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.