%0 Journal Article %J Neuron %D 2015 %T Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. %A Karaca, Ender %A Harel, Tamar %A Pehlivan, Davut %A Jhangiani, Shalini N %A Gambin, Tomasz %A Coban Akdemir, Zeynep %A Gonzaga-Jauregui, Claudia %A Erdin, Serkan %A Bayram, Yavuz %A Campbell, Ian M %A Hunter, Jill V %A Atik, Mehmed M %A Van Esch, Hilde %A Bo Yuan %A Wiszniewski, Wojciech %A Isikay, Sedat %A Yesil, Gozde %A Yuregir, Ozge O %A Tug Bozdogan, Sevcan %A Aslan, Huseyin %A Aydin, Hatip %A Tos, Tulay %A Aksoy, Ayse %A De Vivo, Darryl C %A Jain, Preti %A Geckinli, B Bilge %A Sezer, Ozlem %A Gul, Davut %A Durmaz, Burak %A Cogulu, Ozgur %A Ozkinay, Ferda %A Topcu, Vehap %A Candan, Sukru %A Cebi, Alper Han %A Ikbal, Mevlit %A Yilmaz Gulec, Elif %A Gezdirici, Alper %A Koparir, Erkan %A Ekici, Fatma %A Coskun, Salih %A Cicek, Salih %A Karaer, Kadri %A Koparir, Asuman %A Duz, Mehmet Bugrahan %A Kirat, Emre %A Fenercioglu, Elif %A Ulucan, Hakan %A Seven, Mehmet %A Guran, Tulay %A Elcioglu, Nursel %A Yildirim, Mahmut Selman %A Aktas, Dilek %A Alikaşifoğlu, Mehmet %A Ture, Mehmet %A Yakut, Tahsin %A Overton, John D %A Yuksel, Adnan %A Ozen, Mustafa %A Donna M Muzny %A Adams, David R %A Eric Boerwinkle %A Chung, Wendy K %A Richard A Gibbs %A Lupski, James R %K Brain %K Cohort Studies %K Databases, Genetic %K Female %K Gene Regulatory Networks %K Genetic Association Studies %K Genetic Variation %K Humans %K Male %K Mendelian Randomization Analysis %K Nervous System Diseases %K Pedigree %X
Development of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations.
%B Neuron %V 88 %P 499-513 %8 2015 Nov 04 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/26539891?dopt=Abstract %R 10.1016/j.neuron.2015.09.048 %0 Journal Article %J J Clin Invest %D 2015 %T Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes. %A Bo Yuan %A Pehlivan, Davut %A Karaca, Ender %A Patel, Nisha %A Charng, Wu-Lin %A Gambin, Tomasz %A Gonzaga-Jauregui, Claudia %A Sutton, V Reid %A Yesil, Gozde %A Bozdogan, Sevcan Tug %A Tos, Tulay %A Koparir, Asuman %A Koparir, Erkan %A Beck, Christine R %A Gu, Shen %A Aslan, Huseyin %A Yuregir, Ozge Ozalp %A Al Rubeaan, Khalid %A Alnaqeb, Dhekra %A Alshammari, Muneera J %A Bayram, Yavuz %A Atik, Mehmed M %A Aydin, Hatip %A Geckinli, B Bilge %A Seven, Mehmet %A Ulucan, Hakan %A Fenercioglu, Elif %A Ozen, Mustafa %A Jhangiani, Shalini %A Donna M Muzny %A Eric Boerwinkle %A Tuysuz, Beyhan %A Alkuraya, Fowzan S %A Richard A Gibbs %A Lupski, James R %K Adolescent %K Adult %K Cell Cycle Proteins %K Child %K Child, Preschool %K Chondroitin Sulfate Proteoglycans %K Chromosomal Proteins, Non-Histone %K Codon, Nonsense %K De Lange Syndrome %K Exome %K Exonucleases %K Gene Expression Profiling %K Gene Expression Regulation %K Genome-Wide Association Study %K Heterozygote %K Histone Deacetylases %K Histone-Lysine N-Methyltransferase %K Humans %K Infant %K Male %K Myeloid-Lymphoid Leukemia Protein %K Phenotype %K Proteins %K Repressor Proteins %K Transcriptome %XCornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual disability (DD/ID), abnormal extremities, and hirsutism. About 65% of patients harbor mutations in genes that encode subunits or regulators of the cohesin complex, including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A (KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be "transcriptomopathies" rather than cohesinopathies.
%B J Clin Invest %V 125 %P 636-51 %8 2015 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/25574841?dopt=Abstract %R 10.1172/JCI77435 %0 Journal Article %J Cell %D 2014 %T Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function. %A Karaca, Ender %A Weitzer, Stefan %A Pehlivan, Davut %A Shiraishi, Hiroshi %A Gogakos, Tasos %A Hanada, Toshikatsu %A Jhangiani, Shalini N %A Wiszniewski, Wojciech %A Withers, Marjorie %A Campbell, Ian M %A Erdin, Serkan %A Isikay, Sedat %A Franco, Luis M %A Gonzaga-Jauregui, Claudia %A Gambin, Tomasz %A Gelowani, Violet %A Hunter, Jill V %A Yesil, Gozde %A Koparir, Erkan %A Yilmaz, Sarenur %A Brown, Miguel %A Briskin, Daniel %A Hafner, Markus %A Morozov, Pavel %A Farazi, Thalia A %A Bernreuther, Christian %A Glatzel, Markus %A Trattnig, Siegfried %A Friske, Joachim %A Kronnerwetter, Claudia %A Bainbridge, Matthew N %A Gezdirici, Alper %A Seven, Mehmet %A Donna M Muzny %A Eric Boerwinkle %A Ozen, Mustafa %A Clausen, Tim %A Tuschl, Thomas %A Yuksel, Adnan %A Hess, Andreas %A Richard A Gibbs %A Martinez, Javier %A Penninger, Josef M %A Lupski, James R %K Abnormalities, Multiple %K Animals %K Central Nervous System Diseases %K Cerebrum %K Child, Preschool %K Endoribonucleases %K Female %K Fibroblasts %K Humans %K Infant %K Male %K Mice %K Mice, Inbred CBA %K Microcephaly %K Mutation, Missense %K Nuclear Proteins %K Peripheral Nervous System Diseases %K Phosphotransferases %K RNA, Transfer %K RNA-Binding Proteins %K Transcription Factors %XCLP1 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.
%B Cell %V 157 %P 636-50 %8 2014 Apr 24 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/24766809?dopt=Abstract %R 10.1016/j.cell.2014.02.058