%0 Journal Article %J Genet Med %D 2019 %T Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies. %A Bo Yuan %A Neira, Juanita %A Pehlivan, Davut %A Santiago-Sim, Teresa %A Song, Xiaofei %A Rosenfeld, Jill %A Posey, Jennifer E %A Patel, Vipulkumar %A Jin, Weihong %A Adam, Margaret P %A Baple, Emma L %A Dean, John %A Fong, Chin-To %A Hickey, Scott E %A Hudgins, Louanne %A Leon, Eyby %A Madan-Khetarpal, Suneeta %A Rawlins, Lettie %A Rustad, Cecilie F %A Stray-Pedersen, Asbjørg %A Tveten, Kristian %A Wenger, Olivia %A Diaz, Jullianne %A Jenkins, Laura %A Martin, Laura %A McGuire, Marianne %A Pietryga, Marguerite %A Ramsdell, Linda %A Slattery, Leah %A Abid, Farida %A Bertuch, Alison A %A Grange, Dorothy %A Immken, Ladonna %A Schaaf, Christian P %A Van Esch, Hilde %A Bi, Weimin %A Cheung, Sau Wai %A Breman, Amy M %A Smith, Janice L %A Shaw, Chad %A Crosby, Andrew H %A Christine M Eng %A Yang, Yaping %A James R Lupski %A Xiao, Rui %A Liu, Pengfei %K Adolescent %K Alleles %K Antigens, Nuclear %K Biological Variation, Population %K Carrier Proteins %K Cell Cycle Proteins %K Child %K Child, Preschool %K Chromosomal Proteins, Non-Histone %K Cohort Studies %K De Lange Syndrome %K Exome %K Female %K Gene Frequency %K Genetic Heterogeneity %K Humans %K INDEL Mutation %K Male %K Mutation %K Nuclear Proteins %K Phenotype %K Polymorphism, Single Nucleotide %K Proto-Oncogene Proteins %K Retrospective Studies %K Whole Exome Sequencing %X

PURPOSE: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective.

METHODS: We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization.

RESULTS: Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS.

CONCLUSION: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.

%B Genet Med %V 21 %P 663-675 %8 2019 03 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/30158690?dopt=Abstract %R 10.1038/s41436-018-0085-6 %0 Journal Article %J Ann Clin Transl Neurol %D 2018 %T Phenotypic expansion in - a common cause of intellectual disability in females. %A Wang, Xia %A Posey, Jennifer E %A Rosenfeld, Jill A %A Bacino, Carlos A %A Scaglia, Fernando %A Immken, Ladonna %A Harris, Jill M %A Hickey, Scott E %A Mosher, Theresa M %A Slavotinek, Anne %A Zhang, Jing %A Beuten, Joke %A Leduc, Magalie S %A He, Weimin %A Vetrini, Francesco %A Walkiewicz, Magdalena A %A Bi, Weimin %A Xiao, Rui %A Liu, Pengfei %A Shao, Yunru %A Gezdirici, Alper %A Gulec, Elif Y %A Jiang, Yunyun %A Darilek, Sandra A %A Hansen, Adam W %A Khayat, Michael M %A Pehlivan, Davut %A Piard, Juliette %A Donna M Muzny %A Hanchard, Neil %A Belmont, John W %A Van Maldergem, Lionel %A Richard A Gibbs %A Eldomery, Mohammad K %A Akdemir, Zeynep C %A Adesina, Adekunle M %A Chen, Shan %A Lee, Yi-Chien %A Lee, Brendan %A James R Lupski %A Eng, Christine M %A Xia, Fan %A Yang, Yaping %A Graham, Brett H %A Moretti, Paolo %X

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.

