title: Compound heterozygous LDLR variant in severely affected familial hypercholesterolemia patient.
abstract: Familial hypercholesterolemia (FH) is most commonly caused by mutations in the LDL receptor (LDLR), which is responsible for hepatic clearance of LDL from the blood circulation. We described a severely affected FH proband and their first-degree blood relatives; the proband was resistant to statin therapy and was managed on an LDL apheresis program. In order to find the causative genetic variant in this family, direct exon sequencing of the LDLR, APOB and PCSK9 genes was performed. We identified a compound heterozygous mutation in the proband with missense p.(W577C) and frameshift p.(G676Afs33) variants at exons 12 and 14 of the LDLR gene respectively. DNA sequencing of LDLR gene from the parents demonstrated that the missense variant was inherited from the mother and frameshift variant was inherited from the father. The frameshift variant resulted in a stop signal 33 codons downstream of the deletion, which most likely led to a truncated protein that lacks important functional domains, including the trans-membrane domain and the cytoplasmic tail domain. The missense variant is also predicted to be likely pathogenic and affect EGF-precursor homology domain of the LDLR protein. The segregation pattern of the variants was consistent with the lipid profile, suggesting a more severe FH phenotype when the variants are in the compound heterozygous state. The finding of a compound heterozygous mutation causing severe FH phenotype is important for the genotype-phenotype correlation and also enlarges the spectrum of FH-causative LDLR variants in the Arab population, including the Saudi population.
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.|Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia.|Molecular Diagnostics Unit, Department of Laboratory and Blood Bank, King Abdullah Medical City, Makkah, Saudi Arabia.
authors.forename: Faisal A
authors.initials: FA
authors.lastname: Al-Allaf
authors.affiliation: King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Alashwal
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.|Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Zainularifeen
authors.initials: Z
authors.lastname: Abduljaleel
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.|Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Mohiuddin M
authors.initials: MM
authors.lastname: Taher
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.|Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Abdellatif
authors.initials: A
authors.lastname: Bouazzaoui
authors.affiliation: King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Hala
authors.initials: H
authors.lastname: Abalkhail
authors.affiliation: Faculty of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Ahmad F
authors.initials: AF
authors.lastname: Al-Allaf
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.|Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D018388:Codon, Terminator; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D018388:Codon, Terminator; D011973:Receptors, LDL
keywords: Arab; cholesterol; compound heterozygous; coronary artery disease (CAD); familial hypercholesterolemia (FH); frameshift variant; genetics; low-density lipoprotein receptor (LDLR); missense variant; sequencing