Submission Details

The ERCC8 gene is located on chromosome 5 at 5q12.1 and encodes the Excision Repair 8, CSA Ubiquitin Ligase Complex Subunit protein, a DNA-binding protein that is important in transcription-coupled excision repair. ERCC8 was first reported in relation to autosomal recessive Cockayne syndrome type 1/A in 1995 (Henning et al., PMID:7664335). Cockayne syndrome type 1 is characterized by normal prenatal growth with the onset of growth and developmental abnormalities in the first two years. By the time the disease has fully manifested itself, height, weight, and head circumference are far below the fifth percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system function leads to severe disability, with death typically occurring in the first or second decade. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability and severity. Therefore, the following disease entities have been split into multiple disease entities, Cockayne syndrome type 1 (OMIM: 216400) and UV-sensitive syndrome 2 (OMIM: 614621). 10 variants (nonsense, frameshift, canonical splice site, and missense) that have been reported in 5 probands in 2 publications (Cao et al., 2004, PMID:14661080; Calmels et al., 2018, PMID:29572252) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be LOF. This gene-disease relationship is also supported by experimental evidence (biochemical function and rescue) (Bregman et al., 1996, PMID:8876179; Houser et al., 1996, PMID:12509261; Ren et al., 2003, PMID:12655141). One mouse model demonstrated that homozygous LOF in ERCC8 results in defective transcription coupled-nucleotide excision repair in response to UV-light damage, a biochemical function and functional alteration also seen in ERCC6. In immortalized Cockayne syndrome type 1 cells with variants in ERCC8 knock-in of the wild-type protein restored the cells’ response to UV-light damange. Patient and cultured cells alike, similarly are less able to survive and/or synthesize DNA following UV irradiation in comparison to WT controls. In summary, ERCC8 is definitively associated with autosomal recessive Cockayne syndrome type 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date July 15, 2022 (SOP Version 9).