Identification and Molecular Characterization of a Novel Large-Scale Variant (Exons 4_18 Loss) in the LDLR Gene as a Cause of Familial Hypercholesterolaemia in an Italian Family

Next-generation sequencing (NGS) is nowadays commonly used for clinical\r\npurposes, and represents an efficient approach for the molecular\r\ndiagnosis of familial hypercholesterolemia (FH). Although the dominant\r\nform of the disease is mostly due to the low-density lipoprotein\r\nreceptor (LDLR) small-scale pathogenic variants, the copy number\r\nvariations (CNVs) represent the underlying molecular defects in\r\napproximately 10\% of FH cases. Here, we reported a novel large deletion\r\nin the LDLR gene involving exons 4-18, identified by the bioinformatic\r\nanalysis of NGS data in an Italian family. A long PCR strategy was\r\nemployed for the breakpoint region analysis where an insertion of six\r\nnucleotides (TTCACT) was found. Two Alu sequences, identified within\r\nintron 3 and exon 18, could underlie the identified rearrangement by a\r\nnonallelic homologous recombination (NAHR) mechanism. NGS proved to be\r\nan effective tool suitable for the identification of CNVs, together with\r\nsmall-scale alterations in the FH-related genes. For this purpose, the\r\nuse and implementation of this cost-effective, efficient molecular\r\napproach meets the clinical need for personalized diagnosis in FH cases.