Identifying disease causal mutation and familial specific polymorphism of KIF22 in spondyloepimetaphyseal dysplasia with joint laxity using family and Korean population study

Abstract

Introduction: Spondyloepimetaphyseal dysplasia with joint laxity is a rare skeletal dysplasia manifesting with short stature, joint laxity with dislocation(s), limb malalignment, and spinal deformity, for which a causative gene mutation has not been discovered. Methods: 8 variations in the KIF22 gene were detected in 7 of 8 patients by using whole exome sequencing. To identifying disease causal mutation and familial specific polymorphism, we performed mutation validation, family study, Korean population study, and protein damage prediction. Results: They revealed that the mutations p.Pro148Leu, p.Pro148Ser or p.Arg149Gln induced by c.442C>T, c.443C>T or c.446G>A co-segregated with the phenotype in familial patients and were present in four out of five sporadic patients. These mutations in KIF22 were absent in unaffected parents and 505 Koreans and implicated as harmful mutations by protein damage prediction tools. The other two novel mutations were found in family members with normal phenotype of the patient and one of them was detected in 2.8% of Korean population. Conclusions: The result of Sanger sequencing validation was identical to the result of whole exome sequencing. There was no false positive signal and the three variants, c.442C>T, c.443C>T and c.446G>A, were only detected in the patients. We classified c.695G>A as a familial specific polymorphism, and c.1677+124A>T as a Korean specific polymorphism.