Submission Details

NLGN4X was first reported in relation to X-linked complex neurodevelopmental disorder in 2003 (Jamain et al., PMID: 12669065). Since then, multiple variants have been reported, including nonsense, frameshift, splice, missense, and large deletion variants. The observed phenotypes in affected males include autism spectrum disorder and/or intellectual disability; attention deficit-hyperactivity disorder is also reported in some individuals. Carrier females are typically unaffected.

Nine variants (nonsense, frameshift, splice, missense, and exonic deletion) that have been reported in nine probands in eight publications (PMIDs: 12669065, 14963808, 16648374, 18231125, 19726642, 23352163, 26350204, 28263302) are included in this curation. Variants in this gene were reported to segregate with disease in a large family with 13 affected males (PMID: 14963808). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function.

In humans, neuroligin 4 (NLGN4) is encoded by two genes, NLGN4X and NLGN4Y, that are localized on the sex chromosomes. NLGN4 is a member of the neuroligin family of neuronal cell-adhesion molecules that are localized postsynaptically, interact with presynaptic neurexins, and play a key role in the maturation and function of synapses. This gene-disease relationship is also supported by mouse models displaying neurodevelopmental phenotypes consistent with autism, functional studies, and protein interaction with neurexins (PMIDs: 21278334, 23183221, 24104404, 29106499). In humans, NLGN4 is preferentially expressed in the cortex, whereas mouse Nlgn4 is primarily expressed in the brainstem, retina, and spinal cord. Additionally, in human neurons NLGN4 is preferentially localized to excitatory synapses and only a subset of inhibitory synapses, whereas in mice Nlgn4 is primarily present in glycinergic and GABAergic synapses. These differences, along with the poor conservation of the mouse ortholog of NLGN4, called Nlgn4-like (Nlgn4l), should be considered when interpreting the relevance of the results obtained in knockout mice.

In summary, there is definitive evidence supporting the relationship between NLGN4X and X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 1, 2018. It was reevaluated on October 10, 2025 (SOP Version 11). Although new evidence was added, the classification did not change.

NLGN4X was first reported in relation to X-linked complex neurodevelopmental disorder in 2003 (Jamain et al., PMID: 12669065). Since then, multiple variants have been reported, including nonsense, frameshift, splice, missense, and large deletion variants. The observed phenotypes in affected males include autism spectrum disorder and/or intellectual disability; attention deficit-hyperactivity disorder is also reported in some individuals. Carrier females are typically unaffected.

Nine variants (nonsense, frameshift, splice, missense, and exonic deletion) that have been reported in nine probands in eight publications (PMIDs: 12669065, 14963808, 16648374, 18231125, 19726642, 23352163, 26350204, 28263302) are included in this curation. Variants in this gene were reported to segregate with disease in a large family comprising 13 males with intellectual disability and/or autism spectrum disorder (PMID: 14963808). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function.

NLGN4X encodes a member of the neuroligin family of neuronal cell-adhesion molecules that are localized postsynaptically, interact with presynaptic neurexins, and play a key role in the maturation and function of synapses. This gene-disease relationship is also supported by mouse models displaying neurodevelopmental phenotypes consistent with autism, functional studies, and protein interaction with neurexins (PMIDs: 21278334, 23183221, 24104404, 29106499). In humans, NLGN4 is preferentially expressed in the cortex, whereas mouse Nlgn4 is primarily expressed in the brainstem, retina, and spinal cord. Additionally, in human neurons NLGN4 is preferentially localized to excitatory synapses and only a subset of inhibitory synapses, whereas in mice Nlgn4 is primarily present in glycinergic and GABAergic synapses. These differences, along with the poor conservation of the mouse ortholog of NLGN4, called Nlgn4-like (Nlgn4l), should be considered when interpreting the relevance of the results obtained in knockout mice.

In summary, there is definitive evidence supporting the relationship between NLGN4X and X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 1, 2018. It was reevaluated on October 10, 2025 (SOP Version 11). Although new evidence was added, the classification did not change.