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

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

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Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.
Department of Molecular Medicine, Center on Aging, The Scripps Research Institute, Jupiter, Florida.
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington.
Division of Medical Genetics, Stanford University School of Medicine, Stanford, California.
Institute Nacional de Medicina Genomica, Mexico City, Mexico.
Department of Pathology, University of Washington, Seattle, Washington.
Department of Genome Sciences, University of Washington, Seattle, Washington.
Division of Genetic Medicine, Seattle Children's Hospital, Seattle, Washington.
Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.


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.


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

[Available on 2019-02-01]

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