texas, during a 5-year period between December 2011 and January 2017. Exome sequencing types included proband exome, trio exome, and critical trio exome, a rapid genomic assay for seriously ill infants.

Main Outcomes and Measures: Indications for testing, diagnostic yield of clinical exome sequencing, turnaround time, molecular findings, patient age at diagnosis, and effect on medical management among a group of critically ill infants who were suspected to have genetic disorders.

Results: The mean (SEM) age for infants participating in the study was 28.5 (1.7) days; of these, the mean (SEM) age was 29.0 (2.2) days for infants undergoing proband exome sequencing, 31.5 (3.9) days for trio exome, and 22.7 (3.9) days for critical trio exome. Clinical indications for exome sequencing included a range of medical concerns. Overall, a molecular diagnosis was achieved in 102 infants (36.7\%) by clinical exome sequencing, with relatively low yield for cardiovascular abnormalities. The diagnosis affected medical management for 53 infants (52.0\%) and had a substantial effect on informed redirection of care, initiation of new subspecialist care, medication/dietary modifications, and furthering life-saving procedures in select patients. Critical trio exome sequencing revealed a molecular diagnosis in 32 of 63 infants (50.8\%) at a mean (SEM) of 33.1 (5.6) days of life with a mean (SEM) turnaround time of 13.0 (0.4) days. Clinical care was altered by the diagnosis in 23 of 32 patients (71.9\%). The diagnostic yield, patient age at diagnosis, and medical effect in the group that underwent critical trio exome sequencing were significantly different compared with the group who underwent regular exome testing. For deceased infants (n = 81), genetic disorders were molecularly diagnosed in 39 (48.1\%) by exome sequencing, with implications for recurrence risk counseling.

Conclusions and Relevance: Exome sequencing is a powerful tool for the diagnostic evaluation of critically ill infants with suspected monogenic disorders in the neonatal and pediatric intensive care units and its use has a notable effect on clinical decision making.

}, keywords = {Adult, Critical Care, Disease Management, Exome, Genetic Counseling, Genetic Diseases, Inborn, Humans, Infant, Infant Care, Infant, Newborn, Intensive Care Units, Pediatric, Length of Stay, Retrospective Studies, Texas, Whole Exome Sequencing}, issn = {2168-6211}, doi = {10.1001/jamapediatrics.2017.3438}, author = {Meng, Linyan and Pammi, Mohan and Saronwala, Anirudh and Magoulas, Pilar and Ghazi, Andrew Ray and Vetrini, Francesco and Zhang, Jing and He, Weimin and Dharmadhikari, Avinash V and Qu, Chunjing and Ward, Patricia and Braxton, Alicia and Narayanan, Swetha and Ge, Xiaoyan and Tokita, Mari J and Santiago-Sim, Teresa and Dai, Hongzheng and Chiang, Theodore and Smith, Hadley and Azamian, Mahshid S and Robak, Laurie and Bostwick, Bret L and Schaaf, Christian P and Potocki, Lorraine and Scaglia, Fernando and Bacino, Carlos A and Hanchard, Neil A and Wangler, Michael F and Scott, Daryl and Brown, Chester and Hu, Jianhong and Belmont, John W and Burrage, Lindsay C and Graham, Brett H and Sutton, Vernon Reid and Craigen, William J and Plon, Sharon E and Lupski, James R and Beaudet, Arthur L and Gibbs, Richard A and Muzny, Donna M and Miller, Marcus J and Wang, Xia and Leduc, Magalie S and Xiao, Rui and Liu, Pengfei and Shaw, Chad and Walkiewicz, Magdalena and Bi, Weimin and Xia, Fan and Lee, Brendan and Eng, Christine M and Yang, Yaping and Lalani, Seema R} } @article {67, title = {Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.}, journal = {Hum Genet}, volume = {135}, year = {2016}, month = {2016 May}, pages = {569-586}, abstract = {

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.

