Acute Intermittent Porphyria: Predicted Pathogenicity ofHMBSVariants 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 14/58 NSVs as “likely-pathogenic”. In vitro expression identified 10/58 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 to 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.

Acute hepatic porphyrias: Recommendations for evaluation and long‐term management

“…In addition, there are no strong genotype–phenotype correlations that predict disease severity or prognosis, although certain mutations may be associated with recurrent AIP attacks . Genetic testing should be performed in a laboratory experienced with distinguishing pathogenic mutations from incidental polymorphisms …”

“…The combined prevalence of these disorders is estimated to be ∼5 per 100,000, with instances of higher prevalence due to founder effects . The penetrance of AIP, HCP, and VP is low, as >90% of heterozygotes for disease‐causing mutations remain asymptomatic for life …”

“…The majority of symptomatic AHP patients are those with sporadic attacks; approximately 3%‐5% have recurrent attacks . The incidence of asymptomatic latent patients is unknown, though studies indicate they are more frequent than previously thought . ASHE represents about 10% of AHP patients .…”

Acute Intermittent Porphyria in children: A case report and review of the literature

“…The patient reported by Anyaegbu et al (2012) had an elevated urine PBG at 263.2 mM (normal <1.3) and reportedly had an HMBS missense mutation that encoded p.R321H. However, this mutation is the most common benign variant in Caucasians with an allele frequency of ~0.002 and an in vitro expressed activity in the normal range (122% of mean expressed wild-type activity) confirming it as a benign variant (20). In this patient, HMBS sequencing should be repeated to identify the causative mutation.…”

Effects of hemin and hemodialysis in a patient with acute intermittent porphyria and renal failure

“…To date, .400 HMBS gene mutations, predominantly point mutations, have been identified as responsible mutations for AIP. 3 Most heterozygotes for HMBS mutations are asymptomatic (.80%). Factors such as certain medications, stress, dieting, and infections can provoke acute attacks, and unidentified modifying genes may increase attack susceptibility.…”