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

• Published in: Human molecular genetics Vol. 27; no. 7; pp. 1164 - 1173
• Main Authors: Lenglet, Hugo, Schmitt, Caroline, Grange, Thomas, Manceau, Hana, Karboul, Narjesse, Bouchet-Crivat, Florian, Robreau, Anne-Marie, Nicolas, Gael, Lamoril, Jerôme, Simonin, Sylvie, Mirmiran, Arienne, Karim, Zoubida, Casalino, Enrique, Deybach, Jean-Charles, Puy, Hervé, Peoc'h, Katell, Gouya, Laurent
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.04.2018; Oxford University Press (OUP)
• Subjects: Databases, Nucleic Acid; Endocrinology and metabolism; Female; France; France - epidemiology; Gene-Environment Interaction; Genetics; Hematology; Human genetics; Human health and pathology; Humans; Hydroxymethylbilane Synthase; Hydroxymethylbilane Synthase - genetics; Hépatology and Gastroenterology; Infectious diseases; Life Sciences; Male; Mutation, Missense; Penetrance; Porphyria, Acute Intermittent; Porphyria, Acute Intermittent - enzymology; Porphyria, Acute Intermittent - epidemiology; Porphyria, Acute Intermittent - genetics; Prevalence; Tissues and Organs; Urology and Nephrology; France
• DOI: 10.1093/hmg/ddy030
• ISSN: 0964-6906; 1460-2083

Abstract Acute intermittent porphyria (AIP) is a disease affecting the heme biosynthesis pathway caused by mutations 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 from the 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 42 missense 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 and modulated by kinship and the area in which the person was living, demonstrating strong influences of genetic and environmental modifiers on inheritance. Null alleles were associated with a more severe phenotype and a higher penetrance than for other mutant 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 dominant model, instead of being modulated by strong environmental and genetic factors independent from HMBS. An oligogenic inheritance model with environmental modifiers might better explain AIP penetrance and heritability.