Case Report: Functional validation of a PKD1 c.7489 + 5G>A variant in an ADPKD family.

Functional validation confirms the PKD1 c.7489 + 5G>A variant causes pathogenic exon skipping in an ADPKD family, enabling successful prevention of disease transmission.

• Why it matters: Accurate classification of genetic variants is crucial for effective diagnosis and reproductive decision-making in ADPKD, but many variants remain uncertain. Understanding the functional impact of specific variants helps improve genetic counseling and intervention strategies.
• What they did: The team performed a minigene assay on a three-generation ADPKD family with a heterozygous PKD1 c.7489 + 5G>A variant, demonstrating it causes exon 18 skipping and a frameshift, reclassifying it as pathogenic. They then used preimplantation genetic testing for monogenic disorders (PGT-M) with haplotype analysis and direct mutation detection to select unaffected embryos.
• The result: This approach led to an unaffected pregnancy, confirmed by prenatal diagnosis, illustrating how functional validation of variants can guide reproductive choices and prevent disease inheritance in ADPKD families.