The Prevalence and Genetic Spectrum of Familial Hypercholesterolemia in Qatar Based on Whole Genome Sequencing of 14,000 Subjects

Abstract

Familial hypercholesterolemia (FH) is an inherited disease characterized by reduced efficiency of low-density lipoprotein-cholesterol (LDL-C) removal from the blood and, consequently, an increased risk of life-threatening early cardiovascular complications. In Qatar, the prevalence of FH has not been determined and the disease, as in many countries, is largely underdiagnosed. In this study, we combined whole-genome sequencing data from the Qatar Genome Program with deep phenotype data from Qatar Biobank for 14,056 subjects to determine the genetic spectrum and estimate the prevalence of FH in Qatar. We used the Dutch Lipid Clinic Network (DLCN) as a diagnostic tool and scrutinized 11 FH-related genes for known pathogenic and possibly pathogenic mutations. Results revealed an estimated prevalence of 0.8% (1:125) for definite/probable cases of FH in the Qatari population. We detected 16 known pathogenic/likely pathogenic mutations in LDLR and one in PCSK9; all in a heterozygous state with high penetrance. The most common mutation was rs1064793799 (c.313+3A >C) followed by rs771019366 (p.Asp90Gly); both in LDLR. In addition, we identified 18 highly penetrant possibly pathogenic variants, of which 5 were Qatari-specific, in LDLR, APOB, PCSK9 and APOE, which are predicted to be among the top 1% most deleterious mutations in the human genome but further validations are required to confirm their pathogenicity. We did not detect any homozygous FH or autosomal recessive mutations in our study cohort. This pioneering study provides a reliable estimate of FH prevalence in Qatar based on a significantly large population-based cohort, whilst uncovering the spectrum of genetic variants associated with FH.

Keywords: FH; LDL-C; LDLR; dyslipidemias; familial hypercholesterolemia; hypercholesterolemia; monogenic.

FIGURE 1

Classification of study cohort into FH subtypes based on phenotypic data. The flow chart depicts the workflow for the classification of study cohorts into FH subtypes based on phenotypic data only to fulfill DLCN criteria for FH classification. Bar charts represent numbers of individuals classified as definite, probable, possible and unlikely cases of FH in the analysis cohort.

FIGURE 2

Identified mutations in the LDLR gene. 16 known pathogenic variants (marked in red) and 3 possibly pathogenic mutations (marked in black) were detected in LDLR in our study cohort. The number of subjects carrying each mutation is depicted by dots above each variant. Protein change is in reference to the NCBI sequence NP_000518.1.

FIGURE 3

Lipid profiles of FH definition groups in the study cohort. Study subjects were categorized into definite, probable, possible and unlikely FH cases based on DLCN criteria, and using phenotype and genotype data. Bar charts represent levels of total cholesterol, HDL-C, LDL-C and triglycerides. LDL-C measurements were corrected for medication. Statistically significant (P < 0.05) differences among each FH definition compared to unlikely FH are denoted with an asterisk (*) in each plot.

FIGURE 4

Prevalence of familial hypercholesterolemia (FH) in Qatar. The study cohort comprised 13,677 individuals. 109 subjects were identified as definite and probable cases of FH based on the Dutch Lipid Clinic Network (DLCN) criteria, yielding a prevalence of ∼1 in 125 in Qatar. 52 subjects were identified as definite cases of FH, indicating a prevalence of ∼1 in 263 for definite FH. Of the 52 definite cases, 39 subjects carried a known pathogenic mutation in LDLR or PCSK9 and showed FH-related phenotypes. 57 subjects were identified as probable cases of FH with 51 subjects showing FH-related phenotypes (DLCN score 6–8), while 6 subjects carried a known pathogenic mutation (DLCN score 8), but their LDL-C levels were below the threshold of 4.0 mmol/L defined by DLCN criteria.