title: Acute Intermittent Porphyria: Predicted Pathogenicity of HMBS Variants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease.
abstract: 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.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York.
authors.forename: Brenden
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York.
authors.forename: Constanza
authors.initials: C
authors.lastname: Solis-Villa
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hakenberg
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York.
authors.forename: Wanqiong
authors.initials: W
authors.lastname: Qiao
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York.
authors.forename: Ramakrishnan R
authors.initials: RR
authors.lastname: Srinivasan
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York.
authors.forename: Makiko
authors.initials: M
authors.lastname: Yasuda
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York.
authors.forename: Manisha
authors.initials: M
authors.lastname: Balwani
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York.
authors.forename: Dana
authors.initials: D
authors.lastname: Doheny
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York.
authors.forename: Inga
authors.initials: I
authors.lastname: Peter
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York.
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York. robert.desnick@mssm.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D003198:Computer Simulation; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D008297:Male; D019683:Penetrance; D017118:Porphyria, Acute Intermittent / Q000208:ethnology / Q000235:genetics*; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics*
keywords: allele frequency; allele prevalence; disease penetrance; in silico prediction; in vitro expression