With the advent of precision and genomic medicine, a critical issue is whether a disease gene variant is pathogenic or benign. Such is the case for the three autosomal dominant acute hepatic porphyrias (AHPs), including acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, each resulting from the half-normal enzymatic activities of hydroxymethylbilane synthase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase, respectively. To date, there is no public database that documents the likely pathogenicity of variants causing the porphyrias, and more specifically, the AHPs with biochemically and clinically verified information. Therefore, an international collaborative with the European Porphyria Network and the National Institutes of Health/National Center for Advancing Translational Sciences/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NCATS/NIDDK)-sponsored Porphyrias Consortium of porphyria diagnostic experts is establishing an online database that will collate biochemical and clinical evidence verifying the pathogenicity of the published and newly identified variants in the AHP-causing genes. The overall goal of the International Porphyria Molecular Diagnostic Collaborative is to determine the pathogenic and benign variants for all eight porphyrias. Here we describe the overall objectives and the initial efforts to validate pathogenic and benign variants in the respective heme biosynthetic genes causing the AHPs.

1st Faculty of Medicine Charles University Prague Prague Czech Republic

Biochemistry and Molecular Genetics Department Hospital Clínic IDIBAPS University of Barcelona Barcelona Spain

Centre Français des Porphyries Hôpital Louis Mourier Assistance Publique Hôpitaux de Paris Colombes and Centre de Recherche sur l'Inflammation UMR1149 INSERM Université Paris Diderot Paris France

Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York NY USA

Department of Internal Medicine University of Utah Salt Lake City UT USA

Department of Medical Biochemistry and Immunology University Hospital of Wales Cardiff UK

Department of Medicine University of California San Francisco CA USA

Department of Medicine Wake Forest University Winston Salem NC USA

Department of Preventive Medicine and Community Health University of Texas Medical Branch Galveston TX USA

Dipartimento di Medicina Interna Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Università degli Studi di Milano Milan Italy

Institute of Medical Genetics University Hospital of Wales Cardiff UK

Norwegian Porphyria Centre Department of Medical Biochemistry and Pharmacology Haukeland University Hospital Bergen Norway

Porphyria Center Rotterdam Center for Lysosomal and Metabolic Disorders Department of Internal Medicine Erasmus MC University Medical Center Rotterdam The Netherlands

Porphyria Centre Sweden Centre for Inherited Metabolic Diseases Karolinska Institutet Karolinska University Hospital Stockholm Sweden

Porphyria Research Unit Department of Medicine University Central Hospital of Helsinki Helsinki Finland

The Norwegian Quality Improvement of Laboratory Examinations Haraldsplass Deaconness Hospital Bergen Medical Faculty University of Bergen Bergen Norway

See more in PubMed

Anderson KE, Sassa S, Bishop DF, Desnick RJ. Disorders of heme biosynthesis: X-linked sideroblastic anemia and the porphyrias In: Beaudet AL, Vogelstein B, Kinzler KW, et al., eds. The online metabolic and molecular bases of inherited disease. New York, NY: McGraw-Hill; 2014. https://ommbid.mhmedical.com/content.aspx?bookid=971&sectionid=62638866#1102890723 Accessed 8 May 2019.

Puy H, Gouya L, Deybach JC. Porphyrias. Lancet. 2010;375:924–937. PubMed

Bonkovsky HL, Maddukuri VC, Yazici C, et al. Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. Am J Med. 2014;127:1233–1241. PubMed PMC

Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017;377:862–872. PubMed

Bonkovsky HL, Guo JT, Hou W, Li T, Narang T, Thapar M. Porphyrin and heme metabolism and the porphyrias. Compr Physiol. 2013;3:365–401. PubMed

Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. 2005;142:439–450. PubMed

Aarsand AK, Petersen PH, Sandberg S. Estimation and application of biological variation of urinary delta-aminolevulinic acid and porphobilinogen in healthy individuals and in patients with acute intermittent porphyria. Clin Chem. 2006;52:650–656. PubMed

Woolf J, Marsden JT, Degg T, et al. Best practice guidelines on first-line laboratory testing for porphyria. Ann Clin Biochem. 2017;54:188–198. PubMed

Zhang J, Yasuda M, Desnick RJ, Balwani M, Bishop D, Yu C. A LC-MS/MS method for the specific, sensitive, and simultaneous quantification of 5-aminolevulinic acid and porphobilinogen. J Chromatogr B Analyt Technol Biomed Life Sci. 2011;879:2389–2396. PubMed PMC

Whatley SD, Badminton MN. Role of genetic testing in the management of patients with inherited porphyria and their families. Ann Clin Biochem. 2013;50:204–216. PubMed

The 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015;526:68–74. PubMed PMC

Lek M, Karczewski KJ, Minikel EV, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–291. PubMed PMC

Stenson PD, Mort M, Ball EV, et al. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–677. PubMed PMC

Chen B, Solis-Villa C, Hakenberg J, et al. Acute intermittent porphyria: predicted pathogenicity of HMBS variants indicates extremely low penetrance of the autosomal dominant disease. Hum Mutat. 2016;37:1215–1222. PubMed PMC

Puy H, Deybach JC, Lamoril J, et al. Molecular epidemiology and diagnosis of PBG deaminase gene defects in acute intermittent porphyria. Am J Hum Genet. 1997;60:1373–1383. PubMed PMC

Robreau-Fraolini AM, Puy H, Aquaron C, et al. Porphobilinogen deaminase gene in African and Afro-Caribbean ethnic groups: mutations causing acute intermittent porphyria and specific intragenic polymorphisms. Hum Genet. 2000;107:150–159. PubMed

Solis C, Martinez-Bermejo A, Naidich TP, et al. Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias. Arch Neurol. 2004;61:1764–1770. PubMed

Tandy-Connor S, Guiltinan J, Krempely K, et al. False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care. Genet Med. 2018;20:1515–1521. PubMed PMC

Friez MJ. Attention: direct-to-consumer patrons: proceed with caution. Genet Med. 2018;20:1508–1509. PubMed

Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–424. PubMed PMC

Ellard S, Baple EL, Owens M, et al. ACGS Best Practice Guidelines for Variant Classification. 2018. http://www.acgs.uk.com/media/1092626/uk_practice_guidelines_for_variant_classification_2017.pdf. Accessed 27 July 2018.

Ellard S, Baple EL, Owens M, et al. ACGS Best Practice Guidelines for Variant Classification. 2017. http://www.acgs.uk.com/media/1140458/uk_practice_guidelines_for_variant_classification_2018_v1.0.pdf.

Cotton RG, Al Aqeel AI, Al-Mulla F, et al. Capturing all disease-causing mutations for clinical and research use: toward an effortless system for the Human Variome Project. Genet Med. 2009;11:843–849. PubMed

Johnston JJ, Biesecker LG. Databases of genomic variation and phenotypes: existing resources and future needs. Hum Mol Genet. 2013;22:R27–R31. PubMed PMC

Bennetts B, Caramins M, Hsu A, et al. Quality standards for DNA sequence variation databases to improve clinical management under development in Australia. Appl Transl Genom. 2014;3:54–57. PubMed PMC

Adams DR, Eng CM. Next-generation sequencing to diagnose suspected genetic disorders. N Engl J Med. 2018;379:1353–1362. PubMed

Milko LV, Funke BH, Hershberger RE, et al. Development of Clinical Domain Working Groups for the Clinical Genome Resource (ClinGen): lessons learned and plans for the future. Genet Med. 2019;21: 987–993. PubMed PMC

den Dunnen JT, Dalgleish R, Maglott DR, et al. HGVS recommendations for the description of sequence variants: 2016 update. Hum Mutat. 2016;37:564–569. PubMed

Whatley SD, Mason NG, Woolf JR, Newcombe RG, Elder GH, Badminton MN. Diagnostic strategies for autosomal dominant acute porphyrias: retrospective analysis of 467 unrelated patients referred for mutational analysis of the HMBS, CPOX, or PPOX gene. Clin Chem. 2009;55: 1406–1414. PubMed

Marsden JT, Rees DC. Urinary excretion of porphyrins, porphobilinogen and delta-aminolaevulinic acid following an attack of acute intermittent porphyria. J Clin Pathol. 2014;67:60–65. PubMed

Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017;66:1314–1322. PubMed PMC

Hift RJ, Davidson BP, van der Hooft C, Meissner DM, Meissner PN. Plasma fluorescence scanning and fecal porphyrin analysis for the diagnosis of variegate porphyria: precise determination of sensitivity and specificity with detection of protoporphyrinogen oxidase mutations as a reference standard. Clin Chem. 2004;50:915–923. PubMed

Nordmann Y, Puy H. Human hereditary hepatic porphyrias. Clin Chim Acta. 2002;325:17–37. PubMed

Guo R, Lim CK, Peters TJ. Accurate and specific HPLC assay of coproporphyrinogen III oxidase activity in human peripheral leucocytes. Clin Chim Acta. 1988;177:245–252. PubMed

Guo R, Lim CK, Peters TJ. High-performance liquid chromatographic assays for protoporphyrinogen oxidase and ferrochelatase in human leucocytes. J Chromatogr. 1991;566:383–396. PubMed

Schmitt C, Gouya L, Malonova E, et al. Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria. Hum Mol Genet. 2005;14:3089–3098. PubMed

Mustajoki P Normal erythrocyte uroporphyrinogen I synthase in a kindred with acute intermittent porphyria. Ann Intern Med. 1981; 95:162–166. PubMed

McColl KE, Moore MR, Thompson GG, Goldberg A. Screening for latent acute intermittent porphyria: the value of measuring both leucocyte delta-aminolaevulinic acid synthase and erythrocyte uroporphyrinogen-1-synthase activities. J Med Genet. 1982;19:271–276. PubMed PMC

Bonaiti-Pellie C, Phung L, Nordmann Y. Recurrence risk estimation of acute intermittent porphyria based on analysis of porphobilinogen deaminase activity: a Bayesian approach. Am J Med Genet. 1984; 19:755–762. PubMed

Lamon JM, Frykholm BC, Tschudy DP. Family evaluations in acute intermittent porphyria using red cell uroporphyrinogen I synthetase. J Med Genet. 1979;16:134–139. PubMed PMC

Meissner PN, Day RS, Moore MR, Disler PB, Harley E. Protoporphyrinogen oxidase and porphobilinogen deaminase in variegate porphyria. Eur J Clin Invest. 1986;16:257–261. PubMed

Lamoril J, Puy H, Whatley SD, et al. Characterization of mutations in the CPO gene in British patients demonstrates absence of genotypephenotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria. Am J Hum Genet. 2001; 68:1130–1138. PubMed PMC

Mustajoki P, Desnick RJ. Genetic heterogeneity in acute intermittent porphyria: characterisation and frequency of porphobilinogen deaminase mutations in Finland. Br Med J (Clin Res Ed). 1985;291:505–509. PubMed PMC

Yasuda M, Chen B, Desnick RJ. Recent advances on porphyria genetics: inheritance, penetrance & molecular heterogeneity, including new modifying/causative genes. Mol Genet Metab. 2018;S1096–7192:30645. PubMed PMC

Grandchamp B, De Verneuil H, Beaumont C, Chretien S, Walter O, Nordmann Y. Tissue-specific expression of porphobilinogen deaminase. Two isoenzymes from a single gene. Eur J Biochem. 1987;162:105–110. PubMed

Chen CH, Astrin KH, Lee G, Anderson KE, Desnick RJ. Acute intermittent porphyria: identification and expression of exonic mutations in the hydroxymethylbilane synthase gene. An initiation codon missense mutation in the housekeeping transcript causes “variant acute intermittent porphyria” with normal expression of the erythroid-specific enzyme. J Clin Invest. 1994;94:1927–1937. PubMed PMC

Lenglet H, Schmitt C, Grange T, et al. From a dominant to an oligogenic model of inheritance with environmental modifiers in acute intermittent porphyria. Hum Mol Genet. 2018;27:1164–1173. PubMed

Riera C, Lois S, de la Cruz X. Prediction of pathological mutations in proteins: the challenge of integrating sequence conservation and structure stability principles. WIREs Comput Mol Sci. 2014;4:249–268.

Choi Y, Sims GE, Murphy S, Miller JR, Chan AP. Predicting the functional effect of amino acid substitutions and indels. PLoS ONE. 2012;7:e46688. PubMed PMC