@article {515, title = {Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 03}, pages = {663-675}, abstract = {

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.

}, keywords = {Adolescent, Alleles, Antigens, Nuclear, Biological Variation, Population, Carrier Proteins, Cell Cycle Proteins, Child, Child, Preschool, Chromosomal Proteins, Non-Histone, Cohort Studies, De Lange Syndrome, Exome, Female, Gene Frequency, Genetic Heterogeneity, Humans, INDEL Mutation, Male, Mutation, Nuclear Proteins, Phenotype, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins, Retrospective Studies, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-018-0085-6}, author = {Yuan, Bo and Neira, Juanita and Pehlivan, Davut and Santiago-Sim, Teresa and Song, Xiaofei and Rosenfeld, Jill and Posey, Jennifer E and Patel, Vipulkumar and Jin, Weihong and Adam, Margaret P and Baple, Emma L and Dean, John and Fong, Chin-To and Hickey, Scott E and Hudgins, Louanne and Leon, Eyby and Madan-Khetarpal, Suneeta and Rawlins, Lettie and Rustad, Cecilie F and Stray-Pedersen, Asbj{\o}rg and Tveten, Kristian and Wenger, Olivia and Diaz, Jullianne and Jenkins, Laura and Martin, Laura and McGuire, Marianne and Pietryga, Marguerite and Ramsdell, Linda and Slattery, Leah and Abid, Farida and Bertuch, Alison A and Grange, Dorothy and Immken, LaDonna and Schaaf, Christian P and Van Esch, Hilde and Bi, Weimin and Cheung, Sau Wai and Breman, Amy M and Smith, Janice L and Shaw, Chad and Crosby, Andrew H and Eng, Christine and Yang, Yaping and Lupski, James R and Xiao, Rui and Liu, Pengfei} } @article {174, title = {Exome sequencing reveals homozygous TRIM2 mutation in a patient with early onset CMT and bilateral vocal cord paralysis.}, journal = {Hum Genet}, volume = {134}, year = {2015}, month = {2015 Jun}, pages = {671-3}, abstract = {

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

}, keywords = {Adult, Charcot-Marie-Tooth Disease, Exome, Female, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Infant, Newborn, Male, Mutation, Missense, Nuclear Proteins, Vocal Cord Paralysis}, issn = {1432-1203}, doi = {10.1007/s00439-015-1548-3}, author = {Pehlivan, Davut and Coban Akdemir, Zeynep and Karaca, Ender and Bayram, Yavuz and Jhangiani, Shalini and Yildiz, Edibe Pembegul and Muzny, Donna and Uluc, Kayihan and Gibbs, Richard A and Elcioglu, Nursel and Lupski, James R and Harel, Tamar} } @article {253, title = {Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function.}, journal = {Cell}, volume = {157}, year = {2014}, month = {2014 Apr 24}, pages = {636-50}, abstract = {

CLP1 is a RNA kinase involved in tRNA splicing. Recently, CLP1 kinase-dead mice were shown to display a neuromuscular disorder with loss of motor neurons and muscle paralysis. Human genome analyses now identified a CLP1 homozygous missense mutation (p.R140H) in five unrelated families, leading to a loss of CLP1 interaction with the tRNA splicing endonuclease (TSEN) complex, largely reduced pre-tRNA cleavage activity, and accumulation of linear tRNA introns. The affected individuals develop severe motor-sensory defects, cortical dysgenesis, and microcephaly. Mice carrying kinase-dead CLP1 also displayed microcephaly and reduced cortical brain volume due to the enhanced cell death of neuronal progenitors that is associated with reduced numbers of cortical neurons. Our data elucidate a neurological syndrome defined by CLP1 mutations that impair tRNA splicing. Reduction of a founder mutation to homozygosity illustrates the importance of rare variations in disease and supports the clan genomics hypothesis.

}, keywords = {Abnormalities, Multiple, Animals, Central Nervous System Diseases, Cerebrum, Child, Preschool, Endoribonucleases, Female, Fibroblasts, Humans, Infant, Male, Mice, Mice, Inbred CBA, Microcephaly, Mutation, Missense, Nuclear Proteins, Peripheral Nervous System Diseases, Phosphotransferases, RNA, Transfer, Transcription Factors}, issn = {1097-4172}, doi = {10.1016/j.cell.2014.02.058}, author = {Karaca, Ender and Weitzer, Stefan and Pehlivan, Davut and Shiraishi, Hiroshi and Gogakos, Tasos and Hanada, Toshikatsu and Jhangiani, Shalini N and Wiszniewski, Wojciech and Withers, Marjorie and Campbell, Ian M and Erdin, Serkan and Isikay, Sedat and Franco, Luis M and Gonzaga-Jauregui, Claudia and Gambin, Tomasz and Gelowani, Violet and Hunter, Jill V and Yesil, G{\"o}zde and Koparir, Erkan and Yilmaz, Sarenur and Brown, Miguel and Briskin, Daniel and Hafner, Markus and Morozov, Pavel and Farazi, Thalia A and Bernreuther, Christian and Glatzel, Markus and Trattnig, Siegfried and Friske, Joachim and Kronnerwetter, Claudia and Bainbridge, Matthew N and Gezdirici, Alper and Seven, Mehmet and Muzny, Donna M and Boerwinkle, Eric and Ozen, Mustafa and Clausen, Tim and Tuschl, Thomas and Yuksel, Adnan and Hess, Andreas and Gibbs, Richard A and Martinez, Javier and Penninger, Josef M and Lupski, James R} }