Search for Disease-Causing Variants in Families with Skeletal Deformities Using Whole Exome Sequencing

Abstract

Congenital skeletal anomalies represent diverse genetic conditions both phenotypically and phylogenetically. Understanding the physio-pathological pathways under these anomalies is challenging due to mutational consequences in terms of unique and spatiotemporal modes of action. Furthermore, clinical characterization and skeletal imaging by advanced genetic testing have served as the foundation for diagnosis and management. It is anticipated that the whole exome sequencing will shed light on the unidentified mutations of skeletal dysplasias as well as the variables leading to the development of novel strategies to combat skeletal anomalies in the population. The current research delved into the examination of two consanguineous Pakistani families at the clinical and genetic levels. The study revealed intra-familial and inter familial variability of phenotypes in both families. Family A in the study was clinically assessed and classified as an autosomal dominant split hand and foot malformation (SHFM). The exome analysis of Family A yielded several heterozygous genetic variants related to the SHFM phenotypes. On the basis of pathogenicity and involvement in limb development, the HOXD13 gene variant [c.500A>G; p.(Tyr167Cys)] was prioritized and analyzed for segregation. This missense heterozygous variant co-segregated with the phenotypes of the affected members in family A. Recently, the same pathogenic HOXD13 variant has been reported with the phenotype of type 1b and 1c syndactyly showing the broad clinical spectrum of the HOXD13 gene in multiple aspects of development. Similarly, Family B was also placed under the category of postaxial polydactyly. An isolated form of postaxial polydactyly along with the recessive inheritance pattern was concluded in Family B. The genome of the affected member underwent whole exome sequencing and several filters were applied to the exome data to focus on pathogenic variants associated with post-axial polydactyly. Several variants underwent segregation analysis but none of them segregated with the disorder. Therefore, it is recommended to further analyze the exome data of family B and identify new valuable insights into genetic patterns of type B postaxial polydactyly.