en Molecular Genetics & Genomics Molecular Genetics & Genomics مقاله موردی Case Report <strong>Background:</strong> familial hypercholesterolemia (FH), a hereditary disorder, is caused by pathogenic variants in the <em>LDLR</em>, <em>APOB</em>, and <em>PCSK9</em> genes. This study has assessed genetic variants in a family, clinically diagnosed with FH. <strong>Methods:</strong> 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. <strong>Results:</strong> A novel splice site variant (c.345-2A>G) was detected in the <em>LDLRAP1&nbsp;</em>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. <strong>Conclusion:</strong> <em>LDLRAP1</em> c.345-2A>G could alter the phosphotyrosine-binding domain, which acts as an important part of biological pathways related to lipid metabolism. Genetic research, LDLRAP1, Hypercholesterolemia, Hydroxymethylglutaryl-CoA Reductase Inhibitors 374 379 http://ibj.pasteur.ac.ir/browse.php?a_code=A-10-3953-2&slc_lang=en&sid=1 Najmeh Ahangari najmeh.ahangari@gmail.com 0000-0001-7091-3188 No Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Amirhossein Sahebkar amir_saheb2000@yahoo.com 0000-0002-8656-1444 No Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran Mohsen Azimi-Nezhad aziminm@mums.ac.ir 0000-0001-9926-1283 No UMR INSERM U 1122, IGE-PCV “Interactions Gène-Environnement en Physiopathologie CardioVasculaire”, Université de Lorraine, 54000, Nancy, France. School of Medicine, Neyshabur University of Medical Sciences, Neyshabur, Iran Hamideh Ghazizadeh ghazizadehh981@mums.ac.ir 0000-0002-0231-9547 No Student research committee, Mashhad University of Medical Sciences, Mashhad, Iran; 6International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Mohsen Moohebati MouhebatiM@mums.ac.ir 0000-0002-1813-1995 No Cardiovascular Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Mahmoud Ebrahimi EbrahimiMH@mums.ac.ir 0000-0001-5889-2871 No Cardiovascular Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Habibillah Esmaeili EsmailyH@mums.ac.ir 0000-0003-4139-546X No Department of Biostatistics & Epidemiology, School of Health, Management & Social Determinants of Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran Gordon Ferns G.Ferns@bsms.ac.uk 0000-0002-0957-8349 No Division of Medical Education, Brighton and Sussex Medical School, Falmer, Brighton, Sussex, BN1 9PH, UK Alireza Pasdar pasdara@mums.ac.ir 0000-0002-7864-9729 No Division of Applied Medicine, Medical School, University of Aberdeen, Forester hill, Aberdeen, UK Majid Ghayour Mobarhan ghyourm@mums.ac.ir 0000-0003-4088-0308 Yes International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran