NTNG1

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

Variation in *NTNG1* was first reported in 2005 (Borg et al., PMID: 15870826) in a female with a *de novo* balanced translocation t(1;7)(p13.3;q31.3) and features similar to those of Rett syndrome, including seizures, developmental delay, social deficits, absent speech, unsteady gait, and hand stereotypies. Mapping of both breakpoints demonstrated that *NTNG1* was disrupted at the chromosome 1 breakpoint, while no known gene was disrupted at the chromosome 7 breakpoint. *In silico* algorithms predicted that the translocation would result in protein isoforms with different C-termini, but no functional assays were performed. Because both breakpoints were mapped and *NTNG1* alone is hypothesized to be the cause of this individual’s phenotype, we decided to count this translocation as evidence; however, because positional effects on nearby genes cannot be ruled out, investigation into additional potential etiologies was limited, and no functional evidence was presented, we scored this at 0.1 points (note that because this is a translocation, it cannot be entered into the curation interface). Since then, additional variants have been reported in large exome sequencing studies of individuals with neurodevelopmental disorders. *De novo* missense variants were identified in two patients with autism spectrum disorder (ASD) (O'Roak et al. 2012, PMID: 22495309) and one with a developmental disorder (Kaplanis et al. 2020, PMID: 33057194). These three variants are either absent or present only once in gnomAD v4.1.1, but since they have no supportive functional data, they were not scored. In addition, two truncating variants were reported in probands with neurodevelopmental disorders; one of unknown inheritance in an individual with intellectual disability, and the other one paternally inherited in a patient with ASD, with no information about the father's phenotype (Stessman et al. 2017, PMID: 28191889). Both are present in gnomAD at frequencies higher than expected for a rare condition. Truncating variants were also reported in a control individual and in a parent of a patient with ASD (Satterstrom et al. 2020, PMID: 31981491). *NTNG1* is intolerant to truncating variants (pLI = 1, LOEUF = 0.45, gnomAD v4.1.1), but is not significantly constrained for missense variants (Z = 2.43). Given that the mechanism of pathogenicity is unknown at this time, and truncating variants have been reported in healthy controls and in parents, these truncating variants were also not scored. Although variants in *NTNG1* were first associated with Rett syndrome, we decided to curate for complex neurodevelopmental disorder because the phenotypic features reported in subsequent patients included other neurodevelopmental disorders. The total genetic evidence points awarded in this curation were 0.1 points. This gene-disease relationship is also supported by experimental evidence in mouse models and *in vitro* studies (PMIDs: 25411505, 27345935, 31692205, 32348754). *NTNG1* encodes netrin-G1, a synaptic cell adhesion molecule; interactions between NTNG1 and the netrin-G1 ligand (NGL1) play an important role in axonal guidance, cortical migration and neural circuit functions. The total experimental evidence points awarded were 2.5 points. Of note, homozygous variants leading to loss of function in *NTNG2*, which encodes netrin-G2, cause a neurodevelopmental disorder with hypotonia, intellectual disability, autistic behavior, impaired or absent speech and gait, and hand stereotypies. In summary, there is limited evidence to support the relationship between *NTNG1* and autosomal dominant complex neurodevelopmental disorder. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 2, 2021. It was reevaluated on August 21, 2026 (SOP Version 12). As a result of this reevaluation, no additional patients were identified and the classification did not change.

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0017746

Submitter: Orphanet