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Kolářová, H.* ; Tan, J.* ; Strom, T.M.* ; Meitinger, T.* ; Wagner, M. ; Klopstock, T.*

Lifetime risk of autosomal recessive neurodegeneration with brain iron accumulation (NBIA) disorders calculated from genetic databases.

EBioMedicine 77:103869 (2022)
Publ. Version/Full Text Research data DOI
Open Access Gold
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Background: Neurodegeneration with brain iron accumulation (NBIA) are a group of clinically and genetically heterogeneous diseases characterized by iron overload in basal ganglia and progressive neurodegeneration. Little is known about the epidemiology of NBIA disorders. In the absence of large-scale population-based studies, obtaining reliable epidemiological data requires innovative approaches. Methods: All pathogenic variants were collected from the 13 genes associated with autosomal recessive NBIA (PLA2G6, PANK2, COASY, ATP13A2, CP, AP4M1, FA2H, CRAT, SCP2, C19orf12, DCAF17, GTPBP2, REPS1). The allele frequencies of these disease-causing variants were assessed in exome/genome collections: the Genome Aggregation Database (gnomAD) and our in-house database. Lifetime risks were calculated from the sum of allele frequencies in the respective genes under assumption of Hardy-Weinberg equilibrium. Findings: The combined estimated lifetime risk of all 13 investigated NBIA disorders is 0.88 (95% confidence interval 0.70–1.10) per 100,000 based on the global gnomAD dataset (n = 282,912 alleles), 0.92 (0.65–1.29) per 100,000 in the European gnomAD dataset (n = 129,206), and 0.90 (0.48–1.62) per 100,000 in our in-house database (n = 44,324). Individually, the highest lifetime risks (>0.15 per 100,000) are found for disorders caused by variants in PLA2G6, PANK2 and COASY. Interpretation: This population-genetic estimation on lifetime risks of recessive NBIA disorders reveals frequencies far exceeding previous population-based numbers. Importantly, our approach represents lifetime risks from conception, thus including prenatal deaths. Understanding the true lifetime risk of NBIA disorders is important in estimating disease burden, allocating resources and targeting specific interventions.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Autosomal Recessive Nbia Disorders ; Copan ; Lifetime Risk ; Neurodegeneration ; Pkan ; Plan
ISSN (print) / ISBN 2352-3964
e-ISSN 2352-3964
Journal EBioMedicine
Quellenangaben Volume: 77, Issue: , Pages: , Article Number: 103869 Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam [u.a.]
Reviewing status Peer reviewed
European Commission
Seventh Framework Programme
Retrophin, Inc.
ApoPharma Inc.