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Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically

Originally published, Thrombosis, and Vascular Biology. 2016;36:2439–2445



Next-generation sequencing technology is transforming our understanding of heterozygous familial hypercholesterolemia, including revision of prevalence estimates and attribution of polygenic effects. Here, we examined the contributions of monogenic and polygenic factors in patients with severe hypercholesterolemia referred to a specialty clinic.

Approach and Results—

We applied targeted next-generation sequencing with custom annotation, coupled with evaluation of large-scale copy number variation and polygenic scores for raised low-density lipoprotein cholesterol in a cohort of 313 individuals with severe hypercholesterolemia, defined as low-density lipoprotein cholesterol >5.0 mmol/L (>194 mg/dL). We found that (1) monogenic familial hypercholesterolemia–causing mutations detected by targeted next-generation sequencing were present in 47.3% of individuals; (2) the percentage of individuals with monogenic mutations increased to 53.7% when copy number variations were included; (3) the percentage further increased to 67.1% when individuals with extreme polygenic scores were included; and (4) the percentage of individuals with an identified genetic component increased from 57.0% to 92.0% as low-density lipoprotein cholesterol level increased from 5.0 to >8.0 mmol/L (194 to >310 mg/dL).


In a clinically ascertained sample with severe hypercholesterolemia, we found that most patients had a discrete genetic basis detected using a comprehensive screening approach that includes targeted next-generation sequencing, an assay for copy number variations, and polygenic trait scores.


Familial hypercholesterolemia (FH) is a relatively common disorder, previously thought to have a monogenic basis.1 The paradigmatic heterozygous form of FH (HeFH) is characterized by lifelong elevations in plasma low-density lipoprotein (LDL) cholesterol, typically >5.0 mmol/L (194 mg/dL), sometimes occurring with characteristic physical signs and frequently with a personal or family history of early cardiovascular disease (CVD).1 Recent population-based surveys, including screening with DNA sequencing, suggest that HeFH has a prevalence of ≈1 in 217 individuals in Northern Europe.2 Large-scale whole-exome sequencing efforts indicate that ≈4% of individuals with early coronary heart disease have HeFH resulting from one of several loss-of-function mutations in the LDLR gene encoding the LDL receptor.3 Other large-scale sequencing efforts indicate that within subgroups of individuals with severe hypercholesterolemia, defined as untreated LDL cholesterol >5.0 mmol/L (>194 mg/dL), only ≈2% had a pathogenic mutation in an autosomal dominant FH gene.4

Furthermore, high-throughput DNA sequencing has shown that 20% to 40% of individuals with phenotypic HeFH have no mutation in canonical FH genes, such as LDLR, APOB, or PCSK9.5 A few such individuals have rare mutations in minor genes, such as APOE, ABCG5, ABCG8, LIPA, or STAP1, underlying a phenotype that resembles FH.6 Others carry a disproportionately high burden of multiple small-effect common variants (single nucleotide polymorphisms), each of which incrementally raises plasma LDL cholesterol by a fraction of a millimole per liter, but which cumulatively raise LDL cholesterol into the FH range.5 Other individuals with apparent HeFH have none of the above causes identified, suggesting that mutations inaccessible by exome sequencing, such as intronic variants or copy number variations (CNVs),7 mutations in as yet undefined genes, gene-by-gene interactions, gene-by-environment interactions, non-Mendelian mechanisms (eg, epigenetic imprinting), or purely environmental factors, could explain their phenotype. To the extent that a molecular diagnosis of HeFH is desirable,1,8 for instance as a condition for third-party reimbursement of novel LDL-lowering therapies,9,10 molecular screening may need to concurrently assess monogenic and polygenic determinants, as well as CNVs.

