Submission Details

Variation in NTNG1 was first reported in a female with a de novo balanced translocation t(1;7)(p13.3;q31.3) and features similar to those of Rett syndrome (seizures, developmental delay, social deficits, absent speech, unsteady gait, and hand stereotypies) in 2005 (Borg et al., PMID: 15870826). 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 structural variant, it cannot be entered into the curation interface).

Since then, additional variants have been reported in large exome sequencing studies. 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 absent from gnomAD v2.1.1, but since they have no supportive functional data, they were not scored. In addition, two frameshift 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). Frameshift 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, with 4 truncating alleles in gnomAD v2.1.1 (pLI = 0.92, LOEUF = 0.36), but is not significantly constrained for missense variants (Z = 2.45). Given that the mechanism of pathogenicity is unknown at this time, and truncating variants have been reported in healthy controls and in parents, these frameshift 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. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 2, 2021 (SOP Version 8).

Variation in NTNG1 was first reported in a female with a de novo balanced translocation t(1;7)(p13.3;q31.3) and features similar to those of Rett syndrome (seizures, developmental delay, social deficits, absent speech, unsteady gait, and hand stereotypies) in 2005 (Borg et al., PMID: 15870826). 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 structural variant, it cannot be entered into the curation interface). Since then, additional variants have been reported in large exome sequencing studies. 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 absent from gnomAD v2.1.1, but since they have no supportive functional data, they were not scored. In addition, two frameshift 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). Frameshift 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, with 4 truncating alleles in gnomAD v2.1.1 (pLI = 0.92, LOEUF = 0.36), but is not significantly constrained for missense variants (Z = 2.45). Given that the mechanism of pathogenicity is unknown at this time, and truncating variants have been reported in healthy controls and in parents, these frameshift 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 supported by experimental evidence in mouse models and in vitro studies (PMIDs: 25411505, 27345935, 32348754, 31692205. 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 association between NTNG1 and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 2/2/2021 (SOP Version 8).