Cockayne Syndrome via the ERCC6 Gene

Cockayne Syndrome (CS) presents with sun-sensitivity and postnatal growth failure, but does not have increased skin cancer rates. Other minor features include cachexia, neurological, psychomotor, and mental developmental delays, cataracts, retinopathy, deafness, dental caries, and characteristic facies (Thoms et al. Experimental Dermatology 16:532–544, 2007). Other characteristics include growth retardation, microcephaly and calcifications of the basal ganglia or elsewhere in the central nervous system. Pathologically, neurological impairment correlates with primary demyelinization of neurons. This contrasts to the primary neuronal degeneration found in XP patients. There are three forms of CS: (1) CS Type I is the classic/moderate form usually noticed by 1-2 years of age; (2) CS Type II is the severe form noticed in the neonatal period; and (3) CS Type III is the least severe and later-onset form (Laugel. GeneReviews. 2012). The prevalence of CS is 2.3 per 1,000,000 livebirths, but this is considered a conservative estimate (Kleijer et al. DNA Repair (Amst) 7:744–50, 2008).

Cockayne syndrome is an autosomal recessive disorder. To allow for proper repair and continuation of transcription, the ERCC6 and ERCC8 protein products appear to play an important role in the temporary removal of stalled polymerase II . Interestingly, nucleotide excision repair in cells of CS patients is defective in transcription couple repair (TCR), but exhibits normal global genome repair. This may help to explain the lack of cancer development; whereas both pathways are usually defective in Xeroderma Pigmentation patients who have high rates of skin cancer. Also of interest is that CS cells can repair 6-4 photoproducts, unlike cells from XP patients. Finally, CS cells exhibit an increased rate of apoptosis because of TCR failure and blockage of transcription. Enhanced apoptosis of initially damaged cells could also prevent tumor cell development. (Thoms et al. Experimental Dermatology 16:532–544, 2007). The majority of mutations in ERCC6 are missense, nonsense, splicing and small deletions. Less common types of mutations include small insertions, and large deletions and insertions (Human Gene Mutation Database). There is no reported genotype-phenotype correlation (Laugel. GeneReviews. 2012).

Mutations in ERCC6 cause Cockayne syndrome complementation group type B and account for 65% of cases.

This test provides full coverage of all coding exons of the ERCC6 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).