EXOC6B was first reported in association to autosomal recessive Spondyloepimetaphyseal Dysplasia with Joint Laxity, type 3 in 2016 (Girisha et al., PMID: 26669664). This entity is characterized by multiple joint dislocations, joint laxity, postnatal growth deficiency, scoliosis, leptodactyly, delayed carpal/tarsal bone ossification and spondylar, metaphyseal and epiphyseal dysplasia. It is currently the only phenotype asserted for this gene (OMIM #618395). To date, four different causal variants have been reported in the literature in six probands from four unrelated families - two private homozygous nonsense variants (PMIDs: 26669664 and 36150098), one homozygous multi-exon deletion (PMID: 30284759) and one homozygous single-exon deletion (PMID: 36150098). All reported cases were investigated using broad genetic testing strategies, which excluded other known causes for the skeletal dysplasia phenotype. Segregation analysis was consistent with the autosomal recessive mode of inheritance. A total of 10.5 points was reached for genetic evidence. The proposed mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by expression studies and functional alteration studies using both patients cells and non-patients cells submitted to knockdown of EXOC6B (PMIDs: 38305850, 38305850). Functional data show that the EXOC6B protein is expressed perinuclearly and at the base of the primary cilium in murine prechondrocytes cells, and its expression was significantly reduced following the targeted gene knockdown. Additionally, cells from affected patients exhibited reduced mRNA and/or protein expression of EXOC6B, along with defective ciliogenesis and impaired osteogenic differentiation capacity. The combined score for genetic and functional evidence reaches the threshold of 12 points, and this gene-disease relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. In summary, there is definitive evidence supporting the relationship between EXOC6B and autosomal recessive Spondyloepimetaphyseal Dysplasia with Joint Laxity, type 3. This classification was approved by the ClinGen Skeletal Disorders GCEP on July 2nd, 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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