Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes
2015
Cornelia de Lange syndrome(CdLS) is a genetically
heterogeneous disorderthat 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
cohesincomplex, 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
SMC1Athat 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
KMT2Amutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or
SMC1Athat affected
RNA splicingin 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate
world populationssegregating 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.
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