Lifetime risk of autosomal recessive mitochondrial disorders calculated from genetic databases.

ATPases Associated with Diverse Cellular Activities / genetics Acyl-CoA Dehydrogenase / genetics DNA Polymerase gamma / genetics Databases, Genetic / statistics & numerical data Genes, Recessive Genetic Predisposition to Disease Humans Metalloendopeptidases / genetics Mitochondrial Diseases / epidemiology Solute Carrier Family 22 Member 5 / genetics
Autosomal recessive mitochondrial disorders Lifetime risk POLG Population genetics Prevalence SPG7

Journal

EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039

Informations de publication

Date de publication:
Apr 2020
Historique:
received: 10 01 2020
revised: 25 02 2020
accepted: 05 03 2020
pubmed: 20 4 2020
medline: 26 1 2021
entrez: 20 4 2020
Statut: ppublish

Résumé

Mitochondrial disorders are a group of rare diseases, caused by nuclear or mitochondrial DNA mutations. Their marked clinical and genetic heterogeneity as well as referral and ascertainment biases render phenotype-based prevalence estimations difficult. Here we calculated the lifetime risk of all known autosomal recessive mitochondrial disorders on basis of genetic data. We queried the publicly available Genome Aggregation Database (gnomAD) and our in-house exome database to assess the allele frequency of disease-causing variants in genes associated with autosomal recessive mitochondrial disorders. Based on this, we estimated the lifetime risk of 249 autosomal recessive mitochondrial disorders. Three of these disorders and phenylketonuria (PKU) served as a proof of concept since calculations could be aligned with known birth prevalence data from newborn screening reports. The estimated lifetime risks are very close to newborn screening data (where available), supporting the validity of the approach. For example, calculated lifetime risk of PKU (16·0/100,000) correlates well with known birth prevalence data (18·7/100,000). The combined estimated lifetime risk of 249 investigated mitochondrial disorders is 31·8 (20·9-50·6)/100,000 in our in-house database, 48·4 (40·3-58·5)/100,000 in the European gnomAD dataset, and 31·1 (26·7-36·3)/100,000 in the global gnomAD dataset. The disorders with the highest lifetime risk (> 3 per 100,000) were, in all datasets, those caused by mutations in the SPG7, ACADM, POLG and SLC22A5 genes. We provide a population-genetic estimation on the lifetime risk of an entire class of monogenic disorders. Our findings reveal the substantial cumulative prevalence of autosomal recessive mitochondrial disorders, far above previous estimates. These data will be very important for assigning diagnostic a priori probabilities, and for resource allocation in therapy development, public health management and biomedical research. German Federal Ministry of Education and Research.

Sections du résumé

BACKGROUND BACKGROUND
Mitochondrial disorders are a group of rare diseases, caused by nuclear or mitochondrial DNA mutations. Their marked clinical and genetic heterogeneity as well as referral and ascertainment biases render phenotype-based prevalence estimations difficult. Here we calculated the lifetime risk of all known autosomal recessive mitochondrial disorders on basis of genetic data.
METHODS METHODS
We queried the publicly available Genome Aggregation Database (gnomAD) and our in-house exome database to assess the allele frequency of disease-causing variants in genes associated with autosomal recessive mitochondrial disorders. Based on this, we estimated the lifetime risk of 249 autosomal recessive mitochondrial disorders. Three of these disorders and phenylketonuria (PKU) served as a proof of concept since calculations could be aligned with known birth prevalence data from newborn screening reports.
FINDINGS RESULTS
The estimated lifetime risks are very close to newborn screening data (where available), supporting the validity of the approach. For example, calculated lifetime risk of PKU (16·0/100,000) correlates well with known birth prevalence data (18·7/100,000). The combined estimated lifetime risk of 249 investigated mitochondrial disorders is 31·8 (20·9-50·6)/100,000 in our in-house database, 48·4 (40·3-58·5)/100,000 in the European gnomAD dataset, and 31·1 (26·7-36·3)/100,000 in the global gnomAD dataset. The disorders with the highest lifetime risk (> 3 per 100,000) were, in all datasets, those caused by mutations in the SPG7, ACADM, POLG and SLC22A5 genes.
INTERPRETATION CONCLUSIONS
We provide a population-genetic estimation on the lifetime risk of an entire class of monogenic disorders. Our findings reveal the substantial cumulative prevalence of autosomal recessive mitochondrial disorders, far above previous estimates. These data will be very important for assigning diagnostic a priori probabilities, and for resource allocation in therapy development, public health management and biomedical research.
FUNDING BACKGROUND
German Federal Ministry of Education and Research.

