Clinical and Genetic Study of Hereditary Skeletal Disorders in Three Consanguineous Families

Abstract

Skeleton is an organ system performing numerous multipurpose functions. Number of signaling pathways and genes are involved in the articulate and precise frame work of bones (skeleton). Any alteration/mutation(s) in these signaling pathways and respective gene(s) may result in osteochondrodysplasias/skeletal dysplasia or dystosis. To date, about 461 congenital skeletal dysplasia have been reported and classified into 42 groups. In the present study three consanguineous families of Pakistani origin exhibiting autosomal recessive hereditary skeletal underlying characteristic features of Acromesomelic dysplasia (Family A) and spondylocostal dysostosis (B, C) disorders were studied. Homozygosity mapping technique was used to find out genes responsible for skeletal disorders in these families (A, B and C). Homozygosity mapping of known loci harboring genes for Acromesomelic dysplasia showed linkage to NPR2 gene (9p13.3) in family A. After linkage confirmation, all the exons were subjected to sanger sequencing. Sequencing data analysis revealed no pathogenic variant in 15 exons suggesting that variant can be in any of the remaining six exons. The Family B and C were subjected to homozygosity mapping of known loci harboring genes for spondylocostal dysostosis and the markers failed to show any homozygous pattern for alleles This suggests the involvement of some other pathogenic genes that are contributing to the phenotypes of the patients. In conclusion, we could not identify the causative variant in the sequenced exons of NPR2 gene which suggests the presence of causative variants in remaining exons in family A. The family B and C did not establish any linkage to the known genes underlying the phenotypes of these disorders; therefore, we presume the involvement of a novel gene/s.