Biallelic pathogenic variations in EXOC6B cause Spondyloepimetaphyseal dysplasia with joint laxity, type-3 (SEMDJL3). EXOC6B gene encodes for EXOC6B protein which is a component of exocyst complex. Exocyst complex facilitates transport and tethering of secretory vesicle to plasma membrane prior to fusion. EXOC6B binds with Rab8 GTPases present on the secretory vesicle and interacts with multiple other exocyst subunits within the complex. The association of EXOC6B with Rab8 GTPase and other factors is essential for transportation and delivery of ciliary proteins at the site of primary ciliogenesis. Loss of function of EXOC6B impairs exocysts function thereby affecting the primary ciliogenesis which might be the cause of skeletal features seen in all patients affected with SEMDJL3.
Six affected individuals from four unrelated families with different ethnicities have been reported till date. Exome sequencing along with copy number variant analysis and comparative genomic hybridization (aCGH) were used for molecular testing in these individuals.
The four sequence variants identified in EXOC6B gene (NM_015189.3) are:
1. Homozygous deletion of ~120 kb, c.2122+15447_2197-59588del; p.(Gln708Profs*16) of introns 19-20 of EXOC6B
2. Homozygous deletion, c.915+20070_2197-135947del; p.(Gly305_Gln732del) of exon 9-20 of EXOC6B
3. Non-synonymous substitution, c.401T>G; p.(Leu134Ter) in exon 4 of EXOC6B
4. Non-synonymous substitution, c.906T>A; p.(Tyr302Ter) in exon 9 of EXOC6B
EXOC6B