Affordable Access

deepdyve-link
Publisher Website

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

Authors
  • Chen, Brenden1
  • Solis-Villa, Constanza1
  • Hakenberg, Jörg1
  • Qiao, Wanqiong1
  • Srinivasan, Ramakrishnan R1
  • Yasuda, Makiko1
  • Balwani, Manisha1
  • Doheny, Dana1
  • Peter, Inga1
  • Chen, Rong1
  • Desnick, Robert J2
  • 1 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York.
  • 2 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York. [email protected]
Type
Published Article
Journal
Human Mutation
Publisher
Wiley (John Wiley & Sons)
Publication Date
Nov 01, 2016
Volume
37
Issue
11
Pages
1215–1222
Identifiers
DOI: 10.1002/humu.23067
PMID: 27539938
Source
Medline
Keywords
License
Unknown

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.

Report this publication

Statistics

Seen <100 times