}, keywords = {Chromosomes, Human, Pair 16, Comparative Genomic Hybridization, Female, Forkhead Transcription Factors, Genes, Lethal, Genome, Human, Genomic Imprinting, High-Throughput Nucleotide Sequencing, Humans, Infant, Newborn, Male, Pedigree, Persistent Fetal Circulation Syndrome, Pulmonary Alveoli, Pulmonary Veins, Sequence Deletion}, issn = {1432-1203}, doi = {10.1007/s00439-016-1655-9}, author = {Szafranski, Przemyslaw and Gambin, Tomasz and Dharmadhikari, Avinash V and Akdemir, Kadir Caner and Jhangiani, Shalini N and Schuette, Jennifer and Godiwala, Nihal and Yatsenko, Svetlana A and Sebastian, Jessica and Madan-Khetarpal, Suneeta and Surti, Urvashi and Abellar, Rosanna G and Bateman, David A and Wilson, Ashley L and Markham, Melinda H and Slamon, Jill and Santos-Simarro, Fernando and Palomares, Mar{\'\i}a and Nevado, Juli{\'a}n and Lapunzina, Pablo and Chung, Brian Hon-Yin and Wong, Wai-Lap and Chu, Yoyo Wing Yiu and Mok, Gary Tsz Kin and Kerem, Eitan and Reiter, Joel and Ambalavanan, Namasivayam and Anderson, Scott A and Kelly, David R and Shieh, Joseph and Rosenthal, Taryn C and Scheible, Kristin and Steiner, Laurie and Iqbal, M Anwar and McKinnon, Margaret L and Hamilton, Sara Jane and Schlade-Bartusiak, Kamilla and English, Dawn and Hendson, Glenda and Roeder, Elizabeth R and DeNapoli, Thomas S and Littlejohn, Rebecca Okashah and Wolff, Daynna J and Wagner, Carol L and Yeung, Alison and Francis, David and Fiorino, Elizabeth K and Edelman, Morris and Fox, Joyce and Hayes, Denise A and Janssens, Sandra and De Baere, Elfride and Menten, Bj{\"o}rn and Loccufier, Anne and Vanwalleghem, Lieve and Moerman, Philippe and Sznajer, Yves and Lay, Amy S and Kussmann, Jennifer L and Chawla, Jasneek and Payton, Diane J and Phillips, Gael E and Brosens, Erwin and Tibboel, Dick and de Klein, Annelies and Maystadt, Isabelle and Fisher, Richard and Sebire, Neil and Male, Alison and Chopra, Maya and Pinner, Jason and Malcolm, Girvan and Peters, Gregory and Arbuckle, Susan and Lees, Melissa and Mead, Zoe and Quarrell, Oliver and Sayers, Richard and Owens, Martina and Shaw-Smith, Charles and Lioy, Janet and McKay, Eileen and de Leeuw, Nicole and Feenstra, Ilse and Spruijt, Liesbeth and Elmslie, Frances and Thiruchelvam, Timothy and Bacino, Carlos A and Langston, Claire and Lupski, James R and Sen, Partha and Popek, Edwina and Stankiewicz, Pawe{\l}} } @article {90, title = {Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Feb 04}, pages = {347-57}, abstract = {

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.

}, keywords = {Alleles, Arabs, Arrhythmias, Cardiac, Base Sequence, Child, Child, Preschool, Endoplasmic Reticulum Stress, European Continental Ancestry Group, Exome, Exons, Female, Gene Deletion, Golgi Apparatus, Hispanic Americans, Homozygote, Humans, Infant, Male, Molecular Sequence Data, Muscle Weakness, Pedigree, Rhabdomyolysis}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.12.008}, author = {Lalani, Seema R and Liu, Pengfei and Rosenfeld, Jill A and Watkin, Levi B and Chiang, Theodore and Leduc, Magalie S and Zhu, Wenmiao and Ding, Yan and Pan, Shujuan and Vetrini, Francesco and Miyake, Christina Y and Shinawi, Marwan and Gambin, Tomasz and Eldomery, Mohammad K and Akdemir, Zeynep Hande Coban and Emrick, Lisa and Wilnai, Yael and Schelley, Susan and Koenig, Mary Kay and Memon, Nada and Farach, Laura S and Coe, Bradley P and Azamian, Mahshid and Hernandez, Patricia and Zapata, Gladys and Jhangiani, Shalini N and Muzny, Donna M and Lotze, Timothy and Clark, Gary and Wilfong, Angus and Northrup, Hope and Adesina, Adekunle and Bacino, Carlos A and Scaglia, Fernando and Bonnen, Penelope E and Crosson, Jane and Duis, Jessica and Maegawa, Gustavo H B and Coman, David and Inwood, Anita and McGill, Jim and Boerwinkle, Eric and Graham, Brett and Beaudet, Art and Eng, Christine M and Hanchard, Neil A and Xia, Fan and Orange, Jordan S and Gibbs, Richard A and Lupski, James R and Yang, Yaping} } @article {170, title = {Alu-mediated diverse and complex pathogenic copy-number variants within human chromosome 17 at p13.3.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Jul 15}, pages = {4061-77}, abstract = {

