Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes.

TitleGlobal transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes.
Publication TypeJournal Article
Year of Publication2015
AuthorsYuan, B, Pehlivan, D, Karaca, E, Patel, N, Charng, W-L, Gambin, T, Gonzaga-Jauregui, C, V Sutton, R, Yesil, G, Bozdogan, STug, Tos, T, Koparir, A, Koparir, E, Beck, CR, Gu, S, Aslan, H, Yuregir, OOzalp, Rubeaan, KAl, Alnaqeb, D, Alshammari, MJ, Bayram, Y, Atik, MM, Aydin, H, B Geckinli, B, Seven, M, Ulucan, H, Fenercioglu, E, Ozen, M, Jhangiani, S, Muzny, DM, Boerwinkle, E, Tuysuz, B, Alkuraya, FS, Gibbs, RA, Lupski, JR
JournalJ Clin Invest
Date Published2015 Feb
KeywordsAdolescent, Adult, Cell Cycle Proteins, Child, Child, Preschool, Chondroitin Sulfate Proteoglycans, Chromosomal Proteins, Non-Histone, Codon, Nonsense, De Lange Syndrome, Exome, Exonucleases, Gene Expression Profiling, Gene Expression Regulation, Genome-Wide Association Study, Heterozygote, Histone Deacetylases, Histone-Lysine N-Methyltransferase, Humans, Infant, Male, Myeloid-Lymphoid Leukemia Protein, Phenotype, Proteins, Repressor Proteins, Transcriptome

Cornelia 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.

Alternate JournalJ Clin Invest
PubMed ID25574841
PubMed Central IDPMC4319410
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States

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