Familial Kyphoscoliosis: Association with the IRX Homeobox Gene Family.

Introduction: Genetic analyses of families in which members had kyphoscoliosis (lateral spinal curvature and a thoracic kyphotic curve) identified a 3.5 MB area on chromosome 5p containing genes of the Iroquois (IRX1, IRX2, IRX4) homeobox family which were then sequenced. Objectives: Exons and highly conserved non-coding regions (HNCRs) 500 kb upstream and downstream from IRX1, IRX2 and IRX4 were sequenced in 46 individuals (6 families). Materials and Methods: Selection of sequenced elements was based on PhastCons Placental Mammal Conserved Elements, Multiz Alignment (431 SNPs: 137 novel, 61 in IRX4 regions, 80 in IRX2 regions, 290 in IRX1 regions). Mendelian inconsistencies were detected using PEDCHECK (inconsistency rate: 1.4%; missing data: 2.8%). SNPs and individuals with >10% missing rate were dropped. Association analyses included 391 SNPs. Results: Association analyses resulted in twelve SNPs with p-values < 0.025 (Table). Multiple sequence variants were found surrounding IRX1, the most prominent a single base-pair deletion in all affected individuals genotyped in one family. All individuals with kyphoscoliosis and those with scoliotic curves > 35° had genotypes differing from the reference (unaffected) genotype for 23 SNPs. Several of these were also significant in association analyses. Conclusions: The KS phenotype has been linked to sequence variants within regulatory regions of the IRX homeobox gene family. Further analyses to determine relevance will be done through in vivo and in vitro assays. Significance: Identification of spinal genetic determinants related to axial growth and maturation will aid in understanding pathology and potentially allow for development of directed therapeutic interventions. [ABSTRACT FROM AUTHOR]