A novel ERCC6 splicing variant associated with a mild Cockayne syndrome phenotype

Horm Res Paediatr. 2014;82(5):344-52. doi: 10.1159/000368192. Epub 2014 Nov 1.


Background: Cockayne syndrome is an autosomal recessive, heterogeneous syndrome with classical features, including short stature, microcephaly, developmental delay, neuropathy, and photosensitivity. New genomic approaches offer improved molecular diagnostic potential.

Methods: Whole-exome sequencing was employed to study a consanguineous extended family with severe short stature and variable presentations of peripheral neuropathy, lipoatrophy, photosensitivity, webbed neck, and hirsutism.

Results: We identified a novel homozygous ERCC6 variant at the donor splice site of intron 9 (c.1992 + 3A>G), which was predicted to only slightly perturb splicing efficiencies. Assessment of primary fibroblast-derived mRNAs, however, revealed a dominant splicing species that utilized an unsuspected putative donor splice site within exon 9, resulting in predicted early protein termination (p.Arg637Serfs*34).

Conclusions: We describe a new splicing ERCC6 defect causal of Cockayne syndrome. The application of exome sequence analysis was integral to diagnosis, given the complexity of phenotypic presentation in the affected family members. The novel splicing defect, furthermore, illustrates how a seemingly minor change in the relative strength of a splice site can have significant biological consequences.

Publication types

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

MeSH terms

  • Cockayne Syndrome / diagnosis
  • Cockayne Syndrome / genetics*
  • Codon, Terminator / genetics*
  • DNA Helicases / genetics*
  • DNA Repair Enzymes / genetics*
  • Exome
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Point Mutation*
  • Poly-ADP-Ribose Binding Proteins
  • RNA Splice Sites / genetics*
  • RNA Splicing / genetics*


  • Codon, Terminator
  • Poly-ADP-Ribose Binding Proteins
  • RNA Splice Sites
  • DNA Helicases
  • ERCC6 protein, human
  • DNA Repair Enzymes