Additive Effect of Rare Variants on the Phenotype of Familial Hypercholesterolemia.

BACKGROUND

Autosomal dominant hypercholesterolemia (ADH) is due to deleterious variants in , , or genes. Double heterozygote for these genes induces a more severe phenotype. More recently, a new causative variant of heterozygous ADH was identified in . Here we study the phenotype of 21 adult patients, double heterozygotes for rare and rare variants () in a national wide French cohort.

METHODS

, , , and genes were sequenced in 5743 probands addressed for ADH genotyping. The lipid profile and occurrence of premature atherosclerotic cardiovascular diseases were compared between the carriers (n=21) and the carriers of the same causative variants alone (n=22).

RESULTS

The prevalence of carriers in this French ADH cohort is 0.4%. Overall, LDL (low-density lipoprotein)-cholesterol concentrations were 23% higher in patients than in patients (9.14±2.51 versus 7.43±1.59 mmol/L, .0221). When only deleterious or probably deleterious variants were considered, the LDL-cholesterol concentrations were 46% higher in carriers than in carriers (10.83±3.45 versus 7.43±1.59 mmol/L, .0270). Two patients exhibited a homozygous familial hypercholesterolemia phenotype (LDL-cholesterol >13 mmol/L). Premature atherosclerotic cardiovascular disease was more common in patients than in carriers (70% versus 30%, .026).

CONCLUSIONS

Although an incomplete penetrance should be taken into account for variant classification, these results suggest an additive effect of deleterious variants on ADH phenotype highlighting the relevance of sequencing.