TY - JOUR
T1 - International Porphyria Molecular Diagnostic Collaborative
T2 - an evidence-based database of verified pathogenic and benign variants for the porphyrias
AU - Chen, Brenden
AU - Whatley, Sharon
AU - Badminton, Michael
AU - Aarsand, Aasne K.
AU - Anderson, Karl E.
AU - Bissell, D. Montgomery
AU - Bonkovsky, Herbert L.
AU - Cappellini, Maria D.
AU - Floderus, Ylva
AU - Friesema, Edith C.H.
AU - Gouya, Laurent
AU - Harper, Pauline
AU - Kauppinen, Raili
AU - Loskove, Yonina
AU - Martásek, Pavel
AU - Phillips, John D.
AU - Puy, Hervé
AU - Sandberg, Sverre
AU - Schmitt, Caroline
AU - To-Figueras, Jordi
AU - Weiss, Yedidyah
AU - Yasuda, Makiko
AU - Deybach, Jean Charles
AU - Desnick, Robert J.
N1 - Funding Information:
K.E.A., R.J.D., and J.D.P. are consultants for Alnylam Pharmaceuticals, Recordati Rare Diseases, Mitsubishi Tanabe Pharma. R.J.D. and M.Y. are inventors of intellectual property licensed to Alnylam Pharmaceuticals. K.E.A., R.J.D., and M.Y. have received research grants from Alnylam Pharmaceuticals and Recordati Rare Diseases. J.-C.D. is a consultant for Alnylam Pharmaceuticals and Orphan Europe Recordati Group. H.L.B. is a consultant for Alnylam Pharmaceuticals, Recordati Rare Diseases, and Moderna Therapeutics, Inc. and has received research grants from Alnylam Pharmaceuticals and Gilead Sciences, Inc. E.C.H.F. has received lodging support from Alnylam Pharmaceuticals. The respective honorarium from Alnylam for participating in an advisory group has been paid to Erasmus MC. A.A.K. has received travel and accommodation support from Clinuvel Pharmaceuticals. L.G. has received travel and lodging support from Alnylam Pharmaceuticals and Clinuvel Pharmaceuticals (no honorarium). P.H. has received travel and lodging support from Alnylam Pharmaceuticals and Clinuvel Pharmaceuticals. The respective honorarium from Alnylam for participating in an advisory group has been paid to Karolinska University Hospital or Karolinska Institutet. R.K. received travel and lodging support from Alnylam Pharmaceuticals and Clinuvel Pharmaceuticals and holds stock in Orion Pharma. S.S. received an honorarium from Alnylam for participating in an advisory group. J.T.-F. was compensated for limited in time consulting services by Moderna Therapeutics and Alnylam Pharmaceuticals Spain, SL. This work was primarily supported by the Department of Genetics and Genomic Sciences of the Icahn School of Medicine at Mount Sinai. K.E.A., D.M.B., H.L.B., R.J.D., and J.D.P. receive salary support from the Porphyrias Consortium (U54DK083909), which is part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN) of the National Institutes of Health (NIH). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR), NCATS, funded through collaboration between NCATS and the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK). The other authors declare no conflicts of interest.
Publisher Copyright:
© 2019, American College of Medical Genetics and Genomics.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
KW - acute hepatic porphyrias
KW - benign variants
KW - database
KW - pathologic variants
KW - variant validation
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U2 - 10.1038/s41436-019-0537-7
DO - 10.1038/s41436-019-0537-7
M3 - Article
C2 - 31073229
AN - SCOPUS:85065700023
VL - 21
SP - 2605
EP - 2613
JO - Genetics in Medicine
JF - Genetics in Medicine
SN - 1098-3600
IS - 11
ER -