Silent but significant: Functional elucidation of a synonymous ATP7B mutation in Wilson's disease pedigrees.

INTRODUCTION

Wilson's disease (hepatolenticular degeneration) is a common hereditary neurological disorder. Early diagnosis, particularly the widespread implementation of genetic testing and timely intervention, is crucial for improving the prognosis of this disease. However, limited data exist on genotype-phenotype correlations, thereby impeding accurate early clinical diagnosis.

METHODS

Whole-exome sequencing was performed on the proband and family members to detect genetic variants associated with the clinical phenotype. Bioinformatics tools (HSF, SpliceAI and ESEfinder 3.0) were used to predict the impact of mutations on the splicing function of precursor mRNA. The minigene experiment was conducted to verify the impact of the mutation on the splicing function of the precursor mRNA.

RESULTS

Whole-exome sequencing of the proband identified a synonymous variant c.2145C>T (p. Tyr715=) and a pathogenic frameshift mutation c.2304dupC (p. Met769Hisfs26) in the gene, both associated with the clinical phenotype. The frameshift mutation c.2304dupC (p. Met769His fs26) on the other allele was a known pathogenic variant causing protein truncation. Bioinformatics tools (HSF, SpliceAI, and ESEfinder 3.0) predicted that the c.2145C>T mutation might disrupt nearby splicing sites. minigene assays confirmed aberrant precursor mRNA splicing caused by c.2145C>T (p. Tyr715=) synonymous mutation, resulting in reduced abundance of normal transcripts.

CONCLUSION

The compound heterozygous variants (c.2145C>T and c.2304dupC) in ATP7B likely synergistically contribute to the proband's abnormal clinical phenotype, aligning with the recessive inheritance pattern of Wilson's disease.