Next-generation sequencing (NGS) is a powerful technology that has the potential to address clinically relevant hypotheses related to genetic conditions, such as FH. We have developed an NGS panel for dyslipidemias, including FH, which simultaneously assesses the monogenic and polygenic determinants of severely elevated LDL cholesterol from batches of 24 clinical samples.5 We assess major genes (LDLR, APOB, PCSK9, and LDLRAP1) and minor genes (APOE, ABCG5, ABCG8, LIPA, and STAP1) underlying monogenic FH, as well as single nucleotide polymorphism, genotypes for LDL cholesterol. We include an adjunctive method, namely multiplex ligation primer amplification (MLPA), to detect large-scale CNVs in the LDLR gene.7 This process allows us to address a specific hypothesis, such as what proportion of patients referred to a specialty clinic with possible or probable FH have a monogenic versus polygenic basis. We applied this procedure to samples from 313 individuals referred with severe hypercholesterolemia, defined as LDL cholesterol >5.0 mmol/L (>194 mg/dL), and showed that 53.7% of individuals had monogenic FH mutations and another 13.4% had an extreme polygenic score for high LDL cholesterol. These proportions markedly exceed those observed in population- or cohort-based studies for patients with elevated LDL cholesterol levels, suggesting enrichment for genetic causes through the medical referral process.

Materials and Methods

Materials and Methods are available in the online-only Data Supplement.



Baseline demographic features of the Ontario hypercholesterolemia cohort, overall and subdivided by sex, are shown in Table 1. In total, 91.1% of individuals were self-reported as white, with the remainder being of South Asian, Chinese, African, or unspecified ethnic background. The mean±standard deviation (SD) age was 51.0±15.1 years (range, 18.1–88.8 years), and the mean±SD untreated LDL cholesterol level was 6.78±1.75 mmol/L (262±72 mg/dL), with range 5.01 to 13.3 mmol/L (194–514 mg/dL). According to Dutch Lipid Clinic Network criteria, 65.5% of individuals had definite or probable HeFH. Personal and family (parental) history of early CVD (defined as onset <55 years and <60 years in men and women, respectively) were seen in 17.9% and 46.9% of subjects overall.

Table 1. Demographics of the Ontario Hypercholesterolemia Sample

Age, y51.0±15.149.0±13.452.4±16.0
Female, %58.5
Body mass index, kg/m227.8±5.828.6±5.627.2±6.0
Total cholesterol, mmol/L8.91±1.878.57±1.709.14±1.95
LDL cholesterol, mmol/L6.78±1.756.56±1.646.93±1.81
HDL cholesterol, mmol/L1.36±0.501.26±0.611.43±0.40
Triglyceride, mmol/L1.79±0.891.82±0.731.76±0.99
Personal history of CVD,* %17.925.012.9
Family history of CVD,* %46.950.044.7
Definite or probable HeFH (DLCN criteria),* %65.563.367.1
LDL polygenic risk score, unweighted (uwGRS)13.9±1.7714.0±1.8213.8±1.74
LDL polygenic risk score, weighted (wGRS)1.75±0.241.75±0.251.75±0.23

All values represent the mean±standard deviation. CVD indicates cardiovascular disease (onset <55 y in men; <60 y in women); DLCN, Dutch Lipid Clinics Network; HDL, high-density lipoprotein; HeFH, heterozygous familial hypercholesterolemia; LDL, low-density lipoprotein; uwGRS, unweighted genetic risk score; and wGRS, weighted genetic risk score.

*Based on complete data from 145 individuals.

Monogenic Variants

Likely or definite causal variants in LDLR, APOB, and PCSK9 genes detected in this study are listed in Table I in the online-only Data Supplement. The key findings summarized by mutation type are shown in Table 2. Overall, 148 of 313 (47.3%) individuals had at least 1 likely or definite causal mutation detected by NGS. All these variants were confirmed with Sanger sequencing. A further 20 of 313 (6.4%) had a heterozygous pathogenic CNV detected by MLPA, increasing the proportion of individuals with a mutation to 168 of 313 (53.7%).

Table 2. Genetic Diversity in the Ontario Hypercholesterolemia Sample

Mutation TypeOverall(N=313)LDL Cholesterol,mmol/LNumber of Unique MutationsNovel to This Study
FH mutation-positive1687.36±2.1710516
LDLR (single mutations)1417.40±1.979012
  Copy number variation207.11±1.7780
  Missense (and small in-frame deletion)747.07±1.61515
APOB (missense)156.51±1.3020
PCSK9 (missense)26.38±0.4520
Two mutations107.96±4.50115*
FH mutation-negative1456.23±1.27
 LDL wGRS <1.961036.20±1.22
 LDL wGRS ≥1.96426.28±1.39

All values represent the mean±standard deviation. APOB indicates gene encoding apolipoprotein B; FH, familial hypercholesterolemia; LDL, low-density lipoprotein; LDLR, gene encoding LDL receptor; PSCK9, gene encoding proprotein convertase subtilisin/kexin type 9; wGRS, weighted genetic risk score; and 2 mutations, individuals with 2 likely or definite FH-causing alleles.

