Whole-Exome Sequencing Identifies Mutations of KIF22 in Spondyloepimetaphyseal Dysplasia with Joint Laxity, Leptodactylic Type

Abstract

Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL), leptodactylic (lepto-SEMDJL) or Hall type, is an autosomal-dominant skeletal dysplasia manifesting with short stature, joint laxity with dislocation(s), limb malalignment, and spinal deformity. Its causative gene mutation has not yet been discovered. We captured and sequenced the exomes of eight affected individuals in six unrelated kindreds (three individuals in a family and five simplex individuals). Five novel sequence variants in KIF22, which encodes a member of the kinesin-like protein family, were identified in seven individuals. Sanger sequencing of KIF22 confirmed that c.443C>T (p.Pro148Ser) cosegregated with the phenotype in the affected individuals in the family; c.442C>T (p.Pro148Leu) or c.446G>A (p.Arg149Gln) was present in four of five simplex individuals, but was absent in unaffected individuals in their family and 505 normal cohorts. KIF22 mRNA was detected in human bone, cartilage, joint capsule, ligament, skin, and primary cultured chondrocytes. In silico analysis of KIF22 protein structure indicates that Pro148 and Arg149 are important in maintaining hydrogen bonds in the ATP binding and motor domains of KIF22. We conclude that these mutations in KIF22 cause lepto-SEMDJL.

Zebrafish homologs of 16p11.2, a genomic region associated with brain disorders, are active during brain development, and include two deletion dosage sensor genes

“…Individuals with a point mutation in the motor domain of KIF22 suffer from the autosomal-dominant skeletal disorder spondyloepimetaphyseal dysplasia with joint laxity (Boyden et al, 2011; Min et al, 2011). No phenotype has been reported in Kif22 +/− mice; however, ∼50% of Kif22 − / − mouse embryos do not survive past the morula stage (Ohsugi et al, 2008).…”

Comprehensive genetic exploration of skeletal dysplasia using targeted exome sequencing

“…3 In recent years, researchers have used wholeexome sequencing (WES) and whole-genome sequencing (WGS) techniques to identify novel genes causing skeletal dysplasia. 4,5 However, WES and WGS are very expensive, and the number of variants detected by these techniques is too high for their application in routine genetic testing. In this context, screening of a certain number of genes by panel-based targeted exome sequencing (TES) could be a useful alternative because of its superior accuracy through high depth, simplicity of analysis, and relatively low costs compared with WES, WGS, and Sanger sequencing.…”

A novel multiple joint dislocation syndrome associated with a homozygous nonsense variant in the EXOC6B gene

“…16 Tethering and fusion of exocytic vesicles are required for ciliogenesis, which is important for skeletal development. 17 A postulated role of KIF22 in cartilage biology by implication in intracellular transport and/or cilia-associated transport mechanisms 3,4 indicates a possible link between kinesins (eg KIF22) and the exocyst complex (eg EXOC6B). In line with this, NIN, another gene associated with an SEMD-JL2-like phenotype, 8 encodes ninein required for centrosome maturation and architecture.…”

“…2 Missense variants affecting one of two amino acids in the motor domain of the kinesin family member KIF22 have been identified to cause SEMD-JL2. 3,4 Key features of SEMD with joint laxity, type 1, with or without fractures (SEMD-JL1; MIM 271640), which is caused by biallelic variants in B3GALT6, 5,6 are joint laxity and dislocations and SEMD. Affected individuals show facial dysmorphism, kyphoscoliosis at birth, talipes equinovarus, cleft palate and congenital heart disease.…”