Global Transcriptional Disturbances Underlie Cornelia De Lange Syndrome and Related Phenotypes

J Clin Invest. 2015 Feb;125(2):636-51. doi: 10.1172/JCI77435. Epub 2015 Jan 9.

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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Cell Cycle Proteins / biosynthesis
  • Cell Cycle Proteins / genetics
  • Child
  • Child, Preschool
  • Chondroitin Sulfate Proteoglycans / biosynthesis
  • Chondroitin Sulfate Proteoglycans / genetics
  • Chromosomal Proteins, Non-Histone / biosynthesis
  • Chromosomal Proteins, Non-Histone / genetics
  • Codon, Nonsense*
  • De Lange Syndrome* / genetics
  • De Lange Syndrome* / metabolism
  • De Lange Syndrome* / pathology
  • Exome*
  • Exonucleases
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Genome-Wide Association Study
  • Heterozygote
  • Histone Deacetylases / biosynthesis
  • Histone Deacetylases / genetics
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Infant
  • Male
  • Myeloid-Lymphoid Leukemia Protein / biosynthesis
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Phenotype*
  • Proteins / genetics
  • Proteins / metabolism
  • Repressor Proteins / biosynthesis
  • Repressor Proteins / genetics
  • Transcriptome*

Substances

  • Cell Cycle Proteins
  • Chondroitin Sulfate Proteoglycans
  • Chromosomal Proteins, Non-Histone
  • Codon, Nonsense
  • KMT2A protein, human
  • NIPBL protein, human
  • Proteins
  • Repressor Proteins
  • SMC3 protein, human
  • structural maintenance of chromosome protein 1
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Exonucleases
  • Rad1 protein, human
  • HDAC8 protein, human
  • Histone Deacetylases