*LDLR, I623T was counted once in the missense mutation category.

Most FH mutation-positive Ontario subjects had a heterozygous LDLR gene mutation (141/168 or 83.9%), whereas 15 (8.9%) and 2 (1.2%) of the subjects had mutations in APOB and PCSK9 genes, respectively. No potential causative variants were found in STAP1, APOE, ABCG5, ABCG8, LDLRAP1, or LIPA. Twenty of all FH mutation-positive subjects (11.9%) had a large-scale CNV in the LDLR gene. Although no patient had homozygous FH based on our selection criteria, 10 FH mutation-positive individuals (6.0%) were found to have 2 variant alleles; of the 20 variant alleles in this pool, 14, 4, and 2 were in LDLR, APOB, and PCSK9 genes, respectively (Table I in the online-only Data Supplement). The mean LDL cholesterol in carriers of 2 mutant alleles was nonsignificantly higher than that in the rest of the study sample (Table 2; Figure 1A). Simple heterozygotes for APOB or PCSK9 mutations had significantly lower mean LDL cholesterol than simple heterozygotes for LDLR mutations (Figure 1A).

Figure 1.

Figure 1. Monogenic and polygenic components of hypercholesterolemia in the Ontario cohort. A, Low-density lipoprotein (LDL) cholesterol levels (mean±standard deviations) according to monogenic variant genotype in the Ontario severe hypercholesterolemia sample. Individuals are classified according to presence of 0, 1, or 2 variants (mutations) detected by next-generation sequencing (NGS) and multiplex ligation primer amplification (MLPA) in LDLR, APOB, or PSCK9 genes. Familial hypercholesterolemia mutation-positive individuals (Mut.+) are further subgrouped according to extreme weighted genetic risk score (GRS) <1.96 and ≥1.96, respectively. Comparisons of mean LDL cholesterol levels between selected genotype classes are shown, with nominal significant P<0.05. B, Percentages of individuals with severe hypercholesterolemia within different LDL cholesterol ranges (numbers of individuals shown), classified as having a monogenic variant detected by NGS and MLPA or a polygenic basis defined as an extreme weighted GRS ≥1.96 (≥90th percentile for elevated LDL cholesterol).

Among the 168 FH mutation-positive individuals were 105 unique mutations, 90 of which (85.7%) were within the LDLR gene. Among all mutations found in this study, 16 were novel, of which 12 were within the LDLR gene: 2 splicing, 5 frameshift, 0 nonsense, and 5 missense mutations (Table I in the online-only Data Supplement). When considering only LDLR gene mutations, there were no differences in mean LDL cholesterol levels between subgroups of individuals with different mutation types (Figure 1A).

There was a stepwise significant increase in the proportion of individuals with monogenic mutations according to plasma LDL cholesterol stratum (Figure 1B). For individuals with LDL cholesterol 5.00 to 5.99 mmol/L (194–231 mg/dL), 6.00 to 6.99 mmol/L (232–270 mg/dL), 7.00 to 7.99 mmol/L (271–309 mg/dL), and ≥8.00 mmol/L (≥310 mg/dL), respectively, 42.1%, 40.4%, 69.8%, and 88.0% were positive for a rare mutation.

Polygenic Trait Scores

Of 145 FH mutation-negative Ontario individuals, 42 (29.0%) had an extreme LDL weighted genetic risk score (wGRS) >1.96, defined in Table II in the online-only Data Supplement. This was significantly higher than the proportion of FH mutation-positive individuals (11.9%) who had such an extreme wGRS (odds ratio, 3.02; 95% confidence interval, 1.61–5.68; P<0.0001). Similarly, 11.8% of 1092 individuals in the 1000 Genomes Project had an extreme LDL wGRS >1.96 (Figure 2A). We examined the distribution of wGRS in various cohorts (Figure 2B) and found no difference between 1000 Genomes Project and Ontario FH mutation-positive individuals (mean±SD scores, 1.66±0.27 and 1.68±0.23, respectively, NS). In contrast, the distribution of wGRS in Ontario FH mutation-negative individuals was markedly shifted to the right, with a mean±SD score of 1.84±0.21. Although the absolute differences in mean scores were modest, as is typical for polygenic effects, the differences in overall distribution of scores were highly significant between FH mutation-negative and both FH mutation-positive (P=4.3×1010) and 1000 Genomes Project control individuals (P=2.9×1018).

