Lifetime risk of autosomal recessive mitochondrial disorders calculated from genetic databases
| Autor: | Thomas Meitinger, Sarah L. Stenton, Thomas Klopstock, Holger Prokisch, Matias Wagner, Konrad Oexle, Tim M. Strom, Jing Tan, Saskia B. Wortmann |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Mitochondrial Diseases Research paper genetics [Mitochondrial Diseases] Population genetics lcsh:Medicine Genome Acyl-CoA Dehydrogenase statistics & numerical data [Databases Genetic] genetics [Metalloendopeptidases] 0302 clinical medicine Databases Genetic Prevalence Medicine genetics [ATPases Associated with Diverse Cellular Activities] Exome Genetics lcsh:R5-920 Metalloendopeptidases General Medicine Lifetime risk DNA Polymerase gamma ddc POLG 030220 oncology & carcinogenesis genetics [Solute Carrier Family 22 Member 5] lcsh:Medicine (General) Corrigendum Mitochondrial DNA Mitochondrial disease Genes Recessive General Biochemistry Genetics and Molecular Biology SPG7 03 medical and health sciences Humans Genetic Predisposition to Disease ddc:610 Solute Carrier Family 22 Member 5 Allele frequency Newborn screening business.industry Genetic heterogeneity Autosomal recessive mitochondrial disorders lcsh:R Autosomal Recessive Mitochondrial Disorders Population Genetics Lifetime Risk Polg Spg7 medicine.disease epidemiology [Mitochondrial Diseases] 030104 developmental biology genetics [DNA Polymerase gamma] ATPases Associated with Diverse Cellular Activities genetics [Acyl-CoA Dehydrogenase] business |
| Zdroj: | EBioMedicine 54, 102730 (2020). doi:10.1016/j.ebiom.2020.102730 EBioMedicine EBioMedicine 54:102730 (2020) EBioMedicine, Vol 54, Iss, Pp-(2020) |
| DOI: | 10.1016/j.ebiom.2020.102730 |
| Popis: | 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: 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: 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: 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: German Federal Ministry of Education and Research. Keywords: Autosomal recessive mitochondrial disorders, Population genetics, Prevalence, Lifetime risk, POLG, SPG7 |
| Databáze: | OpenAIRE |
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