FAAH2 was first reported in relation to X-linked intellectual disability in 2010 (Whibley et al., PMID: 20655035). Since this first report, additional studies have reported variants in FAAH2 in individuals with neurological disorders. However, the phenotypic spectrum in reported individuals is wide, ranging from severe neonatal presentation with early death to late onset neuromuscular and psychiatric presentations.
Four variants (loss of function and deletions) that have been reported in four probands in three publications (PMIDs: 20655035, 34645488, 36964972 and SCV: 004804629.1) are included in this curation. FAAH2 is not constrained for loss-of-function variants (pLI = 0, gnomAD v2.1.1) or missense variants (Z = –3.63). Therefore, all cases were scored 0. This gene-disease relationship is not supported by experimental evidence.
In summary, the evidence supporting the relationship between FAAH2 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 FAAH2 plays in this disease. This gene-disease relationship was originally evaluated in September 2024. In June of 2025, it was recurated; no new evidence was added, but the gruop reconsidered the original scoring due to constraint information. As a result, the classification changed from limited to disputed. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 12, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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