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@ARTICLE{Tan:151525,
      author       = {Tan, Jing and Wagner, Matias and Stenton, Sarah L. and
                      Strom, Tim M. and Wortmann, Saskia B. and Prokisch, Holger
                      and Meitinger, Thomas and Oexle, Konrad and Klopstock,
                      Thomas},
      title        = {{L}ifetime risk of autosomal recessive mitochondrial
                      disorders calculated from genetic databases},
      journal      = {EBioMedicine},
      volume       = {54},
      issn         = {2352-3964},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DZNE-2020-01109},
      pages        = {102730},
      year         = {2020},
      abstract     = {BackgroundMitochondrial 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.MethodsWe 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.FindingsThe 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.InterpretationWe
                      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.FundingGerman Federal Ministry of
                      Education and Research.},
      keywords     = {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 / Mitochondrial
                      Diseases: genetics / Solute Carrier Family 22 Member 5:
                      genetics},
      cin          = {AG Wagner / AG Levin},
      ddc          = {610},
      cid          = {I:(DE-2719)1011201 / I:(DE-2719)1111016},
      pnm          = {344 - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC7163308},
      pubmed       = {pmid:32305867},
      doi          = {10.1016/j.ebiom.2020.102730},
      url          = {https://pub.dzne.de/record/151525},
}