Alu repetitive elements are known to be major contributors to genome instability by generating Alu-mediated copy-number variants (CNVs). Most of the reported Alu-mediated CNVs are simple deletions and duplications, and the mechanism underlying Alu-Alu-mediated rearrangement has been attributed to non-allelic homologous recombination (NAHR). Chromosome 17 at the p13.3 genomic region lacks extensive low-copy repeat architecture; however, it is highly enriched for Alu repetitive elements, with a fraction of 30\% of total sequence annotated in the human reference genome, compared with the 10\% genome-wide and 18\% on chromosome 17. We conducted mechanistic studies of the 17p13.3 CNVs by performing high-density oligonucleotide array comparative genomic hybridization, specifically interrogating the 17p13.3 region with \~{}150 bp per probe density; CNV breakpoint junctions were mapped to nucleotide resolution by polymerase chain reaction and Sanger sequencing. Studied rearrangements include 5 interstitial deletions, 14 tandem duplications, 7 terminal deletions and 13 complex genomic rearrangements (CGRs). Within the 17p13.3 region, Alu-Alu-mediated rearrangements were identified in 80\% of the interstitial deletions, 46\% of the tandem duplications and 50\% of the CGRs, indicating that this mechanism was a major contributor for formation of breakpoint junctions. Our studies suggest that Alu repetitive elements facilitate formation of non-recurrent CNVs, CGRs and other structural aberrations of chromosome 17 at p13.3. The common observation of Alu-mediated rearrangement in CGRs and breakpoint junction sequences analysis further demonstrates that this type of mechanism is unlikely attributed to NAHR, but rather may be due to a recombination-coupled DNA replicative repair process.

}, keywords = {Alleles, Alu Elements, Base Sequence, Chromosomes, Human, Pair 17, Comparative Genomic Hybridization, DNA Copy Number Variations, Female, Gene Duplication, Gene Rearrangement, Genome, Human, Genomic Instability, Genomics, Homologous Recombination, Humans, Male, Molecular Sequence Data, Segmental Duplications, Genomic, Sequence Deletion}, issn = {1460-2083}, doi = {10.1093/hmg/ddv146}, author = {Gu, Shen and Yuan, Bo and Campbell, Ian M and Beck, Christine R and Carvalho, Claudia M B and Nagamani, Sandesh C S and Erez, Ayelet and Patel, Ankita and Bacino, Carlos A and Shaw, Chad A and Stankiewicz, Pawe{\l} and Cheung, Sau Wai and Bi, Weimin and Lupski, James R} } @article {164, title = {Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3.}, journal = {Am J Hum Genet}, volume = {96}, year = {2015}, month = {2015 May 07}, pages = {841-9}, abstract = {

Multiple pterygium syndrome (MPS) is a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis, and congenital contractures of the limbs. MPS typically segregates as an autosomal-recessive disorder, but rare instances of autosomal-dominant transmission have been reported. Whereas several mutations causing recessive MPS have been identified, the genetic basis of dominant MPS remains unknown. We identified four families affected by dominantly transmitted MPS characterized by pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis. Exome sequencing identified predicted protein-altering mutations in embryonic myosin heavy chain (MYH3) in three families. MYH3 mutations underlie distal arthrogryposis types 1, 2A, and 2B, but all mutations reported to date occur in the head and neck domains. In contrast, two of the mutations found to cause MPS in this study occurred in the tail domain. The phenotypic overlap among persons with MPS, coupled with physical findings distinct from other conditions caused by mutations in MYH3, suggests that the developmental mechanism underlying MPS differs from that of other conditions and/or that certain functions of embryonic myosin might be perturbed by disruption of specific residues and/or domains. Moreover, the vertebral fusions in persons with MPS, coupled with evidence of MYH3 expression in bone, suggest that embryonic myosin plays a role in skeletal development.

