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

Jonathan M. Swartz, Aysehan Akinci, Shayne F. Andrew, Ahmet Sigirci, Joel N. Hirschhorn, Ron G. Rosenfeld, Andrew Dauber, Vivian Hwa

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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

Methods: Wholeexome 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.

Original languageEnglish (US)
Pages (from-to)344-352
Number of pages9
JournalHormone Research in Paediatrics
Issue number5
StatePublished - Nov 27 2014
Externally publishedYes


  • Cockayne syndrome
  • ERCC6 variant
  • Short stature

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology


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