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

Abstract

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.

Funding: This work was carried out in the framework of TIRCON ("Treat Iron-Related Childhood-Onset Neurodegeneration").

Keywords: Autosomal recessive NBIA disorders; CoPAN; Lifetime risk; Neurodegeneration; PKAN; PLAN.

Figure 1

Distribution of NBIA subtypes in the worldwide gnomAD dataset (a), European (non-Finnish) gnomAD dataset (b) and the in-house database (c). The distribution is based on a calculation of lifetime risk per 100,000 based on the allele frequency of 1059 variants in a total of 13 NBIA genes associated with autosomal recessive NBIA disorders. Each colour represent a specific disorder as shown in the legend on the bottom right corner. The section “Other” is comprised of disorders with a lifetime risk below 0.017 per 100,000. ACP, Aceruloplasminemia; CoPAN, COASY protein-associated neurodegeneration; FAHN, Fatty acid-hydroxylase-associated neurodegeneration; gnomAD, genome Aggregation Database; KRS, Kufor-Rakeb syndrome; LKDMN, Leukodystrophy with dystonia and motor neuropathy; MPAN, Mitochondrial membrane protein-associated neurodegeneration; NBIA, Neurodegeneration with brain iron acumulation; NBIA 8, Neurodegeneration with brain iron acumulation 8; PKAN, Panthothenate kinase-associated neurodegeneration; PLAN, Phospholipase A2-associated neurodegeneration; SPG 50, Spastic paraplegia 50, autosomal recessive; WSS, Woodhouse-Sakati syndrome.

Figure 2

Calculated lifetime risk per 100,000 based on the frequency of 1059 disease-causing alleles in all 13 genes associated with autosomal recessive NBIA disorders. Its comparison among the worldwide gnomAD dataset, European (non-Finnish) dataset and the in-house database is provided. Error bars represent 95%-confidence intervals. gnomAD, genome Aggregation Database; NBIA, Neurodegeneration with brain iron accumulation.

Figure 3

Distribution of both reported and non-reported loss of function, and missense variants in all 13 studied NBIA genes. (a) depicts a correlation between the number of reported variants and a year of gene identification and association with an NBIA disorder. (b) shows a correlation between the number of variants that was adjusted with a factor for the gene size (number of amino acids of a gene x/average number of amino acids of all 13 NBIA genes) and the time period since the identification and association with an NBIA disorder (i.e. 2021 - the year of publication). Due to the multivariate testing, p-value of less than 0.01 was considered statistically significant (Spearman correlation coefficient, Bonferroni correction for 5 hypotheses). For each gene, a year of description and/or the size of the gene in kb is shown below (A, B).^,,, , , , , , , , , Data are expressed as whole numbers. LoF, Loss of Function; NBIA, Neurodegeneration with Brain Iron accumulation; n, number.