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, Ronald (Ron) Rosenfeld, Andrew Dauber, Vivian Hwa

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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
Volume82
Issue number5
DOIs
StatePublished - Nov 27 2014

Fingerprint

Cockayne Syndrome
RNA Splice Sites
Exome
Phenotype
Hirsutism
Microcephaly
Molecular Pathology
Peripheral Nervous System Diseases
Introns
Sequence Analysis
Exons
Neck
Fibroblasts
Messenger RNA
Proteins

Keywords

  • Cockayne syndrome
  • ERCC6 variant
  • Short stature

ASJC Scopus subject areas

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

Cite this

Swartz, J. M., Akinci, A., Andrew, S. F., Sigirci, A., Hirschhorn, J. N., Rosenfeld, R. R., ... Hwa, V. (2014). A novel ERCC6 splicing variant associated with a mild Cockayne syndrome phenotype. Hormone Research in Paediatrics, 82(5), 344-352. https://doi.org/10.1159/000368192

A novel ERCC6 splicing variant associated with a mild Cockayne syndrome phenotype. / Swartz, Jonathan M.; Akinci, Aysehan; Andrew, Shayne F.; Sigirci, Ahmet; Hirschhorn, Joel N.; Rosenfeld, Ronald (Ron); Dauber, Andrew; Hwa, Vivian.

In: Hormone Research in Paediatrics, Vol. 82, No. 5, 27.11.2014, p. 344-352.

Research output: Contribution to journalArticle

Swartz, JM, Akinci, A, Andrew, SF, Sigirci, A, Hirschhorn, JN, Rosenfeld, RR, Dauber, A & Hwa, V 2014, 'A novel ERCC6 splicing variant associated with a mild Cockayne syndrome phenotype', Hormone Research in Paediatrics, vol. 82, no. 5, pp. 344-352. https://doi.org/10.1159/000368192
Swartz JM, Akinci A, Andrew SF, Sigirci A, Hirschhorn JN, Rosenfeld RR et al. A novel ERCC6 splicing variant associated with a mild Cockayne syndrome phenotype. Hormone Research in Paediatrics. 2014 Nov 27;82(5):344-352. https://doi.org/10.1159/000368192
Swartz, Jonathan M. ; Akinci, Aysehan ; Andrew, Shayne F. ; Sigirci, Ahmet ; Hirschhorn, Joel N. ; Rosenfeld, Ronald (Ron) ; Dauber, Andrew ; Hwa, Vivian. / A novel ERCC6 splicing variant associated with a mild Cockayne syndrome phenotype. In: Hormone Research in Paediatrics. 2014 ; Vol. 82, No. 5. pp. 344-352.
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