Genetic variations in familial hypercholesterolemia and cascade screening in East Asians

Familial hypercholesterolemia (FH) is a monogenic disorder of lipoprotein metabolism leading to an increased risk of premature cardiovascular disease. Genetic testing for FH is not commonly used in Asian countries. We aimed to define the genetic spectrum of FH in Hong Kong and to test the feasibility of cascade genetic screening.

Ninety-six Chinese subjects with a clinical diagnosis of FH were recruited, and family-based cascade screening incorporating genetic testing results was performed.

Forty-two distinct mutations were identified in 67% of the index FH cases. The majority of causative mutations were in the LDLR gene. The three commonest mutations in the LDLR gene were NM_000527.4(LDLR): c.1241 T>G, NM_000527.4(LDLR): c.1474G>A, and NM_000527.4(LDLR): c. 682G>A, and nine novel variants were identified. The NM_000384.2(APOB): c.10579 C>T variant of the APOB gene was found in 5% of the index subjects. The presence of causative mutation significantly increased the odds of successful family recruitment for screening with an OR of 3.7 (95% CI: 1.53-9.11, p = 0.004).

Approximately two-third of the subjects in this clinically ascertained sample of patients with FH had a discrete genetic basis. Genetic identification improves the response rate and efficiency of family screening.