SETD5 was first reported in relation to autosomal dominant syndromic complex neurodevelopmental disorder in 2013 (PMID: 24680889). Phenotypic features often reported in probands include: dysmorphic features, leg length discrepancies, feeding difficulties, developmental delays, autism, skeletal anomalies, and congenital malformations of various organ systems. This curation includes 19 variants (frameshift, deletions, missense, splice site) reported probands with phenotypic similarity (PMIDs: 28881385, 028120103, 28263952, 26482601, 29158550, 27375234, 32793091, 31656537, 29805509, 24680889, 25138099, 28549204). More evidence is available in the literature but the maximum score for genetic evidence (12 points) has been reached. Of note, three individuals with variants in SETD5 and a distinct phenotype consistent with Moya Moya Disease, a rare, progressive cerebrovascular disorder caused by blocked arteries in the basal ganglia have also been reported, however that association has not been confirmed or reported again (PMID: 31474762). These individuals with Moya Moya did not have any neurodevelopmental delays and therefore were not scored in this curation. The mechanism of pathogenicity appears to be loss-of-function.
In summary, there is definitive evidence supporting the relationship between SETD5 and autosomal dominant syndromic complex neurodevelopmental disorder. This has been repeatedly demonstrated in the clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on the meeting date July 27, 2023 (SOP Version 9).
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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