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

Najmeh Ahangari, Amirhossein Sahebkar, Mohsen Azimi-Nezhad, Hamideh Ghazizadeh, Mohsen Moohebati, Mahmoud Ebrahim, Habibollah Esmaeili, Gordon A. Ferns, Alireza Pasdar, Majid Ghayour Mobarhan* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)374-379
Number of pages6
JournalIranian biomedical journal
Issue number5
Early online date15 May 2021
Publication statusPublished - 1 Sept 2021

Bibliographical note

This work was supported by Mashhad University of Medical Sciences, Mashhad, Iran through a grant (no. 951825), as a Ph.D. thesis project. The authors gratefully acknowledge the participated families.


  • Genetic research
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Hypercholesterolemia


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