U2AF2 – Neurodevelopmental Disorder

U2AF2, a critical splicing factor, has emerged as a key player in neurodevelopmental disorders. Recent studies provide compelling genetic and experimental evidence linking heterozygous de novo missense variants in this gene with a spectrum of neurodevelopmental abnormalities that include microcephaly, hypoplasia of the corpus callosum, delayed speech and language development, seizures, and intellectual disability (PMID:36747105). The involvement of U2AF2 in pre-mRNA splicing underscores its biological indispensability, and disruptions in its function have been consistently associated with neurological deficits.

The clinical validity of the U2AF2–neurodevelopmental disorder association is considered strong. In a detailed case report, a patient carrying the de novo heterozygous missense variant c.603G>T (p.Glu201Asp) demonstrated exon 6 skipping and production of a truncated protein (PMID:36747105). This finding is bolstered by a multi-patient study that uncovered 23 distinct de novo missense variants in 46 unrelated individuals (PMID:37962958), collectively substantiating the gene–disease relationship.

Genetic evidence supports an autosomal dominant mode of inheritance for U2AF2-associated neurodevelopmental disorders. The variant spectrum is enriched for missense changes, with the reported c.603G>T (p.Glu201Asp) representing a prototypical example. Although the variants are predominantly de novo, there is a lack of additional affected relatives demonstrating segregation, which is typical in sporadic presentations of neurodevelopmental disorders. Such findings emphasize the utility of de novo mutational analysis in the diagnostic workflow.

Functional studies reinforce the genetic findings. Patient-derived lymphoblastoid cells exhibited exon skipping and a consequent reduction in functional U2AF2 protein levels. Furthermore, in vitro analyses and cellular assays have demonstrated that these pathogenic variants disrupt the normal splicing process, a disruption that is highly consistent with the established role of U2AF2 in pre-mRNA processing (PMID:8713106; PMID:9447963). Together, these functional data not only validate the pathogenicity of the reported variants but also provide mechanistic insights into disease causation.

While there is no substantial conflicting evidence in the supplied data, the complex nature of splicing regulation suggests that additional modulatory factors might influence disease severity. Nonetheless, the convergence of genetic and functional evidence provides a coherent narrative supporting U2AF2’s role in neurodevelopmental pathology.

In summary, the integration of robust de novo mutational data and consistent functional assays firmly establishes a strong association between U2AF2 and neurodevelopmental disorders. This evidence not only guides diagnostic decision‑making but also holds promise for future therapeutic targeting. Key take‑home message: Comprehensive evaluation of U2AF2 variants greatly informs the clinical diagnosis and management of neurodevelopmental disorders.

References

• Journal of human genetics • 2023 • A presumed missense variant in the U2AF2 gene causes exon skipping in neurodevelopmental diseases PMID:36747105
• Molecular and cellular biology • 1998 • Sip1, a novel RS domain-containing protein essential for pre-mRNA splicing PMID:9447963
• Biochemical and biophysical research communications • 1996 • Biochemical properties of a novel U2AF65 protein isoform generated by alternative RNA splicing PMID:8713106

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