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The association between NLGN4Y and autism (MONDO_0005260) is supported by limited genetic and experimental evidence. One study using 335 male samples identified a single missense variant, while a separate analysis of 85 autistic males detected a novel missense change among nine variants; however, both studies noted limitations regarding family cosegregation and functional validation (PMID:18628683, PMID:35169779).
The genetic evidence is notable for a reported missense variant, c.2036T>C (p.Ile679Val), which was observed in an autism proband as well as his affected father, suggesting possible cosegregation in a limited setting (PMID:18628683). However, the absence of additional familial segregation data, and the observation that synonymous variants dominated in the second study, diminishes the overall support.
The inheritance pattern appears to be consistent with Y-linked transmission, considering that NLGN4Y is located on the Y chromosome. The limited segregation data, with only one additional affected relative identified in the reported case, further underscores the need for caution in clinical interpretation.
Functional studies have provided only modest insights into the pathogenicity of the NLGN4Y variants. While one analysis compared the functional deficits of NLGN4Y with its homolog NLGN4X and observed severe maturation and synaptogenesis deficits in the latter, robust and consistent assays directly supporting the pathogenicity of the NLGN4Y variant are lacking (PMID:32243781).
Both the genetic and experimental data indicate that the current evidence does not exceed the threshold for a strong gene–disease association. The limited number of probands, minimal segregation analysis, and inconclusive functional studies currently constrain the clinical utility of this association in diagnostic decision‑making.
Key take‑home sentence: While isolated observations implicate NLGN4Y in autism, the current evidence remains limited, warranting further studies for definitive clinical application.
Gene–Disease AssociationLimitedA single proband with the missense variant c.2036T>C (p.Ile679Val) (PMID:18628683) and minimal segregation data, compounded by a second study showing predominantly synonymous variants (PMID:35169779), support a limited association. Genetic EvidenceLimitedGenetic data are based on one reported missense variant observed in a proband and his affected father, with a small cohort analysis failing to reveal a strong pathogenic signal (PMID:18628683, PMID:35169779). Functional EvidenceLimitedFunctional studies are inconclusive owing to the absence of robust assays directly supporting the pathogenicity of the variant, with comparative studies providing only indirect evidence (PMID:32243781, PMID:18628683). |