Likelihood of a novel pathogenic LDLR mutant allele inherited preferentially within an Indian family with familial hypercholesterolemia

Abstract Background & Aims: Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by increased levels of low-density lipoprotein cholesterol (LDL-C). LDL receptor (LDLR) gene mutations is the primary genetic cause thereby necessitating the screening of family members for early detection and management. We aim to report an Indian family with FH harboring a novel pathogenic nonsense mutation in LDLR gene with a strong likelihood of preferential transmission. Methods EDTA blood samples were collected from the available family members upon obtaining written informed consent. Genotyping for LDLR mutation was performed by PCR amplification and Sanger sequencing. 11 of the 16 family members were clinically affected and identified as having dyslipidemia. A novel mutation (c.743_744delinsAA) in exon 5 of LDLR gene was identified in the proband and 05 of the investigated family members that were dyslipidemic. In silico tools predicted, the novel mutation to be pathogenic and deleterious. Conclusions The present case study of an Indian family with FH identifies a novel pathogenic LDLR mutation (c.743_744delinsAA), which is predicted to induce non-decay mediated mRNA decay (NMD). Based on the inheritance pattern of the mutant LDLR allele, across the 3 generations, there seem to be a strong likelihood of preferential transmission of mutant allele indicating genetically-biased fertilization over the wild-type allele. This case report for a first time suggests a strong likelihood of preferential transmission in FH and underscores the importance of genetic testing for FH diagnosis as well as cascade screening for early detection, risk stratification and implementation of preventive strategies.