Identifiants

DOI: 10.1016/j.ebiom.2020.102730 PMID: 32305867 PMC: PMC7163308
pubmed: 32305867
pii: S2352-3964(20)30105-5
doi: 10.1016/j.ebiom.2020.102730
pmc: PMC7163308
pii:
doi:

Substances chimiques

SLC22A5 protein, human 0
Solute Carrier Family 22 Member 5 0
Acyl-CoA Dehydrogenase EC 1.3.8.7
DNA Polymerase gamma EC 2.7.7.7
POLG protein, human EC 2.7.7.7
Metalloendopeptidases EC 3.4.24.-
SPG7 protein, human EC 3.4.24.-
ATPases Associated with Diverse Cellular Activities EC 3.6.4.-

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

102730

Commentaires et corrections

Type : ErratumIn

Informations de copyright

Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest TK reports grants from the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG), the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) and the European Commission, outside the submitted work. TK also reports grants, personal fees, and non-financial and other support from ApoPharma Inc, Retrophin Pharmaceuticals, Santhera Pharmaceuticals, GenSight Biologics and Stealth Biotherapeutics, outside the submitted work. HP reports grants from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF). All other authors do not report any conflict of interests.

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Auteurs

Jing Tan (J)

Institute of Human Genetics, School of Medicine, Technische Universität München, Munich, Germany; Friedrich-Baur-Institute, Department of Neurology, University Hospital, LMU Munich, Munich, Germany.

Matias Wagner (M)

Institute of Human Genetics, School of Medicine, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany. Electronic address: matias.wagner@mri.tum.de.

Sarah L Stenton (SL)

Institute of Human Genetics, School of Medicine, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

Tim M Strom (TM)

Institute of Human Genetics, School of Medicine, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

Saskia B Wortmann (SB)

Institute of Human Genetics, School of Medicine, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany; Department of Pediatrics, University Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria.

Holger Prokisch (H)

Institute of Human Genetics, School of Medicine, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

Thomas Meitinger (T)

Institute of Human Genetics, School of Medicine, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

Konrad Oexle (K)

Institute of Neurogenomics, Neurogenetic Systems Analysis Unit, Helmholtz Zentrum München, Neuherberg, Germany.

Thomas Klopstock (T)

Friedrich-Baur-Institute, Department of Neurology, University Hospital, LMU Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. Electronic address: tklopsto@med.LMU.de.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de transport › Protéines AAA › ATPases associated with diverse cellular activities › Lifetime risk of autosomal recessive...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Flavoprotéines › Acyl-CoA dehydrogenase › Lifetime risk of autosomal recessive...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines mitochondriales › DNA Polymerase gamma › Lifetime risk of autosomal recessive...
questionsmedicales.fr › Sciences de l'information › Mémorisation et recherche des informations › Bases de données comme sujet › Bases de données factuelles › Bases de données génétiques › Lifetime risk of autosomal recessive...
questionsmedicales.fr › Phénomènes génétiques › Modes de transmission héréditaire › Gènes récessifs › Lifetime risk of autosomal recessive...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Lifetime risk of autosomal recessive...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Lifetime risk of autosomal recessive...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Peptide hydrolases › Metalloproteases › Metalloendopeptidases › Lifetime risk of autosomal recessive...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Maladies mitochondriales › Lifetime risk of autosomal recessive...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Protéines transporteurs de solutés › Transporteurs de cations organiques › Membre-5 de la famille-22 de transporteurs de solutés › Lifetime risk of autosomal recessive...