Background Cockayne syndrome (CS) is a rare, autosomal recessive multisystem disorder characterised by prenatal or postnatal growth failure, progressive neurological dysfunction, ocular and skeletal abnormalities and premature ageing. About half of the patients with symptoms diagnostic for CS show cutaneous photosensitivity and an abnormal cellular response to UV light due to mutations in either the ERCC8/CSA or ERCC6/CSB gene. Studies performed thus far have failed to delineate clear genotype-phenotype relationships. We have carried out a four-centre clinical, molecular and cellular analysis of 124 patients with CS.
Methods and results We assigned 39 patients to the ERCC8/CSA and 85 to the ERCC6/CSB genes. Most of the genetic variants were truncations. The missense variants were distributed non-randomly with concentrations in relatively short regions of the respective proteins. Our analyses revealed several hotspots and founder mutations in ERCC6/CSB. Although no unequivocal genotype-phenotype relationships could be made, patients were more likely to have severe clinical features if the mutation was downstream of the PiggyBac insertion in intron 5 of ERCC6/CSB than if it was upstream. Also a higher proportion of severely affected patients was found with mutations in ERCC6/CSB than in ERCC8/CSA.
Conclusion By identifying >70 novel homozygous or compound heterozygous genetic variants in 124 patients with CS with different disease severity and ethnic backgrounds, we considerably broaden the CSA and CSB mutation spectrum responsible for CS. Besides providing information relevant for diagnosis of and genetic counselling for this devastating disorder, this study improves the definition of the puzzling genotype-phenotype relationships in patients with CS.
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NC, EB and NJ contributed equally.
Contributors NC, EB, NJ and CO carried out the sequence analysis; HF, TN, ML and CO did the RRS measurements and contributed to the genetic analysis, as did YN and NJ, who also did the lentivirus complementation. SM, KS, MK, MAS, MS, VL and ARL provided patient material and clinical data; MS, VL, DO, TO and ARL conceived and designed the study, and, together with NC and EB, wrote the paper. All authors approved the final manuscript.
Funding This work was funded by Associazione Italiana per la Ricerca sul Cancro Grant IG 13537 (MS) and IG 17710 (DO); Collaborative Projects on Rare Diseases by Istituto Superiore Sanità 526D/17 IST-CNR (MS); a grant for Research for overcoming intractable diseases (H26-general-046) from The Ministry of Health Labour and Welfare of Japan, KAKENHI Grants-in-Aid for Scientific Research (B) (26291005) from JSPS, KAKENHI Grants-in-Aid for Scientific Research (A) (Overseas Academic Research) (15H02654) from JSPS, a science research grant from the Uehara Memorial Foundation, and a scientific research grant from Daiko Foundation to TO and a grant from Agence de la Biomedecine to VL and NC.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Work from the UK and Japan had approval from the Ethics Research Committees of the University of Sussex and the Ethics Committee for Human Genome Studies in the Research Institute of Environmental Medicine, Nagoya University. The results from Strasbourg and Pavia are from retrospective collections of clinical and molecular data, which do not require specific ethics committee approval at these institutions for this particular work. All patient clinical data have been obtained in a manner conforming with IRB and granting agency ethical guidelines.
Provenance and peer review Not commissioned; externally peer reviewed.
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