👤 Marta Futema

Heterozygous Familial Hypercholesterolaemia (HeFH) is caused by pathogenic variants in Variants in Among 54 818 unrelated participants, 167 were heterozygote for an FH-causing variant, giving a prevalence of 1:328 (95% CI 1:285 to 1:386). Prevalence was similar across ancestries, including African (1:388) and South Asian (1:276). Variant distribution was: The prevalence and gene distribution of FH-causing variants in 100KGP are consistent with UK estimates. Differences in variant spectrum across ancestries were observed; however, FH prevalence was similar. Participants who consented to the return of actionable findings were informed, providing direct clinical benefit from genomic research. Show less

Familial hypercholesterolaemia (FH) is a genetic disorder due to pathogenic variants in LDLR, APOB, and PCSK9 genes, characterised by elevated low-density lipoprotein cholesterol (LDL-C) concentration and a significantly increased risk of premature coronary heart disease. Annotating whole genome sequencing data of 536 FH patients using the VEP plugin UTRannotator, we identified a novel variant c.-35C > G in the 5' untranslated region (5'UTR) of LDLR, predicted to introduce an upstream translation initiation codon and upstream open reading frame (uORF) that is out of frame with the LDLR coding sequence. Using promoter and epitope reporter assays, we demonstrate that the c.-35C > G variant leads to the preferential utilisation of the upstream AUG codon over the wild-type LDLR translation start site. We additionally conducted reporter assays for a previously reported variant that introduces a novel AUG codon through a deletion at position -22 of the 5'UTR (c.-22del) and obtained similar results. These findings confirm a novel type of FH-causing LDLR variants, leading to a premature start of translation and a truncation, underscoring the need for expanded genetic screening beyond coding regions. Future studies should focus on further characterising 5'UTR variants to better understand their role in FH. Show less

Familial hypercholesterolaemia (FH) is an inherited disease of high LDL cholesterol (LDL-C) caused by defects in LDLR, APOB, APOE, and PCSK9 genes. A pathogenic variant cannot be found in ∼60% of clinical FH patients. Using whole genome sequencing (WGS), we examined genetic determinants of FH. Whole genome sequencing data generated by the 100 000 Genomes Project (100KGP) included 536 FH patients diagnosed using the FH Simon-Broome criteria. Rare variants in known FH genes were analysed. Genome-wide association study between 443 FH variant-negative unrelated FH cases and 77 275 control participants of the 100KGP was run using high-coverage WGS data. Polygenic risk scores for LDL-C (LDL PRS) and lipoprotein(a) (Lp(a) PRS) were computed. An FH-causing variant was found in 17.4% of FH cases. Genome-wide association study identified the LPA gene locus being significantly associated (P < 1 × 10-8). Familial hypercholesterolaemia variant-negative participants had higher LDL and Lp(a) PRSs in comparison with the controls (P < 1.0 × 10-16 and P < 4.09 × 10-6, respectively). Similar associations were found in the monogenic FH with both LDL and Lp(a) PRSs being higher than in controls (P < 4.03 × 10-4 and P < 3.01 × 10-3, respectively). High LDL PRS was observed in 36.4% of FH variant-negative cases, whereas high Lp(a) PRS in 18.5%, with 7.0% having both high LDL and Lp(a) PRSs. This genome-wide analysis of monogenic and polygenic FH causes confirms a complex and heterogeneous architecture of hypercholesterolaemia, with the LPA gene playing a significant role. Both Lp(a) and LDL-C should be measured for precision FH diagnosis. Specific therapies to lower Lp(a) should be targeted to those who will benefit most. Show less

Heterozygous familial hypercholesterolemia (FH), a monogenic cause for premature coronary artery disease (CAD) is often underdiagnosed. In individuals who meet the FH diagnostic criteria and lack pathogenic variants, polygenic factors are recognized as potential contributors. This study aimed to characterize the spectrum of genetic variants and determine the low-density lipoprotein polygenic risk score (LDL-PRS) among clinically diagnosed FH participants from South India. We recruited 116 unrelated participants with a pretreatment LDL- C concentration ≥ 190 mg/dl and a DLCN (Dutch Lipid Clinic Network) score ≥ 3. Targeted next-generation sequencing (NGS) of 23 lipid related genes and 12-SNP (Single nucleotide polymorphism) genotyping were performed. NGS identified 39 variants including 13 pathogenic and 26 variants of unknown significance (VUS) some of which were in non-classical genes: ABCG5, ABCG8, APOE, PPP1R17, SREBF2. Pathogenic variants were detected in 66.7% of those with definite FH,19.7% in probable FH and 2.7% in possible FH. Overall,66% were variant negative. Among variant negative (FH/V-) participants, 64% demonstrated high LDL-PRS, whereas 70% of variant positive participants also exhibited elevated scores; suggesting a contributory role of polygenic factors across both groups. Additionally, the observation that variant positive individuals with high LDL-PRS have an increased risk of coronary artery disease (CAD) adds important nuance to risk stratification within genetically confirmed FH patients. Confirmation of diagnosis by genetic testing is essential for the diagnosis of FH. Although LDL-PRS may offer little benefit in variant negative cases and improve CAD risk prediction in variant positive individuals, large scale studies are essential to validate its clinical utility and assess whether inclusion of additional LDL- raising SNPs could enhance the detection of polygenic FH in the Indian population. Show less

Individuals with familial hypercholesterolaemia (FH) have severely elevated plasma concentrations of low-density lipoprotein cholesterol (LDL-C) from birth and as a consequence have an elevated morbidity and mortality due to the development of coronary heart disease (CHD). Monogenic FH can be caused by carrying a single copy of a pathogenic variant in any of four genes (LDLR/APOB/PCSK9/APOE), which are all involved in the clearance of LDL-C from the blood by the liver. FH is one of the most common inherited disorders, with an estimated prevalence of carriers of around 1/280 individuals in most populations and ancestry groups. However, such variants can be found usually only in 20%-30% of clinically FH subjects, and in the majority of the no-variant individuals, the phenotype is most likely explained by the inheritance of a greater-than-average number of common variants of small effect, with such individuals better given the diagnosis of 'polygenic hypercholesterolaemia'. Also, in a proportion of no-variant subjects who meet the clinical criteria, the most likely explanation is due to overproduction of Lp(a) which is an LDL-C particle with a bound copy of the 'little-a' protein. Here, we review the research that has elucidated the genetic architecture of the FH phenotype and discuss recent studies and future prospects of finding additional genes where variants can cause FH. Show less

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (-1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10(-8))) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (-1.0 s.d. (s.e.=0.173), P-value=7.32 × 10(-9)). This is consistent with an effect between 0.5 and 1.5 mmol l(-1) dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale. Show less