TY  - JOUR
AU  - Tan, Jing
AU  - Wagner, Matias
AU  - Stenton, Sarah L.
AU  - Strom, Tim M.
AU  - Wortmann, Saskia B.
AU  - Prokisch, Holger
AU  - Meitinger, Thomas
AU  - Oexle, Konrad
AU  - Klopstock, Thomas
TI  - Lifetime risk of autosomal recessive mitochondrial disorders calculated from genetic databases
JO  - EBioMedicine
VL  - 54
SN  - 2352-3964
CY  - Amsterdam [u.a.]
PB  - Elsevier
M1  - DZNE-2020-01109
SP  - 102730
PY  - 2020
AB  - 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.
KW  - ATPases Associated with Diverse Cellular Activities: genetics
KW  - Acyl-CoA Dehydrogenase: genetics
KW  - DNA Polymerase gamma: genetics
KW  - Databases, Genetic: statistics & numerical data
KW  - Genes, Recessive
KW  - Genetic Predisposition to Disease
KW  - Humans
KW  - Metalloendopeptidases: genetics
KW  - Mitochondrial Diseases: epidemiology
KW  - Mitochondrial Diseases: genetics
KW  - Solute Carrier Family 22 Member 5: genetics
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC7163308
C6  - pmid:32305867
DO  - DOI:10.1016/j.ebiom.2020.102730
UR  - https://pub.dzne.de/record/151525
ER  -