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. 2021 Sep 1;25(5):374-9.
doi: 10.52547/ibj.25.5.374. Epub 2021 May 15.

A Novel Splice Site Variant in the LDLRAP1 Gene Causes Familial Hypercholesterolemia

Najmeh Ahangari  1 , Amirhossein Sahebkar  2   3 , Mohsen Azimi-Nezhad  4 , Hamideh Ghazizadeh  5   6   7 , Mohsen Moohebati  8 , Mahmoud Ebrahim  8 , Habibollah Esmaeili  9 , Gordon A Ferns  10 , Alireza Pasdar  1   11 , Majid Ghayour Mobarhan  6
Affiliations

A Novel Splice Site Variant in the LDLRAP1 Gene Causes Familial Hypercholesterolemia

Najmeh Ahangari et al. Iran Biomed J. .

Abstract

Background: familial hypercholesterolemia (FH), a hereditary disorder, is caused by pathogenic variants in the LDLR, APOB, and PCSK9 genes. This study has assessed genetic variants in a family, clinically diagnosed with FH.

Methods: A family was recruited from MASHAD study in Iran with possible FH based on the Simon Broom criteria. The DNA sample of an affected individual (proband) was analyzed using whole exome sequencing, followed by bioinformatics and segregation analyses.

Results: A novel splice site variant (c.345-2A>G) was detected in the LDLRAP1 gene, which was segregated in all affected family members. Moreover, HMGCR rs3846662 g.23092A>G was found to be homozygous (G/G) in the proband, probably leading to reduced response to simvastatin and pravastatin.

Conclusion: LDLRAP1 c.345-2A>G could alter the phosphotyrosine-binding domain, which acts as an important part of biological pathways related to lipid metabolism.

Keywords: Genetic research; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; LDLRAP1.

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Conflict of interest statement

None declared.

Figures

Fig. 1
Fig. 1
The clinical feature of FH in the proband. (A) Xanthelasmata formed in the inner canthus of the eyelid as well as xanthomas in elbows and hands (within the circles); (B) pedigree of the family showing a novel LDLRAP1 variant (c.345-2A>G). The arrow shows the proband; (C) the normal ‘A’ nucleotide at the splice site using CLC workbench v.7.8.1; (D) LDLRAP1 variant identified in the proband, siblings, and parents. Mut, mutant
See this image and copyright information in PMC

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