SLITRK2

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

The *SLITRK2* gene encodes a transmembrane protein expressed at postsynaptic neurons that regulates neurite outgrowth and excitatory synapse formation. *SLITRK2* was first reported in relation to X‑linked complex neurodevelopmental disorder in 2022 (El Chehadeh et al., PMID: 35840571). Affected individuals present with global developmental delay, intellectual disability of variable severity, neuropsychiatric and behavioral problems (including anxiety, autism spectrum disorder, ADHD, and aggressive behavior), and motor abnormalities such as unsteady gait, spasticity, or dystonia. Additional findings in a subset of individuals include seizures, feeding difficulties, kyphoscoliosis, short stature, and nonspecific structural brain abnormalities. Eight variants (6 missense and 2 nonsense) that have been reported in seven males and one female in two publications (PMIDs: 35840571, 38283150) are included in this curation. *SLITRK2* has a single protein-coding exon, which is its last exon, and is not predicted to undergo nonsense-mediated decay. The variants were either *de novo* (in two probands) or inherited from an unaffected mother, suggestive of an X‑linked recessive pattern of inheritance. Functional studies showed that four missense variants and a nonsense variant resulting in a truncated protein had impaired membrane trafficking and/or impaired excitatory synapse-promoting effects (PMID: 35840571). Two missense variants with no evidence of altered function, a missense variant in a male proband with a likely pathogenic variant in *ARX*, and a *de novo* missense variant in a female reported three times in gnomAD, were scored 0 points. The mechanism of pathogenicity appears to be loss of function. *SLITRK2* is not strongly constrained for loss‑of‑function variation (pLI = 0.75, LOEUF = 0.58, gnomAD 4.1.1) or missense variants (Z = 2.76). This gene-disease relationship is also supported by a mouse model. *Slitrk2* conditional knockout mice exhibit memory deficits and abnormal gait, while hippocampal CA1-specific conditional knockout of Slitrk2 impaired excitatory synapse maintenance and caused abnormalities in spatial reference memory (PMID: 35840571). In summary, there is limited evidence to support the relationship between *SLITRK2* and X-linked 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 classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 2, 2025 (SOP Version 12).

Inheritance Pattern: XL

Disease ID:MONDO:0957203

Submitter: Ambry Genetics

Inheritance Pattern: XL

Disease ID:MONDO:0957203

Submitter: PanelApp Australia