Hypomorphic alleles pose challenges in rare disease genomic variant interpretation

Area of Science:

• Genetics
• Molecular Biology
• Medical Science

Background:

• Wilson's disease is a genetic disorder caused by mutations in the ATP7B gene, leading to copper accumulation.
• Understanding the molecular mechanisms of ATP7B dysfunction is crucial for developing effective treatments.

Observation:

• RNA sequencing of a Wilson's disease patient's liver tissue revealed aberrant splicing of the ATP7B gene.
• Sashimi plots visualized exon skipping, specifically the loss of exon 13, in the ATP7B transcript.

Findings:

• An intronic variant within the ATP7B gene was identified as the cause of exon 13 skipping.
• The loss of exon 13 results in the deletion of a transmembrane domain and disruption of the first phosphorylation domain of the ATP7B protein.

Implications:

• This discovery provides a novel molecular explanation for Wilson's disease pathogenesis in this patient.
• Identifying the functional impact of intronic variants can improve diagnostic accuracy and therapeutic strategies for genetic disorders.