ArticleHuman mutation2017
Aggregation of population-based genetic variation over protein domain homologues and its potential use in genetic diagnostics.
Article in Human mutation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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25 citing papers in PubMed, 55 citations in OpenAlex.
- CCDC89 is required for optimal sperm motility and male fertility in mammals.Human reproduction (Oxford, England) · 2025Article
- Conserved missense variant pathogenicity and correlated phenotypes across paralogous genes.Genome biology · 2025Article
- Genetic variants in DDX53 contribute to autism spectrum disorder associated with the Xp22.11 locus.American journal of human genetics · 2025Article
- Genetic constraint at single amino acid resolution in protein domains improves missense variant prioritisation and gene discovery.Genome medicine · 2024Article
- A unified analysis of evolutionary and population constraint in protein domains highlights structural features and pathogenic sites.Communications biology · 2024Article
- Genetic variants inmedRxiv : the preprint server for health sciences · 2023Article
- Evaluating the use of paralogous protein domains to increase data availability for missense variant classification.Genome medicine · 2023Article
- The unique structural characteristics of the Kir 7.1 inward rectifier potassium channel: a novel player in energy homeostasis control.American journal of physiology. Cell physiology · 2023Review
- Article
- De novo mutation hotspots in homologous protein domains identify function-altering mutations in neurodevelopmental disorders.American journal of human genetics · 2023Article
- Protein domains provide a new layer of information for classifying human variations in rare diseases.Frontiers in bioinformatics · 2023Article
- ECNano: A cost-effective workflow for target enrichment sequencing and accurate variant calling on 4800 clinically significant genes using a single MinION flowcell.BMC medical genomics · 2022Article
- GeneTerpret: a customizable multilayer approach to genomic variant prioritization and interpretation.BMC medical genomics · 2022Article
- Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome.Molecular psychiatry · 2021Article
- Mapping OMIM Disease-Related Variations on Protein Domains Reveals an Association Among Variation Type, Pfam Models, and Disease Classes.Frontiers in molecular biosciences · 2021Article
- Missense variant contribution to USP9X-female syndrome.NPJ genomic medicine · 2020Article
- Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum.American journal of human genetics · 2020Article
- De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders.American journal of human genetics · 2020Article
- Identification of pathogenic variant enriched regions across genes and gene families.Genome research · 2020Article
- MetaDome: Pathogenicity analysis of genetic variants through aggregation of homologous human protein domains.Human mutation · 2019Article
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Authors and funding
5 authors at 1 institution in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Whole exomes of patients with a genetic disorder are nowadays routinely sequenced but interpretation of the identified genetic variants remains a major challenge. The increased availability of population-based human genetic variation has given rise to measures of genetic tolerance that have been used, for example, to predict disease-causing genes in neurodevelopmental disorders. Here, we investigated whether combining variant information from homologous protein domains can improve variant interpretation. For this purpose, we developed a framework that maps population variation and known pathogenic mutations onto 2,750 "meta-domains." These meta-domains consist of 30,853 homologous Pfam protein domain instances that cover 36% of all human protein coding sequences. We find that genetic tolerance is consistent across protein domain homologues, and that patterns of genetic tolerance faithfully mimic patterns of evolutionary conservation. Furthermore, for a significant fraction (68%) of the meta-domains high-frequency population variation re-occurs at the same positions across domain homologues more often than expected. In addition, we observe that the presence of pathogenic missense variants at an aligned homologous domain position is often paired with the absence of population variation and vice versa. The use of these meta-domains can improve the interpretation of genetic variation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.