ArticleAmerican journal of human genetics2022
Rare genetic variants in genes and loci linked to dominant monogenic developmental disorders cause milder related phenotypes in the general population.
Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers, 1 of them a synthesis that pooled it.
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Who cites it
35 citing papers in PubMed, 1 synthesis or guideline pooled it, 65 citations in OpenAlex.
- Transitional care and clinical management of adolescents, young adults, and suspected new adult patients with congenital central hypoventilation syndrome.Clinical autonomic research : official journal of the Clinical Autonomic Research Society · 2023Pooled it
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- Expert consensus on the reporting and clinical follow up of individuals with incidentally discovered germline RET variants in the UK.Endocrine-related cancer · 2026Article
- Comprehensive Assessment of the KDM2B-Associated Neurodevelopmental Disorder and the 12q24.31 Microdeletion Syndrome.Clinical genetics · 2026Article
- Resolving Diagnostic Uncertainty in Neurodevelopmental Disorders Using Exome Sequencing Supported by Literature-Based Multi-Omics Evidence.Biomolecules · 2026Article
- Bi-allelic variants in neuronal adhesion molecule astrotactin 1 gene ASTN1 cause diverse neurodevelopmental disorders.American journal of human genetics · 2026Article
- Clinical and genetic features of multiple primary tumours cohorts with a renal cell carcinoma: Implications for molecular genetic investigations.International journal of cancer · 2025Article
- Genome region aware CADD thresholds for noncoding variant prioritization.NAR genomics and bioinformatics · 2025Article
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- A calcium-sensing receptor allelic series and underdiagnosis of genetically driven hypocalcemia.American journal of human genetics · 2025Article
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- Genetic advances in neurodevelopmental disorders.Medical review (2021) · 2025Review
- BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations.European journal of human genetics : EJHG · 2025Article
- Genetic impact of copy number variations on congenital heart defects: Current insights and future directions.Global medical genetics · 2025Review
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- Exploring the genetic etiology across the continuum of the general psychopathology factor: a Swedish population-based family and twin study.Molecular psychiatry · 2024Article
- Sequencing and characterizing short tandem repeats in the human genome.Nature reviews. Genetics · 2024Review
- Evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability.European journal of human genetics : EJHG · 2024Article
- Clustering of predicted loss-of-function variants in genes linked with monogenic disease can explain incomplete penetrance.Genome medicine · 2024Article
- Investigating the role of common cis-regulatory variants in modifying penetrance of putatively damaging, inherited variants in severe neurodevelopmental disorders.Scientific reports · 2024Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Many rare monogenic diseases are known to be caused by deleterious variants in thousands of genes, however the same variants can also be found in people without the associated clinical phenotypes. The penetrance of these monogenic variants is generally unknown in the wider population, as they are typically identified in small clinical cohorts of affected individuals and families with highly penetrant variants. Here, we investigated the phenotypic effect of rare, potentially deleterious variants in genes and loci where similar variants are known to cause monogenic developmental disorders (DDs) in a large population cohort. We used UK Biobank to investigate phenotypes associated with rare protein-truncating and missense variants in 599 monoallelic DDG2P genes by using whole-exome-sequencing data from ∼200,000 individuals and rare copy-number variants overlapping known DD loci by using SNP-array data from ∼500,000 individuals. We found that individuals with these likely deleterious variants had a mild DD-related phenotype, including lower fluid intelligence, slower reaction times, lower numeric memory scores, and longer pairs matching times compared to the rest of the UK Biobank cohort. They were also shorter, had a higher BMI, and had significant socioeconomic disadvantages: they were less likely to be employed or be able to work and had a lower income and higher deprivation index. Our findings suggest that many genes routinely tested within pediatric genetics have deleterious variants with intermediate penetrance that may cause lifelong sub-clinical phenotypes in the general adult population.
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