ArticleHuman molecular genetics2015
Proteins linked to autosomal dominant and autosomal recessive disorders harbor characteristic rare missense mutation distribution patterns.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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33 citing papers in PubMed.
- Probabilistic mapping of sub-genic intolerance reveals functional and disease-critical protein regions.bioRxiv : the preprint server for biology · 2026Article
- Untargeted proteomics enables ultra-rapid variant prioritisation in mitochondrial and other rare diseases.Genome medicine · 2025Article
- A series of reviews in familial cancer: genetic cancer risk in context variants of uncertain significance in MMR genes: which procedures should be followed?Familial cancer · 2025Review
- Proteome-wide assessment of differential missense variant clustering in neurodevelopmental disorders and cancer.Cell genomics · 2025Article
- Enhancing Missense Variant Pathogenicity Prediction with MissenseNet: Integrating Structural Insights and ShuffleNet-Based Deep Learning Techniques.Biomolecules · 2024Article
- Comparative analysis of in-silico tools in identifying pathogenic variants in dominant inherited retinal diseases.Human molecular genetics · 2024Article
- Proteome-Wide Assessment of Clustering of Missense Variants in Neurodevelopmental Disorders Versus Cancer.medRxiv : the preprint server for health sciences · 2024Article
- Article
- Faltwerk: a library for spatial exploratory data analysis of protein structures.Bioinformatics advances · 2023Article
- Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy.Brain : a journal of neurology · 2022Article
- Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure.Nature communications · 2022Article
- Disease relevance of rare VPS13B missense variants for neurodevelopmental Cohen syndrome.Scientific reports · 2022Article
- Analysis of missense variants in the human genome reveals widespread gene-specific clustering and improves prediction of pathogenicity.American journal of human genetics · 2022Article
- Overcoming constraints on the detection of recessive selection in human genes from population frequency data.American journal of human genetics · 2022Article
- Identification of discriminative gene-level and protein-level features associated with pathogenic gain-of-function and loss-of-function variants.American journal of human genetics · 2021Article
- Article
- The gut-microbiota-brain axis in autism: what Drosophila models can offer?Journal of neurodevelopmental disorders · 2021Review
- Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.Genome medicine · 2021Article
- Strategies to Uplift Novel Mendelian Gene Discovery for Improved Clinical Outcomes.Frontiers in genetics · 2021Review
- CRISPR Gene-Editing Models Geared Toward Therapy for Hereditary and Developmental Neurological Disorders.Frontiers in pediatrics · 2021Review
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7 authors.
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Abstract
The role of rare missense variants in disease causation remains difficult to interpret. We explore whether the clustering pattern of rare missense variants (MAF < 0.01) in a protein is associated with mode of inheritance. Mutations in genes associated with autosomal dominant (AD) conditions are known to result in either loss or gain of function, whereas mutations in genes associated with autosomal recessive (AR) conditions invariably result in loss-of-function. Loss-of-function mutations tend to be distributed uniformly along protein sequence, whereas gain-of-function mutations tend to localize to key regions. It has not previously been ascertained whether these patterns hold in general for rare missense mutations. We consider the extent to which rare missense variants are located within annotated protein domains and whether they form clusters, using a new unbiased method called CLUstering by Mutation Position. These approaches quantified a significant difference in clustering between AD and AR diseases. Proteins linked to AD diseases exhibited more clustering of rare missense mutations than those linked to AR diseases (Wilcoxon P = 5.7 × 10(-4), permutation P = 8.4 × 10(-4)). Rare missense mutation in proteins linked to either AD or AR diseases was more clustered than controls (1000G) (Wilcoxon P = 2.8 × 10(-15) for AD and P = 4.5 × 10(-4) for AR, permutation P = 3.1 × 10(-12) for AD and P = 0.03 for AR). The differences in clustering patterns persisted even after removal of the most prominent genes. Testing for such non-random patterns may reveal novel aspects of disease etiology in large sample studies.
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