ArticleGenetics in medicine : official journal of the American College of Medical Genetics2018
Noncoding copy-number variations are associated with congenital limb malformation.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 53 citations in OpenAlex.
- Decoding structural birth defects through genomic landscapes: Innovative frameworks for diagnosis (Review).International journal of molecular medicine · 2026Review
- Structural variants in the 3D genome as drivers of disease.Nature reviews. Genetics · 2025Review
- Evaluating genome sequencing strategies: trio, singleton, and standard testing in rare disease diagnosis.Genome medicine · 2025Article
- The Biological Function of Genome Organization.International journal of molecular sciences · 2025Review
- Increased enhancer-promoter interactions during developmental enhancer activation in mammals.Nature genetics · 2024Article
- Methods of Detection and Mechanisms of Origin of Complex Structural Genome Variations.Methods in molecular biology (Clifton, N.J.) · 2024Review
- POSTRE: a tool to predict the pathological effects of human structural variants.Nucleic acids research · 2023Article
- High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations.European journal of human genetics : EJHG · 2023Article
- SCIP: software for efficient clinical interpretation of copy number variants detected by whole-genome sequencing.Human genetics · 2023Article
- The performance of genome sequencing as a first-tier test for neurodevelopmental disorders.European journal of human genetics : EJHG · 2023Article
- CRISPR-Cas9-mediated functional dissection of the foxc1 genomic region in zebrafish identifies critical conserved cis-regulatory elements.Human genomics · 2022Article
- Developmental genomics of limb malformations: Allelic series in association with gene dosage effects contribute to the clinical variability.HGG advances · 2022Article
- Xq27.1 palindrome mediated interchromosomal insertion likely causes familial congenital bilateral laryngeal abductor paralysis (Plott syndrome).Journal of human genetics · 2022Article
- Computational and experimental methods for classifying variants of unknown clinical significance.Cold Spring Harbor molecular case studies · 2022Article
- Combining callers improves the detection of copy number variants from whole-genome sequencing.European journal of human genetics : EJHG · 2022Article
- Position effects at the FGF8 locus are associated with femoral hypoplasia.American journal of human genetics · 2021Article
- Mechanisms Underlying the Suppression of Chromosome Rearrangements by Ataxia-Telangiectasia Mutated.Genes · 2021Review
- Genome sequencing in families with congenital limb malformations.Human genetics · 2021Article
- CNVxplorer: a web tool to assist clinical interpretation of CNVs in rare disease patients.Nucleic acids research · 2021Article
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27 authors at 17 institutions in 9 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
PurposeCopy-number variants (CNVs) are generally interpreted by linking the effects of gene dosage with phenotypes. The clinical interpretation of noncoding CNVs remains challenging. We investigated the percentage of disease-associated CNVs in patients with congenital limb malformations that affect noncoding cis-regulatory sequences versus genes sensitive to gene dosage effects.MethodsWe applied high-resolution copy-number analysis to 340 unrelated individuals with isolated limb malformation. To investigate novel candidate CNVs, we re-engineered human CNVs in mice using clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing.ResultsOf the individuals studied, 10% harbored CNVs segregating with the phenotype in the affected families. We identified 31 CNVs previously associated with congenital limb malformations and four novel candidate CNVs. Most of the disease-associated CNVs (57%) affected the noncoding cis-regulatory genome, while only 43% included a known disease gene and were likely to result from gene dosage effects. In transgenic mice harboring four novel candidate CNVs, we observed altered gene expression in all cases, indicating that the CNVs had a regulatory effect either by changing the enhancer dosage or altering the topological associating domain architecture of the genome.ConclusionOur findings suggest that CNVs affecting noncoding regulatory elements are a major cause of congenital limb malformations.
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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.