Figure 2.

Figure 2. Polygenic component of hypercholesterolemia in the Ontario cohort. A, Percentages of individuals from various samples and subgroups with an extreme weighted genetic risk score (wGRS) ≥1.96 (≥90th percentile for elevated low-density lipoprotein [LDL] cholesterol), including the 1000 Genomes (1KG, Release 1; control cohort and individuals with and without a monogenic cause for familial hypercholesterolemia (FH) detected by next-generation sequencing or multiplex ligation primer amplification in the Ontario cohort. Total numbers of individuals and percentages with extreme wGRSs are shown. FH mutation-negative with severe hypercholesterolemia had significantly higher odds of an extreme wGRS than mutation-positive individuals (odds ratio, 3.02; 95% confidence interval, 1.61–5.68; P<0.0001) and normal controls from the 1KG cohort. B, Distribution of wGRSs for elevated LDL cholesterol in individuals from the 1KG cohort, and Ontario individuals with severe hypercholesterolemia who are FH mutation-positive or negative. There is no significant difference in the distribution of wGRSs between 1KG and FH mutation-positive individuals, whereas the distribution of wGRSs in FH mutation-negative individuals differs significantly from both these other groups (P=2.9×1018 and P=4.3×1010, respectively).

We then evaluated the mean LDL cholesterol levels in mutation-negative individuals according to extreme wGRS and found no difference (Table 2). We also found no difference in mean LDL cholesterol levels in FH mutation-positive individuals according to extreme wGRS (Figure 1A).

Combining Monogenic and Polygenic Determinants

Overall, the percentage of Ontario individuals with severe hypercholesterolemia who had an identifiable probable genetic cause detected with NGS was 148 of 313 (47.3%), which increased to 168 of 313 (53.7%) with MLPA results. This increased further to 210 of 313 (67.1%) when individuals with an extreme wGRS were included. Because LDL cholesterol levels increased, so did the percentage of individuals with an identifiable genetic cause. Specifically, for individuals with LDL cholesterol 5.00 to 5.99 mmol/L (194–231 mg/dL), 6.00 to 6.99 mmol/L (232–270 mg/dL), 7.00 to 7.99 mmol/L (271–309 mg/dL), and ≥8.00 mmol/L (≥310 mg/dL), respectively, 57.0%, 59.5%, 79.2%, and 92.0% had a genetic basis for their elevated LDL cholesterol (Figure 1B). Furthermore, polygenic determinants were less common among individuals with the highest LDL cholesterol levels (Figure 1B).


High-throughput NGS has transformed our understanding of HeFH. Here, we applied targeted NGS with custom annotation, coupled with MLPA evaluation of large-scale CNV and polygenic GRS assessment in a cohort of 313 individuals with severe hypercholesterolemia, in whom FH was the likely clinical diagnosis. We found that (1) monogenic FH-causing mutations detected by targeted NGS were present in 47.3% of individuals; (2) the percentage of individuals with monogenic mutations increased to 53.7% when heterozygous CNVs were included; (3) 83.9% of monogenic mutations were within the LDLR gene; (4) the percentage of individuals with a genetic component further increased to 67.1% when individuals with extreme wGRS were included; (5) the percentage of individuals with an identified genetic component increased from 57.0% to 92.0% as LDL cholesterol level increased from 5.0 to >8.0 mmol/L (194 to >310 mg/dL); and (6) individuals with LDLR gene mutations had higher mean LDL cholesterol levels than individuals either with APOB or PSCK9 mutations or those with an extreme wGRS.

Within this clinical cohort, NGS alone underestimated the number of individuals with a genetic basis for severe hypercholesterolemia. About half of individuals were FH mutation-positive solely based on NGS results, but this increased to more than two-thirds of individuals when CNVs and extreme polygenic wGRS were considered. We suggest that these additional genetic determinants should be considered in routine molecular assessment of patients with severe hypercholesterolemia. The actual proportion of patients with each type of genetic determinant will vary between cohorts and populations. At present, at least 2 methods are required: our NGS method (see Materials and Methods) and pipeline reports both small monogenic variants and polygenic risk scores, whereas detection of CNVs requires that the independent MLPA method is run in parallel. However, we note that there has been marked progress in improving bioinformatic annotation tools to predict CNVs from NGS data.11 It is likely that in the near future, a single platform, namely NGS plus bioinformatics, will permit reporting of small-scale sequence variants, large-scale CNVs, and genetic risk scores. MLPA could then be reserved for confirming predicted CNVs from NGS results.

