Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes

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Yuan, Bo
Pehlivan, Davut
Karaca, Ender
Patel, Nisha
Charng, Wu-Lin
Gambin, Tomasz
Gonzaga-Jauregui, Claudia
Sutton, V. Reid
Yesil, Gozde
Bozdogan, Sevcan Tug
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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 nova 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.
Yuan B., Pehlivan D., Karaca E., Patel N., Charng W., Gambin T., Gonzaga-Jauregui C., Sutton V. R. , Yesil G., Bozdogan S. T. , et al., -Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes-, JOURNAL OF CLINICAL INVESTIGATION, cilt.125, ss.636-651, 2015
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