ArticleGenetics in medicine : official journal of the American College of Medical Genetics2019
Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 112 papers, 1 of them a synthesis that pooled it.
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112 citing papers in PubMed, 1 synthesis or guideline pooled it, 220 citations in OpenAlex.
- A cohort study of fetal urinary tract abnormalities and chromosomal copy number variations: a retrospective analysis of 9-year data.Archives of gynecology and obstetrics · 2026Pooled it
- Are CNV Risk Scores Linked to Neurodevelopmental and Mental Health Characteristics Within CNV-Associated Intellectual Disability?medRxiv : the preprint server for health sciences · 2026Article
- High-throughput evaluation of in vitro CRISPR activities enables optimized large-scale multiplex enrichment of rare variants.Nature biomedical engineering · 2026Article
- Functional impact of genetic background on variable expressivity in neurodevelopmental disorders.Nature communications · 2026Article
- Evolutionary instability drives structural diversity and disease susceptibility at the 16p12.2 locus.bioRxiv : the preprint server for biology · 2026Article
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- Monogenic defects in Russian children with autism spectrum disorders.World journal of clinical pediatrics · 2025Article
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- Exome sequencing in severe non-syndromic specific learning and language disorders in a French cohort.Molecular autism · 2025Article
- Quantifying the impact of genetic mutations on enhancer dynamics.bioRxiv : the preprint server for biology · 2025Article
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- An integrated framework for functional dissection of variable expressivity in genetic disorders.medRxiv : the preprint server for health sciences · 2025Article
- Investigating the sources of variable impact of pathogenic variants in monogenic metabolic conditions.Nature communications · 2025Article
- The impact of a secondary, rare, non-pathogenic PKD1 variant on disease progression in autosomal dominant polycystic kidney disease.Journal of nephrology · 2025Article
- Genomic diversity in functionally relevant genes modifies neurodevelopmental versus neoplastic risks in individuals with germline PTEN variants.NPJ genomic medicine · 2025Article
- Review
- Understanding rare variant contributions to autism: lessons from dystrophin-deficient model.NPJ genomic medicine · 2025Article
- Integrative genetic analysis: cornerstone of precision psychiatry.Molecular psychiatry · 2025Review
- Unveiling Secondary Mutations in Blended Phenotypes: Dual ERCC4 and OTOA Pathogenic Variants Through WES Analysis.International journal of molecular sciences · 2024Article
- Genetic Heterogeneity in Four Probands RevealsBiomedicines · 2024Article
52 more citing papers are in PubMed but not listed here.
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Authors and funding
56 authors at 20 institutions in 9 countries.
Funding
Abstract
purposeTo assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants.
methodsWe analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants.
resultsThe number of rare likely deleterious variants in functionally intolerant genes ("other hits") correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes.
conclusionAccurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.
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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.