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Recent studies have demonstrated a strong association between pathogenic variants in MSL2 (HGNC:25544) and neurodevelopmental disorder (MONDO:0700092). Multiple independent cohorts have identified de novo protein‑truncating variants in MSL2, establishing a robust link between aberrant chromatin regulation and neurodevelopmental phenotypes (PMID:33860439).
The genetic evidence supports an autosomal dominant inheritance pattern. In several investigations, heterozygous de novo variants – including the stop‐gain variant c.67G>T (p.Gly23Ter) – were identified in affected individuals, with case series reporting substantial counts such as 108 de novo events in one large cohort (PMID:33860439) and 25 affected probands in a dedicated study (PMID:38815585). Additional reports document further protein‑truncating events, reinforcing the pathogenicity of loss‑of‑function mutations in MSL2 (PMID:38702431).
Detailed case‐control and multi‑patient studies have identified MSL2 variants across neurodevelopmental disorder cohorts. The variant spectrum includes several de novo protein‑truncating alleles, and the recurrence of such mutations across unrelated patients provides a strong genetic signal. For example, the c.67G>T (p.Gly23Ter) variant exemplifies the class of alleles contributing to the disorder. Although segregation data from affected relatives is limited given the de novo occurrence, the collective burden in multiple independent studies supports a strong association.
Complementary functional assessments provide further support. Experimental studies in model systems, including Drosophila assays, have demonstrated that perturbation in MSL2 disrupts the formation of the multisubunit MSL complex, essential for proper histone H4 lysine 16 acetylation. In patient‑derived induced pluripotent stem cells, MSL2 haploinsufficiency correlates with altered expression of downstream targets, lending biological plausibility to the observed clinical phenotype (PMID:9736618).
No significant conflicting evidence has emerged; on the contrary, the convergence of genetic and functional data underscores the pathogenic mechanism of MSL2 loss‑of‑function in neurodevelopmental disorder. While additional studies continue to expand the phenotypic spectrum, the aggregate evidence exceeds the ClinGen scoring maximum, solidifying its clinical validity.
In summary, the strong genetic and experimental evidence positions MSL2 as a critical gene in neurodevelopmental disorder. This association has direct implications for diagnostic decision‑making and supports the inclusion of MSL2 in prospective gene panels, with potential commercial and therapeutic applications.
Key Take‑home sentence: MSL2 loss‑of‑function variants are a robust biomarker for neurodevelopmental disorder, offering clear clinical utility for diagnostic and genetic counseling purposes.
Gene–Disease AssociationStrongMultiple independent studies report heterozygous de novo protein‑truncating variants in MSL2, including a cohort of 25 probands (PMID:38815585) and 108 de novo events in large-scale screening (PMID:33860439), with corroborative evidence from additional case series and functional assays. Genetic EvidenceStrongRobust genetic findings include recurrent de novo variants such as c.67G>T (p.Gly23Ter) identified across multiple cohorts, supporting a loss‑of‑function mechanism in an autosomal dominant setting. Functional EvidenceModerateFunctional studies demonstrate that MSL2 disruption impairs chromatin complex formation and downstream target gene regulation, consistent with its role in neurodevelopment; supported by experimental data from iPSC models and Drosophila assays (PMID:9736618). |