A Novel Pathogenic LDLR Nonsense Variant in a Consanguineous Indian Familial Hypercholesterolaemia Family — Every Offspring Inherited the Mutant Allele

Key finding

What did standard medicine miss or get wrong? The variant is novel. A commercial FH panel would have returned "no pathogenic variant detected" in a patient with definite clinical FH. The variant — c.743_744delinsAA in exon 5 of LDLR, a nonsense change predicted deleterious by SIFT and MutationTaster — had never been reported. It was found because the team sequenced the exome instead of interrogating a fixed list of known mutations. Almost every commercially available FH genotyping panel is populated from European and, secondarily, East Asian variant catalogues. South Asian LDLR variant spectra include a long tail of population-specific changes that those panels cannot see. The clinical consequence is a specific, predictable form of false reassurance: clinically definite FH + negative panel = "genetically unconfirmed," which in practice becomes softer treatment, no cascade scr

Framework connections: The Loaded Dice (Lp(a)), The Burn and Crash Model

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