A recent large-scale sequencing study performed in individuals with LDL cholesterol >4.91 mmol/L (>190 mg/dL) ascertained through CVD case–control and population-based samples showed, perhaps surprisingly, prevalence of FH mutation-positive individuals of only ≈2%.4 This is much lower than the 47.3% of individuals with LDL cholesterol >5 mmol/L observed in our clinically ascertained cohort. Why is there such a wide disparity in the prevalence of FH mutation-positive individuals? The most likely explanation is the difference in ascertainment strategy.

Individuals in our study were all medically identified with severe hypercholesterolemia, resulting in referral for assessment and treatment advice. From the outset, they represented a selected group of individuals, in whom FH was already considered as possible on clinical grounds. In contrast, agnostic screening in broader, nonselected cohorts, when genetic dyslipidemia is not at top-of-mind, could be expected to yield a lower prevalence of FH mutation-positive individuals for the LDL cholesterol level, especially if family history was not considered.4 Similar disparities of frequencies of FH mutation-positive individuals have been observed previously.12 For instance, 35% to 65% of patients in other clinically ascertained hypercholesterolemia cohorts of various ethnic backgrounds were FH mutation-positive by DNA sequencing,1315 in contrast to only 2.4% of individuals with total cholesterol >7 mmol/L (>271 mg/dL) ascertained agnostically in a population-based study.16 This disparity was proposed to be related to enrichment for FH mutation-positive individuals through the medical referral process combined with unavailability of other prioritizing clinical data, such as family history in population-based samples.6 Also, unmeasured types of variation, such as CNVs and polygenic effects, may be present in a high proportion of hypercholesterolemic individuals from population-based samples.

Our findings also indicate that as LDL cholesterol increases, so does the likelihood that the patient is FH mutation-positive. A critical point of inflection seems to be LDL cholesterol >8.0 mmol/L (>310 mg/dL), where almost all patients have a monogenic basis, whereas almost none have a polygenic basis. In contrast, at the lower end of the severe hypercholesterolemia range, that is, LDL cholesterol 5.0 to 6.9 mmol/L, ≈15% to 20% of individuals have an extreme wGRS. Among individuals with a monogenic basis for their severe hypercholesterolemia, we found no differences between genetic subgroups. Interestingly, several patients carried 2 mutant alleles, of which 1 always affected LDLR: in 4 cases, the second mutation was also in the LDLR gene (ie, compound heterozygotes), whereas in 6 cases the second mutation was in either APOB or PSCK9 genes (ie, double heterozygotes). Such genotypes have been occasionally reported in some cases of phenotypic homozygous FH.17 Although individuals in this study with this genotype tended to have higher LDL cholesterol levels, the difference was not significant, although this may have reflected the small subgroup size. Alternatively, the mutations found in this subgroup may only have had marginal additive effects on LDL cholesterol levels.

Overall, the odds of FH mutation-negative individuals in this cohort having an extreme wGRS is ≈3-fold greater than both the general population and the FH mutation-positive individuals. This is similar to the ≈2-fold greater odds of an extreme wGRS found FH mutation-negative individuals in a comparable FH cohort studied using an analogous but different risk score.5 An extreme wGRS thus identifies a subset of patients, although by no means all, who are at increased genetic risk for severe hypercholesterolemia. Interestingly, an extreme wGRS did not seem to modulate the severity of the LDL cholesterol phenotype in either FH mutation-positive or mutation-negative subjects, although again this could simply reflect small subgroups and insufficient statistical power. In our 145 FH-mutation negative patients, there was no correlation between LDL cholesterol level and wGRS (r=0.05; P=NS). Nonetheless, the strong association of wGRS with high LDL cholesterol levels shown by discrete statistical analysis (ie, odds ratio, 3.02; P<0.0001) confirms the validity of this score as a genetic marker of risk of elevated LDL cholesterol. However, demonstrating a continuous positive proportional linear relationship between wGRS and LDL cholesterol levels may require a much larger sample size. Alternatively, it is possible that in FH mutation-negative individuals, those with a low wGRS have another unidentified cause for elevated LDL cholesterol, independent of wGRS. Furthermore, in FH mutation-positive individuals, the influence on phenotype of the monogenic mutation could trump that of the polygenic wGRS.

