Clinical and molecular genetic analysis of a Chinese patient with Cockayne syndrome caused by ERCC8 gene synonymous variant at splicing site and exon 1 deletion.

BACKGROUND

Cockayne Syndrome (CS) is a rare autosomal recessive genetic disease, mainly caused by ERCC8 and ERCC6 gene defect. However, many of its molecular characteristics remain unclear. In this study, molecular genetic analysis was performed on a patient to clarify her genetic etiology.

RESULTS

A 7-year-old girl fever for 4 days and thrombocytopenia for half a day. Her main clinical manifestations included lethargy after infection, short stature, microcephaly, mental retardation, facial aging, skin photosensitivity. Laboratory tests indicated liver and kidney damage, thrombocytopenia, and brain MRI revealed progressive brain damage. Whole exome sequencing showed that the proband had a c.1041G > A (p. Gln347=) heterozygous synonymous variation and a suspected large fragment heterozygous deletion containing exon 1 of ERCC8 gene. Sanger sequencing and Quantitative real-time PCR were respectively used to confirm inheritance from her phenotypically normal mother and father. Transcriptome sequencing showed a deletion of exon 10. According to the ACMG guidelines, the two variations were classified as pathogenic variants.

CONCLUSIONS

This study reported the rare case of CS caused by the c.1041G > A synonymous variation causing exon 10 deletion by affecting splicing and large fragment deletion containing exon 1 by preventing its allele from initiating transcription, expanding the variation spectrum of the ERCC8 gene. It reminds us that although synonymous variations are rare, they may affect splicing when they occur at the junction of exons and introns.