Dataset Information

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.

SUBMITTER: Chen B

PROVIDER: S-EPMC5063710 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Chen Brenden B Solis-Villa Constanza C Hakenberg Jörg J Qiao Wanqiong W Srinivasan Ramakrishnan R RR Yasuda Makiko M Balwani Manisha M Doheny Dana D Peter Inga I Chen Rong R Desnick Robert J RJ

Human mutation 20160905 11

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 datab ...[more]

PMID: 27539938

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Project description:BackgroundAcute intermittent porphyria (AIP) is a rare inherited disorder with extremely low prevalence. Early detection of patients with potential pathogenic hydroxymethylbilane synthase (HMBS) variants is crucial for clinical prognosis. This study was designed to investigate the prevalence of pathogenic HMBS variants in Chinese population.MethodsThe China Metabolic Analysis Project (ChinaMAP) database was employed to predict the prevalence of pathogenic HMBS variants in the Chinese population according to the variant interpretation guidelines of The American College of Medical Genetics and Genomics (ACMG). And the prevalence of pathogenic HMBS variants in Mixed American (AMR), African/African American (AFR), and Non-Finnish European (NFE) populations were estimated based on the Genome Aggregation Database (gnomAD) genome V3.0 database according to the guidelines of ACMG. An epidemiological investigation of AIP was conducted in Hebei Province, China through collecting the annual newly-diagnosed AIP cases of inpatients in 32 comprehensive grade III A hospitals from January 2011 to December 2020 in Hebei, China.ResultsA total of 5 pathogenic/likely pathogenic (P/LP) HMBS variants were identified and the prevalence of pathogenic HMBS variants was predicted to be 1/1,765. Furthermore, based on the gnomAD genome V3.0 database, the estimated prevalence of pathogenic HMBS variants was 1/1,367, 1/1,403, and 1/621 in AMR, AFR, and NFE populations, respectively. The distribution of these variants varied among different racial populations. Moreover, AIP patients were predominantly hospitalized in comprehensive grade III A tertiary hospitals in Hebei province over a 10-year period. A total of 39 patients were newly-diagnosed with AIP, and a majority of them were female (n=36). The annual incidence between 2011 and 2017 {0.03 [95% confidence interval (CI): 0.01 to 0.11] to 0.05 (95% CI: 0.07 to 0.14) per million population} was generally lower than [0.07 (95% CI: 0.03 to 0.17) to 0.08 (95% CI: 0.03 to 0.18) per million] in 2018 and thereafter.ConclusionsChina has made great strides in the management of AIP. More nationwide epidemiological surveys and study of the prevalence rate of AIP patients in China are urgently required.

Project description:Background: Early detection and diagnosis are important crucial to prevent life-threatening acute attacks in patients with acute intermittent porphyria (AIP). We aim to provide comprehensive data on the clinical and hydroxymethylbilane synthase (HMBS) gene variant characteristics and genotype-phenotype association of Chinese patients with AIP in order to improve clinicians' knowledge of AIP and reduce misdiagnosis and mistaken treatment. Methods: We searched the literature on Chinese patients with AIP in PubMed, Web of Science, Wiley Online Library, ScienceDirect and Chinese literature databases up to August 2023 in our analysis to explore the clinical and HMBS gene variant characteristics of Chinese patients with AIP. Results: A total of 41 original articles associated with Chinese AIP patients were included for analysis: 97 variants were detected in 160 unrelated families, including 35 missense, 29 frameshift, 24 splicing and 9 nonsense variants, with c.517C>T being the most common variant. Clinical data were reported in 77 of 160 patients: Most of them were female (67/77) and the age was 28.8 ± 9.9 years. The most common symptom was abdominal pain (73/77, 94.8%), followed by central nervous system symptoms (45/77, 58.4%). 13.0% (10/77) of patients experienced psychiatric symptoms. Hyponatremia was the most common electrolyte abnormality (42/77). 31 patients received carbohydrate loading therapy, and 30 of them were improved. 6 patients were treated with carbohydrate loading combined with hemin therapy and 5 eventually improved. All variants causing premature stop codons, frameshifts or enzyme activity center may experience more severe clinical phenotypes such as seizures, respiratory paralysis, intracranial hemorrhage disorder or respiratory failure. Conclusion: The most common presenting symptom in Chinese AIP patients was abdominal pain, followed by central nervous system symptoms. The HMBS gene analysis in Chinese AIP patients revealed that the heterogeneity is strong and the most common variant was missense mutation, with c.517C>T being the most common variant. The genotype-phenotype association helps guide clinical diagnosis and treatment. However, the treatment for AIP in China is limited and monolithic, and more attention needs to be paid to the treatment.

Dataset Information

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

Publications

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

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