ArticleAmerican journal of human genetics2017
Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes.
Article in American journal of human genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed.
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- Functional characterization of 42 CK2α de novo variants associated with Okur-Chung neurodevelopmental syndrome.The FEBS journal · 2026Article
- Further characterization of the BRSK2-associated neurodevelopmental disorder.European journal of human genetics : EJHG · 2026Article
- Early-onset Parkinsonism and cognitive delay: think about PPP2R5D.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Article
- NovelNeurology. Genetics · 2025Article
- SETBP1 variants outside the degron disrupt DNA-binding, transcription and neuronal differentiation capacity to cause a heterogeneous neurodevelopmental disorder.Nature communications · 2025Article
- Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes.Nature communications · 2025Article
- Systematic analysis of genetic and phenotypic characteristics reveals antisense oligonucleotide therapy potential for one-third of neurodevelopmental disorders.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
- Genetic advances in neurodevelopmental disorders.Medical review (2021) · 2025Review
- A multiscale functional map of somatic mutations in cancer integrating protein structure and network topology.Nature communications · 2025Article
- Evolutionary constrained genes associated with autism spectrum disorder across 2,054 nonhuman primate genomes.Molecular autism · 2025Article
- Article
- Regulation of cellular and systemic sphingolipid homeostasis.Nature reviews. Molecular cell biology · 2024Review
- A multiscale functional map of somatic mutations in cancer integrating protein structure and network topology.bioRxiv : the preprint server for biology · 2024Article
- Thirteen New Patients ofChildren (Basel, Switzerland) · 2024Article
- A recurrent missense variant in the E3 ubiquitin ligase substrate recognition subunit FEM1B causes a rare syndromic neurodevelopmental disorder.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- Proteome-Wide Assessment of Clustering of Missense Variants in Neurodevelopmental Disorders Versus Cancer.medRxiv : the preprint server for health sciences · 2024Article
- SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis.Brain : a journal of neurology · 2023Article
9 more citing papers are in PubMed but not listed here.
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9 authors.
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Abstract
Haploinsufficiency (HI) is the best characterized mechanism through which dominant mutations exert their effect and cause disease. Non-haploinsufficiency (NHI) mechanisms, such as gain-of-function and dominant-negative mechanisms, are often characterized by the spatial clustering of mutations, thereby affecting only particular regions or base pairs of a gene. Variants leading to haploinsufficency might occasionally cluster as well, for example in critical domains, but such clustering is on the whole less pronounced with mutations often spread throughout the gene. Here we exploit this property and develop a method to specifically identify genes with significant spatial clustering patterns of de novo mutations in large cohorts. We apply our method to a dataset of 4,061 de novo missense mutations from published exome studies of trios with intellectual disability and developmental disorders (ID/DD) and successfully identify 15 genes with clustering mutations, including 12 genes for which mutations are known to cause neurodevelopmental disorders. For 11 out of these 12, NHI mutation mechanisms have been reported. Additionally, we identify three candidate ID/DD-associated genes of which two have an established role in neuronal processes. We further observe a higher intolerance to normal genetic variation of the identified genes compared to known genes for which mutations lead to HI. Finally, 3D modeling of these mutations on their protein structures shows that 81% of the observed mutations are unlikely to affect the overall structural integrity and that they therefore most likely act through a mechanism other than HI.
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