Investigation of genetic mutation in patients with pre-diagnosed spondyloepi(meta)physeal dysplasia

Skeletal dysplasia is a complex disease group consisting of approximately 436 different species characterized by disproportionate short stature and various orthopedic complications. It is subdivided according to clinical, radiological and molecular differences. X-Linked Spondyloepiphyseal Dysplasia Tarda -one of these subtypes- is a X-linked inherited skeletal dysplasia accompanied by progressive spondyloepi(meta)physical dysplasia and premature osteoartritis. The related gene of disorder, sedlin (SEDL, OMIM*300202) is mapped on the Xp22.2 chromosomal location that encodes sedlin protein play a vesicle role transport from the endoplasmic reticulum to the golgi apparatus. Progressive Pseudoromatoid Dysplasia (PPRD) is characterized by enlargement of the elbow joints and arthritis-like findings. It is an autosomal recessive subtype of skeletal dysplasia caused by mutations in WISP3 gene (WNT1-Induced Signal Transduction Protein 3; OMIM * 603400) and localization in the 6q21 chromosomal region. The Whole Exom Sequencing is a technology that enable to determinate the genotypes of unknown disorders, the diagnosis of complex multifactorial diseases that are composed of rare subtypes such as skeletal dysplasia and show genetic heterogeneity of different genotypes causing the same phenotype. In this study, four siblings with skeletal dysplasia who were thought to have hereditary inheritance X-linked or autosomal recessive pattern, screened with whole exom sequencing were determined NM_198239.1: c.210C>A; (p.Cys70Ter) and NM_198239.1:c.302G>A (p.Gly101Glu) homozygous mutations. As a result, on the patients with inherited pattern similar to X-linked recessive; autosomal recessive progressive pseudoromatoid dysplasia was diagnosed and determined their genotype. The detected p.Cys70Ter alteration was observed to be the most frequent pathogenic variant in Turkish patients and consistent with the current literature. It is important to keep in mind that family narratives, clinical and molecular findings may lead to complex disease groups showing genetic heterogeneity but must be supported by molecular studies to provide definitive diagnosis and preimplantation genetic diagnosis for families.