Cockayne syndrome

Gene: ERCC6

Comment on mode of pathogenicity: See reviewer comments. Loss-of-function variants indicated as the mutation consequence in Gene2Phenotype.

Created: 25 Jul 2016, 9:47 a.m.

Comment on list classification: Promoted from red to green due to two expert reviews, and is a confirmed DD gene for Cockayne Syndrome Type B.

Created: 25 Jul 2016, 9:42 a.m.

Relevant phenotype and mode of inheritance collected from OMIM.

Created: 8 Jan 2016, 12:11 p.m.

Green List (high evidence)

The Northern Genetics Service offer Sanger sequencing for all 21 exons of ERCC6 (NM_000124.3), including non coding exon 1; as an NHS service and as part of the Cockayne syndrome Natural History study, which comprises the largest cohort of patients with CS reported to date.

Created: 12 Feb 2016, 1:38 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cockayne syndrome phenotype and UV-sensitive syndrome

Publications

• PMID: 26204423
• 26749132

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Mutations in ERCC6 (CSB) account for around 70% of genetically confirmed cases of Cockayne syndrome (CS). There are regional variations, with a greater proportion of ERCC8 (CSA) mutations accounting for the phenotype in Japan and parts of the Middle East.

Our recent work (PMID: 26749132) indicates that antimorphic mutations produce the Cockayne syndrome phenotype (i.e. those mutations causing major structural perturbations of the protein, such as frameshift and nonsense mutations, together with missense mutations affecting key structural elements of the protein). Mutant ERCC6 mRNAs are known to produce truncated proteins; it remains unclear how much nonsense-mediated decay occurs. Those mutations resulting in a predicted protein of <200 amino acids produce a very mild CS phenotype, or a UV-sensitive syndrome (UVSS) phenotype. Patients with UVSS have a DNA repair and transcription defect that is indistinguishable from that in CS, but do not have small stature, microcephaly, developmental delay or the premature pathological ageing that characterises the CS phenotype. The only manifestations in common with CS are dermal photosensitivity (with no increased skin cancer risk) and hyperpigmentation in sun exposed areas. Historically, this feature was thought typical of CS. However, in the largest cohort of CS patients to date (the Cockayne syndrome Natural History study), we noted that appreciable photosensitivity is found in only 1/3 of affected patients (PMID: 26204423). Please note that the phenotype described as cerebro-oculo-facio-skeletal (COFS) syndrome should not be considered a separate entity; it is essentially a severe CS phenotype with prenatal onset and forms part of the CS continuum.

The Northern Genetics Service Molecular Genetics Laboratory (Newcastle upon Tyne NHS Hospitals FT) provides diagnostic sequencing independently and as part of the Cockayne syndrome Natural History study, and I believe has the greatest experience with mutation positive cases for ERCC6 and ERCC8 internationally.

Created: 10 Feb 2016, 10:01 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
I have already supplied the HPO terms for CS to Genomics England, based on our recent study findings (PMID: 26204423) - all of these are applicable to the phenotypes associated with both ERCC6 and ERCC8. I am happy to annotate this review with them if necessary.

Publications

• PMID: 26204423
• 26749132

Mode of pathogenicity
Other