The analysis of the breakpoint of large rearrangements of LDLR gene in a Taiwanese cohort of patients with familial hypercholesterolemia.

Background: Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism. Large rearrangements such as deletions or duplications of 1 or more exons are estimated to comprise around 5% of mutations in LDLR genes causing FH. Patients with large rearrangement of LDLR often present more severe phenotypes, warranting early detection and intensive lipid lowering treatment. This study aimed to characterize the large rearrangements of LDLR gene in Taiwanese FH patients.

Methods: In the Taiwan FH registry, large deletions and duplications of the LDLR gene were screened using multiplex ligation-dependent probe amplification (MLPA) analysis. Precise genomic breakpoints and recombination mechanisms of the large rearrangements were analyzed using polymerase chain reaction and sequencing.

Results: From January 2017 to June 2024, abnormal MLPA results were detected in 17 probands. Ten large LDLR rearrangements were identified in 12 probands, including 1 duplication and 9 deletions. Six rearrangements were attributed to nonallelic homologous recombination (NAHR), while 4 were nonhomologous end joining (NHEJ). The precise LDLR breakpoint could not be determined in 1 proband with exon 1-6 duplication. The remaining 4 probands with abnormal MLPA patterns were determined as false positives, possibly due to the interference of single nucleotide polymorphisms (SNPs) near the 3' end binding site of the MLPA probe.

Conclusions: Ten novel LDLR large rearrangements were identified in the Taiwan FH registry. The presence of SNPs near the 3' end binding site of the MLPA probe may cause abnormal results, highlighting the importance of precise diagnostic strategies for detecting LDLR large rearrangements.