ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes

Hum Mutat. 2018 Feb;39(2):255-265. doi: 10.1002/humu.23367. Epub 2017 Nov 17.


Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5' incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia. We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome. Two cases, each carrying two novel heterozygous ERCC4 variants, were identified. The first case was a compound heterozygote for: c.2395C > T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130Aspfs*18). Further molecular and cellular studies indicated that the ERCC4 variants in this patient are responsible for a phenotype consistent with a variant of CS. The second case was heterozygous for two variants in cis: c.[1488A > T; c.2579C > A] (p.[Gln496His; Ala860Asp]). While the second case also had several phenotypic features of accelerated aging, we were unable to provide biological evidence supporting the pathogenic roles of the associated ERCC4 variants. Precise genetic causes and disease mechanism of the second case remains to be determined.

Keywords: Atypical Werner syndrome; Cockayne syndrome; ERCC4; Mendelian disease; molecular genetics; segmental progeroid syndromes; xeroderma pigmentosum group F.

Publication types

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

MeSH terms

  • Actins / genetics
  • Aged
  • Cockayne Syndrome / genetics*
  • DNA Repair / genetics
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • Fanconi Anemia / genetics
  • Female
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Lamin Type A / genetics
  • Male
  • Middle Aged
  • Pedigree
  • Xeroderma Pigmentosum / genetics*


  • Actins
  • DNA-Binding Proteins
  • LMNA protein, human
  • Lamin Type A
  • xeroderma pigmentosum group F protein

Supplementary concepts

  • XFE Progeroid Syndrome