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

ABSTRACT: 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.

SUBMITTER: Yuan B

PROVIDER: S-EPMC4319410 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Yuan Bo B Pehlivan Davut D Karaca Ender E Patel Nisha N Charng Wu-Lin WL Gambin Tomasz T Gonzaga-Jauregui Claudia C Sutton V Reid VR Yesil Gozde G Bozdogan Sevcan Tug ST Tos Tulay T Koparir Asuman A Koparir Erkan E Beck Christine R CR Gu Shen S Aslan Huseyin H Yuregir Ozge Ozalp OO Al Rubeaan Khalid K Alnaqeb Dhekra D Alshammari Muneera J MJ Bayram Yavuz Y Atik Mehmed M MM Aydin Hatip H Geckinli B Bilge BB Seven Mehmet M Ulucan Hakan H Fenercioglu Elif E Ozen Mustafa M Jhangiani Shalini S Muzny Donna M DM Boerwinkle Eric E Tuysuz Beyhan B Alkuraya Fowzan S FS Gibbs Richard A RA Lupski James R JR

The Journal of clinical investigation 20150109 2

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 ...[more]

PMID: 25574841

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Project description:Cornelia de Lange Syndrome (CdLS) is a human developmental syndrome with complex multisystem phenotypic features. It has been traditionally considered a cohesinopathy together with other phenotypically related diseases because of their association with mutations in subunits of the cohesin complex. Despite some overlap, the clinical manifestations of cohesinopathies vary considerably and, although their precise molecular mechanisms are not well defined yet, the potential pathomechanisms underlying these diverse developmental defects have been theoretically linked to alterations of the cohesin complex function. The cohesin complex plays a critical role in sister chromatid cohesion, but this function is not affected in CdLS. In the last decades, a non-cohesion-related function of this complex on transcriptional regulation has been well established and CdLS pathoetiology has been recently associated to gene expression deregulation. Up to 70% of CdLS cases are linked to mutations in the cohesin-loading factor NIPBL, which has been shown to play a prominent function on chromatin architecture and transcriptional regulation. Therefore, it has been suggested that CdLS can be considered a transcriptomopathy. Actually, CdLS-like phenotypes have been associated to mutations in chromatin-associated proteins, as KMT2A, AFF4, EP300, TAF6, SETD5, SMARCB1, MAU2, ZMYND11, MED13L, PHIP, ARID1B, NAA10, BRD4 or ANKRD11, most of which have no known direct association with cohesin. In the case of BRD4, a critical highly investigated transcriptional coregulator, an interaction with NIPBL has been recently revealed, providing evidence on their cooperation in transcriptional regulation of developmentally important genes. This new finding reinforces the notion of an altered gene expression program during development as the major etiological basis for CdLS. In this review, we intend to integrate the recent available evidence on the molecular mechanisms underlying the clinical manifestations of CdLS, highlighting data that favors a transcription-centered framework, which support the idea that CdLS could be conceptualized as a transcriptomopathy.

Dataset Information

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

Publications

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

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