ArticleGenome medicine2020
Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders.
Article in Genome medicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43 citing papers in PubMed, 73 citations in OpenAlex.
- Probabilistic mapping of sub-genic intolerance reveals functional and disease-critical protein regions.bioRxiv : the preprint server for biology · 2026Article
- Gene Portals: A Framework for Integrating Clinical, Functional, and Structural Evidence into Rare Disease Variant Classification.medRxiv : the preprint server for health sciences · 2026Article
- Assessment of paralogue annotation for improving diagnostic accuracy inFrontiers in genetics · 2026Article
- Genetic Abnormalities in Neurodevelopmental Disorders with Multidimensional Impairment.Journal of molecular neuroscience : MN · 2025Article
- Familial SYNGAP1 variants define the boundaries of a complex neurodevelopmental disorder with epilepsy.Epilepsia · 2025Article
- Conserved missense variant pathogenicity and correlated phenotypes across paralogous genes.Genome biology · 2025Article
- Leveraging cancer mutation data to inform the pathogenicity classification of germline missense variants.PLoS genetics · 2025Article
- Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.Nature neuroscience · 2024Article
- Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.medRxiv : the preprint server for health sciences · 2024Article
- Genotypic and phenotypic characteristics of sodium channel-associated epilepsy in Chinese population.Journal of human genetics · 2024Article
- Boolean Modeling of Biological Network Applied to Protein-Protein Interaction Network of Autism Patients.Biology · 2024Article
- Genetic constraint at single amino acid resolution in protein domains improves missense variant prioritisation and gene discovery.Genome medicine · 2024Article
- Lethal phenotypes in Mendelian disorders.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- Lethal phenotypes in Mendelian disorders.medRxiv : the preprint server for health sciences · 2024Article
- An Update on Reported Variants in the Skeletal MuscleHuman mutation · 2024Review
- Evaluating the use of paralogous protein domains to increase data availability for missense variant classification.Genome medicine · 2023Article
- Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration.American journal of human genetics · 2023Article
- Spinocerebellar ataxia 38: structure-function analysis shows ELOVL5 G230V is proteotoxic, conformationally altered and a mutational hotspot.Human genetics · 2023Article
- Scorpion Peptides and Ion Channels: An Insightful Review of Mechanisms and Drug Development.Toxins · 2023Review
- Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes.Brain : a journal of neurology · 2023Article
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Authors and funding
31 authors at 20 institutions in 9 countries.
Funding
Abstract
backgroundClassifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs.
methodsGene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments; 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families.
resultsWe demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint.
conclusionThis study represents the first method to incorporate gene family information into a statistical framework to interpret variant data for NDDs and to discover new NDD-associated genes.
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