Atypical features and de novo heterozygous mutations in two siblings with Cockayne syndrome.

Background Cockayne syndrome (CS) is a rare autosomal recessive disorder which displays multiorgan dysfunction, especially within the nervous system including psychomotor retardation, cerebral atrophy, microcephaly, cognitive dysfunction, mental retardation, and seizures. Many genetic variations reported were related to this syndrome, but splicing mutations with cardiac anomalies have not been found in previous studies. Methods Herein, we described a pair of brothers and sisters who present essential manifestations of CS including premature feature, developmental delay, growth failure, microcephaly, and characteristic facial features, such as sunken eyes and a beaked nose. Interestingly, the brother also presented with atypical features which included cardiac anomalies such as left atrioventricular enlargement and cardiac dysfunction such as dilated cardiomyopathy. In addition, whole exome sequencing and RNA sequencing were employed to analyze their genetic landscape. Results WES analysis showed that these two cases carried double unreported heterozygous spliced mutations in the excision repair cross-complementing group 8 (ERCC8, also known as CSA, NM_000082) gene, which were c.78-2 (IVS1) A>T and c.1042-1 (IVS10) G>A, respectively. Moreover, transcript sequencing analysis validated these mutation sites. In this study, Gene Ontology enrichment and KEGG pathway analyses from RNA sequencing demonstrated similarities but some differences when compared with previous studies. Conclusion For patients with Cockayne syndrome, cardiac changes need to be monitored carefully, especially for cases with splicing mutations of the ERCC8 gene.