KIRREL3 was first reported in relation to autosomal dominant intellectual disability (ID) in 2008 (Bhalla et al., PMID: 19012874). The authors found an individual with ID and a balanced translocation disrupting KIRREL3 and CDH15 and went on to identify five additional individuals with ID and KIRREL3 missense variants of unknown inheritance. However, two of the three unique variants had an allele frequency in gnomAD too high to be considered pathogenic. Since then, additional individuals with KIRREL3 missense variants and neurodevelopmental disorders (NDD), including ID, autism, and seizures, have been reported in the literature; at least 5 were de novo (PMIDs: 25363760, 25363768, 28714951, 32503885, 33853164), but 8 were inherited from an unaffected parent (PMIDs: 27824329, 29271092). None of the missense variants were scored due to their presence in gnomAD and/or inheritance from reportedly unaffected parents and a lack of evidence of pathogenicity. Additionally, 3 probands with truncating variants have been reported: one with a de novo variant and ID (PMID: 26411299) and 2 with an inherited variant and ASD (PMID: 37007974). KIRREL3 is not constrained for truncating variants (pLI = 0, gnomAD v4.0.0) or missense variants (Z = 1.59). Therefore, the truncating variants were also not scored.
KIRREL3 is a synaptic cell adhesion protein shown to be required for synapse formation in the rodent hippocampus (PMIDs: 26575286, 28670619). Functional in vitro studies of five KIRREL3 missense variants observed in affected individuals showed decreased synapse formation in hippocampal neurons (PMID: 32503885); however, at least two of these variants were observed at a high frequency in gnomAD, questioning the relevance of this assay for the neurodevelopmental phenotypes observed in humans.
While studies in homozygous null Kirrel3-/- mice and synapse deficits in cultured Kirrel3+/- mouse hippocampal neurons suggest that KIRREL3 plays a role in central nervous system development, none of the experimental evidence was scored due to the lack of compelling genetic evidence.
In summary, the evidence supporting the relationship between KIRREL3 and complex neurodevelopmental disorder has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role of KIRREL3 in this disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 8, 2023 (SOP Version 10).
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