title: A novel multiple joint dislocation syndrome associated with a homozygous nonsense variant in the EXOC6B gene.
abstract: We report two brothers from a consanguineous couple with spondyloepimetaphyseal dysplasia (SEMD), multiple joint dislocations at birth, severe joint laxity, scoliosis, gracile metacarpals and metatarsals, delayed bone age and poorly ossified carpal and tarsal bones, probably representing a yet uncharacterized SEMD with laxity and dislocations. This condition has clinical overlap with autosomal dominantly inherited SEMD with joint laxity, leptodactylic type caused by recurrent missense variants in the kinesin family member 22 gene (KIF22). Single-nucleotide polymorphism array analysis and whole-exome sequencing in the two affected siblings revealed a shared homozygous nonsense variant [c.906T>A/p.(Tyr302*)] in EXOC6B as the most likely cause. EXOC6B encodes a component of the exocyst complex required for tethering secretory vesicles to the plasma membrane. As transport of vesicles from the golgi apparatus to the plasma membrane occurs through kinesin motor proteins along microtubule tracks, the function of EXOC6B is linked to KIF22 suggesting a common pathogenic mechanism in skeletal dysplasias with joint laxity and dislocations.
authors.affiliation: Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.
authors.forename: Katta Mohan
authors.identifier: 0000-0002-0139-8239
authors.initials: KM
authors.lastname: Girisha
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Fanny
authors.initials: F
authors.lastname: Kortüm
authors.affiliation: Division of Pediatric Orthopedics, Department of Orthopedics, Kasturba Medical College, Manipal University, Manipal, India.
authors.forename: Hitesh
authors.initials: H
authors.lastname: Shah
authors.affiliation: University Medical Center Hamburg-Eppendorf, Bioinformatics Service Facility, Hamburg, Germany.|Center for Bioinformatics, University of Hamburg, Hamburg, Germany.|Heinrich-Pette-Institute, Leibniz-Institute for Experimental Virology, Virus Genomics, Hamburg, Germany.
authors.forename: Malik
authors.initials: M
authors.lastname: Alawi
authors.affiliation: Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Dalal
authors.affiliation: Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.
authors.forename: Gandham SriLakshmi
authors.initials: GS
authors.lastname: Bhavani
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kutsche
mesh_terms: D018389:Codon, Nonsense; D059472:Exome; D019204:GTP-Binding Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D004204:Joint Dislocations / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D035781:Siblings; D013577:Syndrome; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; C489222:EXOC6B protein, human; D019204:GTP-Binding Proteins