}, keywords = {Arthrogryposis, Cytoskeletal Proteins, Exome, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Mutation, Myosins, Osteogenesis}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.04.004}, author = {Chong, Jessica X and Burrage, Lindsay C and Beck, Anita E and Marvin, Colby T and McMillin, Margaret J and Shively, Kathryn M and Harrell, Tanya M and Buckingham, Kati J and Bacino, Carlos A and Jain, Mahim and Alanay, Yasemin and Berry, Susan A and Carey, John C and Gibbs, Richard A and Lee, Brendan H and Krakow, Deborah and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} } @article {257, title = {Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome.}, journal = {PLoS Genet}, volume = {10}, year = {2014}, month = {2014 Mar}, pages = {e1004258}, abstract = {

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{\textquoteright}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.

}, keywords = {Abnormalities, Multiple, Actins, Adolescent, Adult, Child, Child, Preschool, Colon, Exome, Female, Heterozygote, Humans, Intestinal Pseudo-Obstruction, Male, Muscle, Smooth, Mutation, Urinary Bladder}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1004258}, author = {Wangler, Michael F and Gonzaga-Jauregui, Claudia and Gambin, Tomasz and Penney, Samantha and Moss, Timothy and Chopra, Atul and Probst, Frank J and Xia, Fan and Yang, Yaping and Werlin, Steven and Eglite, Ieva and Kornejeva, Liene and Bacino, Carlos A and Baldridge, Dustin and Neul, Jeff and Lehman, Efrat Lev and Larson, Austin and Beuten, Joke and Muzny, Donna M and Jhangiani, Shalini and Gibbs, Richard A and Lupski, James R and Beaudet, Arthur} } @article {229, title = {Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Aug 07}, pages = {173-82}, abstract = {

New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such somatically mosaic parents might also have germline mosaicism that can potentially cause unexpected intergenerational recurrences. Here, we show that somatic mosaicism for transmitted mutations among parents of children with simplex genetic disease is more common than currently appreciated. Using the sensitivity of individual-specific breakpoint PCR, we prospectively screened 100 families with children affected by genomic disorders due to rare deletion copy-number variants (CNVs) determined to be de novo by clinical analysis of parental DNA. Surprisingly, we identified four cases of low-level somatic mosaicism for the transmitted CNV in DNA isolated from parental blood. Integrated probabilistic modeling of gametogenesis developed in response to our observations predicts that mutations in parental blood increase recurrence risk substantially more than parental mutations confined to the germline. Moreover, despite the fact that maternally transmitted mutations are the minority of alleles, our model suggests that sexual dimorphisms in gametogenesis result in a greater proportion of somatically mosaic transmitting mothers who are thus at increased risk of recurrence. Therefore, somatic mosaicism together with sexual differences in gametogenesis might explain a considerable fraction of unexpected recurrences of X-linked recessive disease. Overall, our results underscore an important role for somatic mosaicism and mitotic replicative mutational mechanisms in transmission genetics.

}, keywords = {Cell Division, DNA Copy Number Variations, Female, Gametogenesis, Genetic Diseases, Inborn, Genomics, Germ Cells, Germ-Line Mutation, Humans, Male, Models, Genetic, Mosaicism, Mutation, Pedigree, Prospective Studies, Recurrence, Risk, Sex Characteristics, Smith-Magenis Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.07.003}, author = {Campbell, Ian M and Yuan, Bo and Robberecht, Caroline and Pfundt, Rolph and Szafranski, Przemyslaw and McEntagart, Meriel E and Nagamani, Sandesh C S and Erez, Ayelet and Bartnik, Magdalena and Wi{\'s}niowiecka-Kowalnik, Barbara and Plunkett, Katie S and Pursley, Amber N and Kang, Sung-Hae L and Bi, Weimin and Lalani, Seema R and Bacino, Carlos A and Vast, Mala and Marks, Karen and Patton, Michael and Olofsson, Peter and Patel, Ankita and Veltman, Joris A and Cheung, Sau Wai and Shaw, Chad A and Vissers, Lisenka E L M and Vermeesch, Joris R and Lupski, James R and Stankiewicz, Pawe{\l}} } @article {259, title = {Whole-exome sequencing reveals GPIHBP1 mutations in infantile colitis with severe hypertriglyceridemia.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {59}, year = {2014}, month = {2014 Jul}, pages = {17-21}, abstract = {

