The smoothened frizzled class receptor is encoded by the *SMO *gene and is located at 7q32.1. Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in molecular mechanism, phenotypic spectrum, and mode of inheritance. Therefore, Curry-Jones syndrome, somatic mosaic (MIM:601707) and Happle-Tinschert Syndrome were lumped, while Pallister-Hall-like syndrome (OMIM:241800) was split.
Mosaic SMO syndrome is caused by a postzygotic mutation (c.1234 C>T p.Leu412Phe) in the *SMO *gene. The altered amino acid, Leu412, localizes to transmembrane helix 5 of SMO within one of three pivot regions that are likely to have a key role in the conformational changes required for receptor activation (PMID 27236920). This mutant allele is present at levels below 50% in samples and is not reliably detected in blood or saliva (PMID 27236920).
This gene-disease relationship was first described in 2016 (PMID 27236920 Twigg et al., 2016). Sixteen probands reported in six publications were included in this curation (PMIDs: 27236920, 31825089, 31607746, 29335739, 31120550, 36707059). This gene-disease relationship is also supported by biochemical assays, functional alteration, expression, and non-human model organisms (PMIDs: 12192414, 15618519, 21859383, 24859340, 15520185, 15107405).
In summary, there is definitive evidence supporting the relationship between SMO and mosaic SMO syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the Craniofacial Malformations Gene Curation Expert Panel on the meeting date 11/16/2023 (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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