LIFETIME RISK OF AUTOSOMAL RECESSIVE MITOCHONDRIAL DISORDERS CALCULATED FROM GENETIC DATABASES

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.