ArticleGenetics in medicine : official journal of the American College of Medical Genetics2021
Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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36 citing papers in PubMed, 45 citations in OpenAlex.
- Identification and Functional Analysis of a Novel NSD2 Missense Variant in a Patient With Rauch-Steindl Syndrome.Molecular genetics & genomic medicine · 2026Article
- Structural landscape of H3K27me3 recognition by protein domains and their potential for inhibition.The Journal of biological chemistry · 2026Review
- Wolf-Hirschhorn syndrome with growth hormone deficiency: long-term response to RhGH therapy.Hormones (Athens, Greece) · 2026Review
- The SETD2 L1609P mutation found in leukemia disrupts methyltransferase activity and reduces histone H3K36 trimethylation.The Journal of biological chemistry · 2026Article
- Deciphering the Genetic Basis of Congenital Vertebral Malformations Through a Stepwise Diagnostic Approach.International journal of molecular sciences · 2026Article
- A novel NSD2 pathogenic variant in a Chinese patient with Rauch-Steindl syndrome: a case report.BMC neurology · 2026Article
- Phenotypes of Hereditary Diseases Associated With Rauch-Steindl Syndrome.Human mutation · 2026Article
- Case Report: AFrontiers in pediatrics · 2026Article
- Clinical immunology in chromatinopathies: a scoping review.Frontiers in immunology · 2026Article
- Approaches for identification of 5' UTR mutations impacting translation and protein production from neurodevelopmental disorder genes.Cell reports methods · 2025Article
- Identification of potential methyltransferase NSD2 enzymatic inhibitors through a multi-step structure-based drug design.Molecular diversity · 2025Article
- Paraspeckle protein NONO regulates active chromatin by allosterically stimulating NSD1.Cell reports · 2025Article
- H3K36me3 modification by SETD2 is essential for Col11a2 and Sema3e transcription to maintain dentinogenesis in mice.Development (Cambridge, England) · 2025Article
- Disrupted diencephalon development and neuropeptidergic pathways in zebrafish with autism-risk mutations.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Molecular and clinical aspects of histone-related disorders.Human genomics · 2025Review
- A Unique Derivative Chromosome 4 with a Predominant 4p16.3 Microduplication Phenotype and a Literature Review.Molecular syndromology · 2025Article
- Chromatin modifiers in neurodevelopment.Frontiers in molecular neuroscience · 2025Review
- Genetic Findings in Short Turkish Children Born to Consanguineous Parents.Hormone research in paediatrics · 2025Observational
- Assisting the analysis of insertions and deletions using regional allele frequencies.Functional & integrative genomics · 2024Article
- Mechanisms of DNA Methylation Regulatory Function and Crosstalk with Histone Lysine Methylation.Journal of molecular biology · 2024Review
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34 authors at 20 institutions in 7 countries.
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Abstract
purposeDespite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf-Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood.
methodsWe collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro.
resultsThe core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2's folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants.
conclusionNSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch-Steindl syndrome after the delineators of this phenotype.
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