%B Ann Clin Transl Neurol %V 5 %P 1277-1285 %8 2018 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/30349862?dopt=Abstract %R 10.1002/acn3.622 %0 Journal Article %J Am J Hum Genet %D 2017 %T De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder. %A Lessel, Davor %A Schob, Claudia %A Küry, Sébastien %A Reijnders, Margot R F %A Harel, Tamar %A Eldomery, Mohammad K %A Coban-Akdemir, Zeynep %A Denecke, Jonas %A Edvardson, Shimon %A Colin, Estelle %A Stegmann, Alexander P A %A Gerkes, Erica H %A Tessarech, Marine %A Bonneau, Dominique %A Barth, Magalie %A Besnard, Thomas %A Cogné, Benjamin %A Revah-Politi, Anya %A Strom, Tim M %A Rosenfeld, Jill A %A Yang, Yaping %A Posey, Jennifer E %A Immken, Ladonna %A Oundjian, Nelly %A Helbig, Katherine L %A Meeks, Naomi %A Zegar, Kelsey %A Morton, Jenny %A Schieving, Jolanda H %A Claasen, Ana %A Huentelman, Matthew %A Narayanan, Vinodh %A Ramsey, Keri %A Brunner, Han G %A Elpeleg, Orly %A Mercier, Sandra %A Bézieau, Stéphane %A Kubisch, Christian %A Kleefstra, Tjitske %A Kindler, Stefan %A Lupski, James R %A Kreienkamp, Hans-Jürgen %K Adenosine Triphosphatases %K Adolescent %K Amino Acids %K Cell Line %K Cell Line, Tumor %K Central Nervous System %K Child %K Child, Preschool %K Developmental Disabilities %K Female %K HEK293 Cells %K Humans %K Intellectual Disability %K Male %K Mutation, Missense %K RNA %K RNA Helicases %X

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.

%B Am J Hum Genet %V 101 %P 716-724 %8 2017 Nov 02 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/29100085?dopt=Abstract %R 10.1016/j.ajhg.2017.09.014 %0 Journal Article %J Genome Med %D 2017 %T Identification of novel candidate disease genes from de novo exonic copy number variants. %A Gambin, Tomasz %A Bo Yuan %A Bi, Weimin %A Liu, Pengfei %A Rosenfeld, Jill A %A Coban-Akdemir, Zeynep %A Pursley, Amber N %A Nagamani, Sandesh C S %A Marom, Ronit %A Golla, Sailaja %A Dengle, Lauren %A Petrie, Heather G %A Matalon, Reuben %A Emrick, Lisa %A Proud, Monica B %A Treadwell-Deering, Diane %A Chao, Hsiao-Tuan %A Koillinen, Hannele %A Brown, Chester %A Urraca, Nora %A Mostafavi, Roya %A Bernes, Saunder %A Roeder, Elizabeth R %A Nugent, Kimberly M %A Bader, Patricia I %A Bellus, Gary %A Cummings, Michael %A Northrup, Hope %A Ashfaq, Myla %A Westman, Rachel %A Wildin, Robert %A Beck, Anita E %A Immken, Ladonna %A Elton, Lindsay %A Varghese, Shaun %A Buchanan, Edward %A Faivre, Laurence %A Lefebvre, Mathilde %A Schaaf, Christian P %A Walkiewicz, Magdalena %A Yang, Yaping %A Kang, Sung-Hae L %A Lalani, Seema R %A Bacino, Carlos A %A Beaudet, Arthur L %A Breman, Amy M %A Smith, Janice L %A Cheung, Sau Wai %A James R Lupski %A Patel, Ankita %A Shaw, Chad A %A Stankiewicz, Paweł %K Cohort Studies %K DNA Copy Number Variations %K Exons %K Genetic Diseases, Inborn %K Genome, Human %K Homeodomain Proteins %K Humans %K Intracellular Signaling Peptides and Proteins %K Membrane Proteins %K Neurodevelopmental Disorders %K Protein Serine-Threonine Kinases %K Retrospective Studies %K Serine-Threonine Kinase 3 %K Transcription Factors %K Whole Genome Sequencing %X

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.

%B Genome Med %V 9 %P 83 %8 2017 09 21 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/28934986?dopt=Abstract %R 10.1186/s13073-017-0472-7 %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