biostudies-literatureMori TNIA NIH HHSNational Heart, Lung, and Blood InstituteNHGRI NIH HHSNCI NIH HHSNational Institutes of HealthWeNMRNational Human Genome Research Institute255-265https://www.ebi.ac.uk/biostudies/studies/S-EPMC5762268biostudies-literatureUnknown39(2)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.Human mutationERCC4 variants identified in a cohort of patients with segmental progeroid syndromes.PMC5762268U54 HG006493R01CA210916P01AG043376261572R24 AG042328R24AG42328U54HG006493UM1 HG006493R01 CA210916P01 AG043376Barghouthy ASMercado GWade EALee LNiedernhofer LJNickerson DAMartin GMBamshad MJUniversity of Washington Center for Mendelian GenomicsChong JXYousefzadeh MJFaridounnia MMori THudgins LHisama FMOshima JfalseERCC4 variants identified in a cohort of patients with segmental progeroid syndromes.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.2018-01-01T00:00:00Z2018 Feb2024-11-21T04:27:46.402Z2019-03-26T22:50:00ZS-EPMC57622682910524210.1002/humu.23367