HiFi Long‐Read Whole‐Genome Sequencing Deciphers Large Afghan <i>RD3</i> Founder Deletion Causing Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is caused by mutations in at least 30 genes. Biallelic RD3 loss‐of‐function variants underlie rare LCA12. By whole‐exome sequencing (WES), we identified three apparently unrelated LCA12 patients (P1–3) from Afghanistan. A large novel deletion encompassing RD3 exon 3 (c.296+641_ ∗ 606del; p.[?]) was identified homozygously in P1 and P2. In P3, this deletion was hemizygous, in trans to a novel nonsense variant (c.394G &gt; T, p.[Glu132 * ]). Precise determination of breakpoints and SNP haplotypes from PacBio HiFi long‐read whole‐genome sequencing (LR‐WGS) qualified the deletion as a founder mutation. Because millions of Afghans were displaced over decades, it may significantly contribute to LCA not only in Afghanistan and the Greater Middle East, but globally. HiFi LR‐WGS detects structural variations like this RD3 deletion more reliably and precisely than WES and enables tracing the origin of mutations.