The role of polygenic risk in severe hypercholesterolemia requires further evaluation to address several questions. For instance, several risk scores for elevated LDL cholesterol have been proposed18; which one performs best clinically? Are different scores required for different ethnic groups? For the same degree of LDL cholesterol elevation, is there a difference in prognosis or treatment response based on whether the patient has monogenic or polygenic hypercholesterolemia? For instance, when LDL cholesterol is >5.0 mmol/L (>194 mg/dL) and a monogenic FH mutation is present, there is a 22-fold increased risk of early CVD.4 However, even when a monogenic cause is absent, CVD risk in such individuals, whose LDL cholesterol is elevated presumably because of polygenic factors, is increased 6-fold,4 which is not inconsiderable. Given this difference in risk, should more intensive efforts be made to identify FH mutation-positive individuals or is the difference between a 22-fold and 6-fold increase clinically irrelevant? Should intervention be guided predominantly by the degree of LDL cholesterol elevation irrespective of the genetic basis? A mitigating factor is that baseline untreated LDL cholesterol levels may not always be available: in such cases, documenting a patient’s genetic architecture with respect to elevated LDL cholesterol may still be important.

Finally, about one-third (32.9%) of individuals in this study with severe hypercholesterolemia had no identifiable genetic cause, although this was reduced to 8.0% in individuals with LDL cholesterol >8.0 mmol/L (>310 mg/dL). It is possible, although unlikely, that as yet undiscovered monogenic causes of hypercholesterolemia could explain the phenotype in some patients.19,20 Other possible determinants include (1) additional as yet uncharacterized polygenic determinants, some of which may be ethnicity specific; (2) higher order or nonlinear interactions between 2 or more genetic variants that act synergistically to raise LDL cholesterol; (3) the impact of non-Mendelian factors, such as mitochondrial or epigenetic effects; or (4) strong predominant environmental factors or environmental factors that require interactions with either known or unknown genetic determinants to influence the phenotype.

Thus, in a real-world sample, we show that comprehensive screening of patients with severe hypercholesterolemia should include targeted resequencing, preferably using an NGS platform, plus an assay to detect CNVs, plus a set of single nucleotide polymorphisms for a genetic risk score based on the LDL cholesterol-raising alleles. Inclusion of CNVs and a wGRS substantially increases the proportion of individuals with a genetic basis for their clinically ascertained severe hypercholesterolemia, although the actual proportions will vary between cohorts and subpopulations. Stratification by genetic cause can be used in prospective observational or intervention studies, whereas individuals with severe hypercholesterolemia in the absence of a defined genetic cause can be subjects for further investigation to characterize the basis of their phenotype. Finally, because single nucleotide polymorphisms for elevated LDL cholesterol also cluster in families, we think that cascade screening of relatives should proceed whether a proband has elevated LDL cholesterol on either a monogenic or a polygenic basis.

Nonstandard Abbreviations and Acronyms


copy number variation


cardiovascular disease


familial hypercholesterolemia


heterozygous familial hypercholesterolemia


low-density lipoprotein


multiplex ligation primer amplification


next-generation sequencing


weighted genetic risk score


This manuscript was sent to Anne Tybjaerg-Hansen, Consulting Editor, for review by expert referees, editorial decision, and final disposition.

The online-only Data Supplement is available with this article at

Correspondence to Robert A. Hegele, MD, Department of Medicine, Robarts Research Institute, The University of Western Ontario, 4288A-1151 Richmond St North, London, Ontario, Canada N6A 5K8. E-mail


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  • In a clinically ascertained cohort of 313 Ontario patients with hypercholesterolemia, a targeted next-generation sequencing panel identified monogenic mutations in 53.7% and an extreme polygenic risk score in an additional 13.4% of individuals.

  • The percentage of individuals with an identified genetic component increased from 57.0% to 92.0% as LDL cholesterol level increased from 5.0 to >8.0 mmol/L (194 to >310 mg/dL).

  • Next-generation sequencing based on evaluation of hypercholesterolemia needs to consider both monogenic and polygenic causes.