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NUDT2 has emerged as a critical gene in the pathogenesis of intellectual disability (ID). Multiple independent studies have reported that biallelic loss‐of‐function variants in NUDT2 are responsible for a neurodevelopmental disorder characterized by ID and associated neurological features. Evidence stems from detailed case reports, multi‐patient cohort studies, and rigorous functional analyses that converge on a pathogenic mechanism based on impaired mRNA decapping activity (PMID:38243213).
Genetic investigations have identified both compound heterozygous and homozygous variants in affected individuals. Specifically, the pathogenic variant c.34C>T (p.Arg12Ter) and frameshift mutations such as c.186del (p.Ala63fs) have been detected in several families. These findings are consistent with an autosomal recessive pattern, and independent reports underscore the enrichment of loss‐of‐function variants in patients with ID (PMID:38243213, PMID:33058507).
Segregation analysis in some families further supports the autosomal recessive inheritance model. In one cohort, affected siblings demonstrated the co‐segregation of NUDT2 variants, which bolsters the genetic link between the gene and the intellectual disability phenotype. Such familial clustering and the recurrence of similar variant types across unrelated families strengthen the overall genetic evidence.
Complementary functional studies have provided crucial insights into the pathomechanism. Assays in patient‐derived fibroblasts reveal a marked reduction in NUDT2 enzymatic activity, leading to altered mRNA stability and transcriptome changes. In addition, rescue experiments have confirmed that restoring NUDT2 function ameliorates the cellular defects, thereby establishing loss‐of‐function as the core mechanism driving neurodevelopmental pathology (PMID:38141063).
Clinically, affected individuals present with a spectrum of symptoms including intellectual disability (HP:0001249), global developmental delay (HP:0001263), attention deficit hyperactivity disorder (HP:0007018), and motor challenges such as difficulty climbing stairs (HP:0003551). This broad phenotypic profile reflects the diverse impact of NUDT2 dysfunction on neurodevelopment and highlights its importance in diagnostic evaluation.
In conclusion, the integration of robust genetic findings and compelling functional data provides strong evidence supporting the association between biallelic NUDT2 variants and intellectual disability. This synthesis of data not only underpins diagnostic decision‑making and commercial assay development but also lays a foundation for future translational research. Key take‑home sentence: NUDT2 is a clinically actionable gene in intellectual disability, with strong genetic and functional evidence validating its role in neurodevelopment (PMID:27431290).
Gene–Disease AssociationStrongMultiple independent studies reporting NUDT2 variants in at least 10 families, with supportive segregation and functional evidence, establish a strong gene-disease association (PMID:38243213, PMID:38141063). Genetic EvidenceStrongGenetic evidence is bolstered by the identification of pathogenic variants such as c.34C>T (p.Arg12Ter) and c.186del (p.Ala63fs) in multiple affected individuals from unrelated families, consistent with autosomal recessive inheritance (PMID:38243213, PMID:33058507). Functional EvidenceStrongFunctional assessments demonstrate that loss of NUDT2 activity leads to defective mRNA decapping and altered transcript stability, with rescue experiments confirming its role in neurodevelopment (PMID:38141063). |