ArticlePloS one2018
Utilizing ExAC to assess the hidden contribution of variants of unknown significance to Sanfilippo Type B incidence.
Article in PloS one, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 23 citations in OpenAlex.
- A phase I/II study on intracerebroventricular tralesinidase alfa in patients with Sanfilippo syndrome type B.The Journal of clinical investigation · 2023Trial
- Benchmarking genetic birth prevalence estimates against newborn screening data.American journal of human genetics · 2026Article
- Global genetic prevalence estimates of primary hyperoxaluria are greater than previously reported.Clinical kidney journal · 2025Article
- Evaluation of enzyme activity predictions for variants of unknown significance in Arylsulfatase A.Human genetics · 2025Article
- An augmented transformer model trained on protein family specific variant data leads to improved prediction of variants of uncertain significance.Human genetics · 2025Article
- Meta-EA: a gene-specific combination of available computational tools for predicting missense variant effects.Nature communications · 2025Article
- Evaluation of enzyme activity predictions for variants of unknown significance in Arylsulfatase A.bioRxiv : the preprint server for biology · 2024Article
- CAGI, the Critical Assessment of Genome Interpretation, establishes progress and prospects for computational genetic variant interpretation methods.Genome biology · 2024Article
- Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix.Genome biology · 2023Article
- Identification of prolactin receptor variants with diverse effects on receptor signalling.Journal of molecular endocrinology · 2023Article
- A Novel Variant in theBalkan journal of medical genetics : BJMG · 2022Article
- Estimated prevalence of mucopolysaccharidoses from population-based exomes and genomes.Orphanet journal of rare diseases · 2020Article
- Assessment of predicted enzymatic activity of α-N-acetylglucosaminidase variants of unknown significance for CAGI 2016.Human mutation · 2019Article
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4 authors at 1 institution in 1 country.
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Abstract
Given the large and expanding quantity of publicly available sequencing data, it should be possible to extract incidence information for monogenic diseases from allele frequencies, provided one knows which mutations are causal. We tested this idea on a rare, monogenic, lysosomal storage disorder, Sanfilippo Type B (Mucopolysaccharidosis type IIIB). Sanfilippo Type B is caused by mutations in the gene encoding α-N-acetylglucosaminidase (NAGLU). There were 189 NAGLU missense variants found in the ExAC dataset that comprises roughly 60,000 individual exomes. Only 24 of the 189 missense variants were known to be pathogenic; the remaining 165 variants were of unknown significance (VUS), and their potential contribution to disease is unknown. To address this problem, we measured enzymatic activities of 164 NAGLU missense VUS in the ExAC dataset and developed a statistical framework for estimating disease incidence with associated confidence intervals. We found that 25% of VUS decreased the activity of NAGLU to levels consistent with Sanfilippo Type B pathogenic alleles. We found that a substantial fraction of Sanfilippo Type B incidence (67%) could be accounted for by novel mutations not previously identified in patients, illustrating the utility of combining functional activity data for VUS with population-wide allele frequency data in estimating disease incidence.
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