Severe congenital hypertriglyceridemia (HTG) is a rare disorder caused by mutations in genes affecting lipoprotein lipase (LPL) activity. Here we report a 5-week-old Hispanic girl with severe HTG (12,031 mg/dL, normal limit 150 mg/dL) who presented with the unusual combination of lower gastrointestinal bleeding and milky plasma. Initial colonoscopy was consistent with colitis, which resolved with reduction of triglycerides. After negative sequencing of the LPL gene, whole-exome sequencing revealed novel compound heterozygous mutations in GPIHBP1. Our study broadens the phenotype of GPIHBP1-associated HTG, reinforces the effectiveness of whole-exome sequencing in Mendelian diagnoses, and implicates triglycerides in gastrointestinal mucosal injury.

}, keywords = {Colitis, DNA Mutational Analysis, Exome, Female, Humans, Hypertriglyceridemia, Infant, Receptors, Lipoprotein}, issn = {1536-4801}, doi = {10.1097/MPG.0000000000000363}, author = {Gonzaga-Jauregui, Claudia and Mir, Sabina and Penney, Samantha and Jhangiani, Shalini and Midgen, Craig and Finegold, Milton and Muzny, Donna M and Wang, Min and Bacino, Carlos A and Gibbs, Richard A and Lupski, James R and Kellermayer, Richard and Hanchard, Neil A} } @article {297, title = {TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities.}, journal = {Am J Hum Genet}, volume = {93}, year = {2013}, month = {2013 Aug 08}, pages = {197-210}, abstract = {

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.

}, keywords = {Age of Onset, Aging, Premature, Asian Continental Ancestry Group, Base Sequence, Brain, Child, Child, Preschool, Chromosomes, Human, Pair 2, Exons, Female, Genetic Predisposition to Disease, Humans, Language Development Disorders, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Molecular Sequence Data, Pedigree, Sequence Analysis, DNA, Sequence Deletion, Tetraspanins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.05.027}, author = {Wiszniewski, Wojciech and Hunter, Jill V and Hanchard, Neil A and Willer, Jason R and Shaw, Chad and Tian, Qi and Illner, Anna and Wang, Xueqing and Cheung, Sau W and Patel, Ankita and Campbell, Ian M and Gelowani, Violet and Hixson, Patricia and Ester, Audrey R and Azamian, Mahshid S and Potocki, Lorraine and Zapata, Gladys and Hernandez, Patricia P and Ramocki, Melissa B and Santos-Cortez, Regie L P and Wang, Gao and York, Michele K and Justice, Monica J and Chu, Zili D and Bader, Patricia I and Omo-Griffith, Lisa and Madduri, Nirupama S and Scharer, Gunter and Crawford, Heather P and Yanatatsaneejit, Pattamawadee and Eifert, Anna and Kerr, Jeffery and Bacino, Carlos A and Franklin, Adiaha I A and Goin-Kochel, Robin P and Simpson, Gayle and Immken, LaDonna and Haque, Muhammad E and Stosic, Marija and Williams, Misti D and Morgan, Thomas M and Pruthi, Sumit and Omary, Reed and Boyadjiev, Simeon A and Win, Kay K and Thida, Aye and Hurles, Matthew and Hibberd, Martin Lloyd and Khor, Chiea Chuen and Van Vinh Chau, Nguyen and Gallagher, Thomas E and Mutirangura, Apiwat and Stankiewicz, Pawel and Beaudet, Arthur L and Maletic-Savatic, Mirjana and Rosenfeld, Jill A and Shaffer, Lisa G and Davis, Erica E and Belmont, John W and Dunstan, Sarah and Simmons, Cameron P and Bonnen, Penelope E and Leal, Suzanne M and Katsanis, Nicholas and Lupski, James R and Lalani, Seema R} }