Whole-Exome Sequencing Identifies Novel CPAMD8 Variants in Congenital Cataract and Candidate Variants in Pathologic...

To report CPAMD8 variants identified by whole-exome sequencing (WES) in two Chinese families presenting with congenital cataract or pathologic myopia (PM) and to evaluate the evidence supporting their genotype-phenotype relationships.

WES was performed in the probands, followed by Sanger sequencing for variant validation and segregation analysis when DNA samples from family members were available. Candidate variants were interpreted according to ACMG/AMP guidelines.

In Family 1, the proband with congenital cataract carried compound heterozygous CPAMD8 variants, including a likely pathogenic frameshift variant (c.4570delA: p.M1524Cfs*32) and a missense variant of uncertain significance (c.1717G>A: p.D573N). Sanger sequencing confirmed that the two variants were inherited from unaffected parents and were located in trans. In Family 2, the proband with PM, bilateral cataract, and posterior staphyloma carried a heterozygous splice-site variant (c.487-2A>T), classified as likely pathogenic, and an additional missense variant of uncertain significance (c.5342C>G: p.P1781R). However, segregation analysis in other family members and functional validation of the predicted splicing effect were not available.

These findings support a CPAMD8-related congenital cataract phenotype in Family 1 and may inform genetic counseling for affected families. The CPAMD8 variants identified in Family 2 should be interpreted as candidate findings, as their causal relevance to PM remains unconfirmed in the absence of segregation and functional evidence.