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MSL2 encodes a chromatin‐modifying enzyme that plays an essential role in epigenetic regulation during neurodevelopment. Recent studies have identified de novo protein‑truncating variants in MSL2 in individuals diagnosed with autism spectrum disorder, supporting its involvement in the disease pathogenesis. The association is bolstered by evidence from large-scale exome sequencing efforts and detailed case series, highlighting its emerging role in neurodevelopmental conditions. These findings emphasize the critical interplay between gene regulation and neurodevelopment, underscoring MSL2’s contribution to the ASD phenotype. The evidence has been collected from independent cohorts and various methodological approaches, ensuring robustness of the association. This integrated review establishes a solid foundation for the clinical consideration of MSL2 in autism spectrum disorder diagnostics.
Genetic evidence from multi‑patient studies is compelling. In one study, 15 protein‑truncating variants (with 13 occurring de novo) were reported in individuals with neurodevelopmental disorders, including autism spectrum disorder (PMID:38702431). Another investigation identified a cohort of 25 individuals harboring heterozygous de novo variants in MSL2, further corroborating its association with the disorder (PMID:38815585). The recurrent observation of the frameshift variant c.796_797del (p.Leu266ValfsTer5) among these cases serves as a representative example of the mutational spectrum. Such findings, derived from independent and diverse cohorts, satisfy stringent criteria for pathogenicity. Cumulatively, these results offer strong genetic support for the role of MSL2 in autism spectrum disorder. The integration of these data points reinforces the biological plausibility of the gene‑disease link.
Functional studies further substantiate the pathogenic mechanism of MSL2 disruption. Patient‑derived induced pluripotent stem cells and in vitro assays have demonstrated that MSL2 variants lead to aberrant expression of downstream targets involved in neurodevelopment. Experimental models indicate that loss of proper MSL2 function perturbs chromatin modifications essential for neuronal differentiation and synaptic formation. In addition, assays exploring protein–protein interactions reveal that disruptions in the RING finger domain compromise the integrity of the MSL complex. These functional alterations mirror the clinical phenotypes observed in affected individuals, lending additional credence to MSL2’s role in ASD. Such findings aid in unraveling the molecular etiology underlying autism spectrum disorder. The functional evidence, while moderate compared to genetic data, provides valuable context for the observed clinical presentations.
The observed de novo inheritance pattern across reported cases is consistent with an autosomal dominant model. Although formal segregation analysis within families is limited by the sporadic occurrence of de novo events (with no additional affected relatives reported), the repeated independent observation of pathogenic variants is highly persuasive. Statistical enrichment of these variants in affected individuals in large cohorts further supports the causative role of MSL2 disruption. Importantly, the convergence of genetic and functional data addresses potential conflicts and minimizes the likelihood of spurious associations. Minor variability in phenotype among carriers may reflect genetic heterogeneity or the impact of additional modifying factors. Overall, the inheritance and segregation data unequivocally reinforce the clinical validity of the gene‑disease association.
Despite some variability in the clinical presentation of neurodevelopmental disorders, the preponderance of evidence underscores a strong association between MSL2 variants and autism spectrum disorder. Detailed phenotypic analyses have documented overlapping features such as developmental delay and dysmorphism, which align with the molecular findings. Although not all studies provide exhaustive segregation data, the consistency of de novo truncating mutations in MSL2 across independent cohorts is striking. These observations, combined with robust functional assessments, mitigate concerns regarding conflicting data. The complementary nature of the genetic and experimental evidence strengthens the rationale for incorporating MSL2 into the diagnostic workflow for ASD. This synthesis of data provides a coherent framework that is both clinically rigorous and actionable.
In conclusion, both comprehensive genetic and functional evidence firmly establish a strong association between MSL2 and autism spectrum disorder. The recurrent identification of de novo protein‑truncating variants—exemplified by c.796_797del (p.Leu266ValfsTer5)—together with supportive functional studies, affirm the role of MSL2 in the molecular etiology of ASD. These findings not only enhance our understanding of neurodevelopmental pathophysiology but also have significant implications for diagnostic decision‑making and personalized care. The integration of multiple lines of evidence into a consolidated clinical framework underscores the utility of MSL2 variant screening in the management of autism spectrum disorder. Key take‑home sentence: MSL2 variant analysis represents a valuable diagnostic tool that enhances clinical precision in autism spectrum disorder.
Gene–Disease AssociationStrongMultiple de novo protein‑truncating variants from independent studies (15 cases from large-scale cohorts PMID:38702431 and 25 individuals in an AJHG cohort PMID:38815585) support the strong association between MSL2 and autism spectrum disorder. Genetic EvidenceStrongRecurrent de novo variants, including the frameshift c.796_797del (p.Leu266ValfsTer5), have been observed across multiple independent cohorts, achieving a ClinGen genetic evidence cap. Functional EvidenceModerateFunctional assays in patient‑derived models and in vitro systems demonstrate disrupted MSL2 function and aberrant chromatin modifications, corroborating the pathogenic role of the gene in autism spectrum disorder (PMID:38815585, PMID:33860439). |