A CLINICALLY VALIDATED GENETIC SCREENING FOR FAMILIAL HYPERCHOLESTEROLEMIA IN QUÉBEC

Familial Hypercholesterolemia (FH) is the most common genetic disorder in humans with an estimated prevalence of 1/311. In geographic regions with founder effect mutations, such as the province of Québec, prevalence is as high as 1/80. FH is associated with premature atherosclerotic cardiovascular disease caused by elevated low-density lipoprotein cholesterol (LDL-C). Although early diagnosis and therapy of FH can normalize life expectancy, less than 15% of cases are diagnosed. Cascade screening and genetic testing aim to improve diagnosis, treatment, and outcomes in FH.

Here, we report a single center experience with the only clinically validated molecular genetic screening for FH (CLIA compliant) in Canada. We performed next generation sequencing of the LDLR, APOB and PCSK9 genes and multiplex ligation-dependent probe amplification (MLPA) of the LDLR gene to detect genetic mutations and copy number variants. All mutations were reviewed by a geneticist and cross-referenced in ClinVar. Between 2018-2020, we examined 369 FH cases (57% males, 43% females) based on the Canadian FH definition clinical criteria. For index patients, mean age at diagnosis was 40±16 years, while 30±16 years was for cascade screening patients. Baseline (untreated) LDL-C was 6.5±2.0 mmol/L. In 224 patients who underwent genetic testing, a pathogenic mutation was identified in 167 (75%) individuals, in keeping with ∼20% of FH patients with a polygenic form. A majority of affected patients had mutations in the LDLR (87%) or APOB (13%) genes. Interestingly, the genetic panel offered by Québec's Health Ministry, which includes 10 common mutations in French Canadians, only accounted for 46% of identified mutations. Even in patients self-describing as French Canadians, more than 20% did not have a common mutation. We subsequently examined the impact of genetic testing in re-classification of patients’ FH diagnosis. There were 3 (1%) individuals with a “severe hypercholesterolemia” phenotype initially categorized as “not FH” and 85 (38%) with “probable FH” re-classified to “definite FH”.

Genetic testing in patients suspected of having FH provides diagnostic certainty and permits re-classification of individuals with a diagnosis of “severe hypercholesterolemia” or “probable FH” according to current definitions. Furthermore, the limited genetic panel offered by the province of Québec, focusing on common French-Canadian mutations, provides incomplete data in the majority of cases. We therefore propose that most patients with a presumptive diagnosis of FH undergo an unbiased genetic analysis. This study has implications on cascade screening, public health policies and reimbursement of drugs such as PCSK9 inhibitors.