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

TitleERCC4 variants identified in a cohort of patients with segmental progeroid syndromes.
Publication TypeJournal Article
Year of Publication2018
AuthorsMori, T, Yousefzadeh, MJ, Faridounnia, M, Chong, JX, Hisama, FM, Hudgins, L, Mercado, G, Wade, EA, Barghouthy, AS, Lee, L, Martin, GM, Nickerson, DA, Bamshad, MJ, Niedernhofer, LJ, Oshima, J
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics
JournalHum Mutat
Date Published2018 02
KeywordsActins, Aged, Cockayne Syndrome, DNA Repair, DNA-Binding Proteins, Fanconi Anemia, Female, Genetic Predisposition to Disease, Humans, Lamin Type A, Male, Middle Aged, Pedigree, Xeroderma Pigmentosum

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.

Alternate JournalHum. Mutat.
PubMed ID29105242
PubMed Central IDPMC5762268
Grant ListU54 HG006493 / HG / NHGRI NIH HHS / United States
R01 CA210916 / CA / NCI NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
R24 AG042328 / AG / NIA NIH HHS / United States
P01 AG043376 / AG / NIA NIH HHS / United States