期刊
ATHEROSCLEROSIS
卷 321, 期 -, 页码 14-20出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2021.02.003
关键词
Familial hypercholesterolemia; LDL cholesterol; Intron; LDL receptor; RNA splicing; Next-generation sequencing
资金
- ZonMW grant (VIDI) [016.156.445]
In this study, researchers investigated whether variants in intronic regions of LDLR contribute to familial hypercholesterolemia (FH) by affecting pre-mRNA splicing. They identified a deep intronic variant that was found to be causal for FH, indicating the importance of considering intronic regions in sequencing FH patients for accurate diagnosis and treatment.
Background and aims: Familial hypercholesterolemia (FH) is caused by pathogenic variants in LDLR, APOB, or PCSK9 genes (designated FH+). However, a significant number of clinical FH patients do not carry these variants (designated FH-). Here, we investigated whether variants in intronic regions of LDLR attribute to FH by affecting pre-mRNA splicing. Methods: LDLR introns are partly covered in routine sequencing of clinical FH patients using next-generation sequencing. Deep intronic variants, >20 bp from intron-exon boundary, were considered of interest once (a) present in FHpatients (n = 909) with LDL-C >7 mmol/L (severe FH-) or after in silico analysis in patients with LDL-C >5 mmol/L (moderate FH-) and b) absent in FH + patients (control group). cDNA analysis and co segregation analysis were performed to assess pathogenicity of the identified variants. Results: Three unique variants were present in the severe FHgroup. One of these was the previously described likely pathogenic variant c.2140+103G>T. Three additional variants were selected based on in silico analyses in the moderate FHgroup. One of these variants, c.2141-218G>A, was found to result in a pseudo-exon inclusion, producing a premature stop codon. This variant co-segregated with the hypercholesterolemic phenotype. Conclusions: Through a screening approach, we identified a deep intronic variant causal for FH. This finding indicates that filtering intronic variants in FHpatients for the absence in FH + patients might enrich for true FHcausing variants and suggests that intronic regions of LDLR need to be considered for sequencing in FHpatients.
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