AGTR2

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: Orphanet

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: PanelApp Australia

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

Variants in *AGTR2* have been reported in individuals presenting various neurodevelopmental phenotypes, including intellectual disability, autistic features, epileptic seizures, speech delay, restlessness, and hyperactivity, as early as 2002. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, for the purposes of this curation, all of these features have been lumped into one disease entity, X-linked complex neurodevelopmental disorder. Although eight unique variants, including missense and truncating, have been reported in affected humans, the majority (six) have been ruled out from disease-causality based on high frequency in control populations (Piton et al., PMID 23871722), occurrence in unaffected males (Erdmann et al., PMID 14722754), non-segregation within a family (Bienvenu et al., PMID 12746399), and lack of enrichment in patients in a case-control study (Huang et al., PMID 16283672). Given that the two remaining variants are missense with no supporting functional evidence, and *AGTR2* was the only gene sequenced in each case, these variants were awarded 0 points. There are two *Agtr2* mouse models which collectively show altered neuronal spine morphology, spatial memory impairment, delayed learning, and reduced exploratory behavior (PMIDs: 18335189, 7477267). However, due to the scarcity of plausible reports of disease-causing variants in humans, the experimental evidence was not scored. In summary, the evidence supporting the relationship between *AGTR2* and X-linked 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 *AGTR2* plays in this disease. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 2, 2020 (SOP Version 7).