Likelihood of a Novel Pathogenic LDLR Mutant Allele Inherited Preferentially within an Indian Family with Familial...

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C), primarily caused by mutations in the LDL receptor (LDLR) gene. Screening of family members is crucial for early detection and management. Here, we report on an Indian family with FH harboring a novel pathogenic nonsense mutation in the LDLR gene, which exhibits a pattern suggestive of preferential transmission. Whole exome sequencing of a member with definite FH from consanguineous parents, identified by Dutch Lipid Clinic Network Criteria, revealed a novel pathogenic nonsense mutation (c.743_744delinsAA) in exon 5 of the LDLR gene. This mutation was predicted to be deleterious by in silico online tools such as SIFT and MutationTaster. Sanger Sequencing confirmed the presence of this mutation in all available affected family members. Interestingly, despite an expected 50% chance of inheriting the wild-type allele (CG), all offspring consistently inherited the mutant LDLR allele (AA). This observation suggests a non-random pattern of preferential allele transmission, potentially influenced by genetically biased fertilization or genetic factors beyond typical Mendelian inheritance patterns. This study represents the first report of this novel LDLR mutation in an Indian family with FH.

The online version contains supplementary material available at 10.1007/s12291-024-01252-6.