%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 %X

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.

%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