Acute Intermittent Porphyria: Predicted Pathogenicity of HMBS Variants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease

Hum Mutat. 2016 Nov;37(11):1215-1222. doi: 10.1002/humu.23067. Epub 2016 Sep 5.


Acute intermittent porphyria results from hydroxymethylbilane synthase (HMBS) mutations that markedly decrease HMBS enzymatic activity. This dominant disease is diagnosed when heterozygotes have life-threatening acute attacks, while most heterozygotes remain asymptomatic and undiagnosed. Although >400 HMBS mutations have been reported, the prevalence of pathogenic HMBS mutations in genomic/exomic databases, and the actual disease penetrance are unknown. Thus, we interrogated genomic/exomic databases, identified non-synonymous variants (NSVs) and consensus splice-site variants (CSSVs) in various demographic/racial groups, and determined the NSV's pathogenicity by prediction algorithms and in vitro expression assays. Caucasians had the most: 58 NSVs and two CSSVs among ∼92,000 alleles, a 0.00575 combined allele frequency. In silico algorithms predicted 14 out of 58 NSVs as "likely-pathogenic." In vitro expression identified 10 out of 58 NSVs as likely-pathogenic (seven predicted in silico), which together with two CSSVs had a combined allele frequency of 0.00056. Notably, six presumably pathogenic mutations/NSVs in the Human Gene Mutation Database were benign. Compared with the recent prevalence estimate of symptomatic European heterozygotes (∼0.000005), the prevalence of likely-pathogenic HMBS mutations among Caucasians was >100 times more frequent. Thus, the estimated penetrance of acute attacks was ∼1% of heterozygotes with likely-pathogenic mutations, highlighting the importance of predisposing/protective genes and environmental modifiers that precipitate/prevent the attacks.

Keywords: allele frequency; allele prevalence; disease penetrance; in silico prediction; in vitro expression.

MeSH terms

  • Computer Simulation
  • Female
  • Gene Frequency
  • Genetic Variation*
  • Humans
  • Male
  • Penetrance*
  • Porphyria, Acute Intermittent / ethnology
  • Porphyria, Acute Intermittent / genetics*
  • Sequence Analysis, DNA
  • White People / genetics*