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Identification of new genetic modifiers of the phenotype associated with SHOX haploinsufficiency

Abstract

Introduction: Adult height is influenced by environmental and genetic factors, with mutations in the SHOX gene being the most common known cause of monogenic short stature.Pathogenic variants in heterozygosis in this gene are identified in 80% of patients with Leri-Weill Dyschondrosteosis (LWD) and in 2% of children with phenotype compatible with idiopathic short stature (ISS).There is no relationship between the genotype and the phenotype, and even within the same family there is great phenotypic variability regarding the severity of short stature, degree of body disproportion and the development of the Madelung deformity, the last one is a finding characteristic of patients with LWD. A study of an affected family with LWD with SHOX mutation was able to identify a variant in the CYP26C1 gene that segregated with the most severe phenotype. The variants in CYP26C1 explain the phenotypic variability in a small portion of families with SHOX defects. It is believed that there are other factors capable of modulating the phenotype of mutation and that they can better predict the phenotype of patients with this condition. Relevance: The identification of these factors will help in understanding the cellular mechanisms, allowing the development of new therapeutic targets, greater precision in prognosis and genetic counseling.Objective: To evaluate the presence of genetic factors modulating the phenotype of patients with hapoinsufficiency of the SHOX gene in the CYP26C1 gene, the coding, promoter and regulator region of SHOX expression present in trans (this is in the unaffected allele) and in genes that interaction with SHOX. Methodology: We will sequence the CYP26C1 gene, the entire SHOX genomic region (including regulatory regions) as well as several genes that interact with the SHOX action on growth cartilage using a panel customized by large-scale parallel sequencing technology or by sequencing by Sanger.We will initially analyze patients with extreme phenotype within the same family and potentially deleterious genetic variants will be segregated in the other family members. (AU)

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