SF3B4 was first reported in relation to autosomal dominant SF3B4-related acrofacial dysostosis in 2012 (Bernier et al., PMID: 22541558). SF3B4 has been noted to be associated with the following disease entities: Nager acrofacial dysostosis and Rodriguez acrofacial dysostosis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, SF3B4-related acrofacial dysostosis (MONDO:0800483).
Six variants (1 start-loss, 4 frameshift, 1 nonsense) that have been reported in 11 probands in
2 publications (PMID: 22541558, PMID: 23568615) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be LOF. This gene-disease association is also supported by experimental evidence (animal models and expression level evidence) (PMID: 26874011, 31900962, 9097020). SF3B4 KD Xenopus models and heterozygous SF3B4 mutant mice models demonstrated some features of Nager syndrome (PMID: 26874011, 31900962). Additionally, the gene has been shown to be expressed in areas of interest in mice (PMID: 9097020).
In summary, SF3B4 is definitively associated with autosomal dominant SF3B4-related acrofacial dysostosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
This classification was approved by the ClinGen Craniofacial Malformations Gene Curation Expert Panel on 05/18/2023. (Gene Clinical Validity Standard Operating Procedures 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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