SLITRK2 – Neurodevelopmental Disorder

This summary details the association between SLITRK2 and a neurodevelopmental disorder. A range of evidence from detailed case reports and multi‐patient studies supports the involvement of SLITRK2 in neurodevelopmental phenotypes marked by intellectual disability, deficits in communication and social skills, and motor delays. The clinical observations are consistent with an X‑linked inheritance pattern, raising the importance of considering SLITRK2 in diagnostic screening panels for neurodevelopmental disorders.

A recent case report from Frontiers in Genetics (PMID:38283150) documented a single patient with neurodevelopmental issues carrying a loss‑of‑function variant. Specifically, a novel nonsense mutation, c.789T>A (p.Cys263Ter), was identified in exon 5 of SLITRK2. Protein modeling indicated that this variant likely triggers nonsense‑mediated decay, supporting loss‑of‑function as the underlying mechanism.

In addition, a multi‐patient study published in Nature Communications (PMID:35840571) identified six distinct missense variants together with one nonsense allele in SLITRK2 among individuals with neurodevelopmental disorders. These findings underscore the variant spectrum observed in SLITRK2, confirm its X‑linked inheritance, and provide robust genetic evidence through consistent segregation and recurrent identification of damaging alleles in independent cases.

The genetic evidence is further complemented by detailed segregation data obtained in familial analyses, where the loss‑of‑function allele co‑segregated with the neurodevelopmental phenotype, albeit with limited quantification of additional affected relatives. This aggregation of data from unrelated cases supports a strong gene‑disease association.

Functional studies further substantiate the pathogenicity of SLITRK2 variants. Experimental investigations, including cellular assays and conditional knockout mouse models, demonstrated impaired excitatory synapse formation and cognitive deficits (PMID:27812321, PMID:35840571). These data provide moderate functional validation that the observed genetic alterations disrupt SLITRK2’s role in neuronal development, further supporting a loss‑of‑function mechanism.

In conclusion, convergent clinical, genetic, and functional evidence supports a strong association between SLITRK2 variants and neurodevelopmental disorder. This integrated evidence base not only bolsters diagnostic decision‑making but also informs potential avenues for future clinical research and therapeutic development. Key take‑home message: SLITRK2 is a clinically actionable gene for neurodevelopmental disorder screening, highlighting its diagnostic utility in the context of X‑linked neurogenetic conditions.

References

• Frontiers in Genetics • 2023 • Loss-of‑function variant in the LRR domain of SLITRK2 implicated in a neurodevelopmental disorder PMID:38283150
• Nature Communications • 2022 • SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice PMID:35840571
• Frontiers in Molecular Neuroscience • 2016 • Slitrk Missense Mutations Associated with Neuropsychiatric Disorders Distinctively Impair Slitrk Trafficking and Synapse Formation PMID:27812321

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