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

University of Washington Center for Mendelian Genomics

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)255-265
Number of pages11
JournalHuman mutation
Issue number2
StatePublished - Feb 1 2018

Bibliographical note

Funding Information:
Contract Grant Sponsors: National Institutes of Health grants (R24AG42328, R01CA210916, P01AG043376); National Institutes of Health /National Human Genome Research Institute; National Institutes of Health /National Heart, Lung, and Blood Institute (U54HG006493); WeNMR (261572).

Funding Information:
The WeNMR project (European FP7 e-Infrastructure grant, contract no. 261572,, supported by the European Grid Initiative (EGI) through the national GRID Initiatives of Belgium, France, Italy, Germany, the Netherlands, Poland, Portugal, Spain, UK, South Africa, Malaysia, Taiwan, the Latin America GRID infrastructure via the Gisela project, and the US Open Science Grid (OSG) are acknowledged for the use of web portals, computing, and storage facilities.


  • Atypical Werner syndrome
  • Cockayne syndrome
  • ERCC4
  • Mendelian disease
  • molecular genetics
  • segmental progeroid syndromes
  • xeroderma pigmentosum group F

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