From a dominant to an oligogenic model of inheritance with environmental modifiers in acute intermittent porphyria

Abstract

Acute intermittent porphyria (AIP) is a disease affecting the heme biosynthesis pathway caused bymutations of the hydroxymethylbilane synthase (HMBS) gene. AIP is thought to display autosomal dominant inheritance with incomplete penetrance.We evaluated the prevalence, penetrance and heritability of AIP, in families with the disease fromthe French reference center for porphyria (CFP) (602 overt patients; 1968 relatives) and the general population, using Exome Variant Server (EVS; 12 990 alleles) data. The pathogenicity of the 42missense variants identified was assessed in silico, and in vitro, by measuring residual HMBS activity of the recombinant protein. The minimal estimated prevalence of AIP in the general population was 1/1299. Thus, 50 000 subjects would be expected to carry the AIP genetic trait in France. Penetrance was estimated at 22.9% in families with AIP, but at only 0.5-1% in the general population. Intrafamily correlation studies showed correlations to be strong overall andmodulated by kinship and the area in which the person was living, demonstrating strong influences of genetic and environmentalmodifiers on inheritance. Null alleles were associated with amore severe phenotype and a higher penetrance than for othermutant alleles. In conclusion, the striking difference in the penetrance of HMBS mutations between the general population and the French AIP families suggests that AIP inheritance does not follow the classical autosomal dominantmodel, instead of beingmodulated by strong environmental and genetic factors independent fromHMBS. An oligogenic inheritancemodel with environmentalmodifiersmight better explain AIP penetrance and heritability.