A Deletion of More than 800 kb Is the Most Recurrent Mutation in Chilean Patients with <b><i>SHOX</i></b> Gene Defects

Abstract

Background: Deletions in the SHOX gene are the most frequent genetic cause of Leri-Weill syndrome and Langer mesomelic dysplasia, which are also present in idiopathic short stature. Aim: To describe the molecular and clinical findings observed in 23 of 45 non-consanguineous Chilean patients with different phenotypes related to SHOX deficiency. Methods: Multiplex ligation-dependent probe amplification was used to detect the deletions; the SHOX coding region and deletion-flanking areas were sequenced to identify point mutations and single-nucleotide polymorphisms (SNPs). Results: The main genetic defects identified in 21 patients consisted of deletions; one of them, a large deletion of >800 kb, was found in 8 patients. Also, a smaller deletion of >350 kb was observed in 4 patients. Although we could not precisely determine the deletion breakpoint, we were able to identify a common haplotype in 7 of the 8 patients with the larger deletion based on 22 informative SNPs. Conclusion: These results suggest that the large deletion-bearing allele has a common ancestor and was either introduced by European immigrants or had originated in our Amerindian population. This study allowed us to identify one recurrent deletion in Chilean patients; also, it contributed to expanding our knowledge about the genetic background of our population.

Large Deletions at the SHOX Locus in the Pseudoautosomal Region Are Associated with Skeletal Atavism in Shetland Ponies

“…The CRLF2 protein is a type 1 cytokine receptor involved in hematopoietic cell development and in the JAK-STAT pathway, active in bone metabolism and development ( Al-Shami et al 2004 ; Li 2013 ; Hanada et al 2014 ). Poggi et al (2015) reported large deletions in PAR spanning SHOX and CRLF2 in some of the LWD patients, but the common feature among LWD cases is deletions spanning SHOX . Thus, although we cannot exclude that the deletion of CRLF2 is involved in the phenotypic expression of SA, we argue that the similarity to human phenotypes caused by SHOX deficiency support the interpretation that SA is manifested by a reduction of SHOX expression.…”

Skeletal dysplasias in Latin America

“…Regarding genetic studies, the Laboratory of Molecular Biology and Cytogenetics at Pontificia Universidad Católica performs analyses for different genetic conditions, including variants associated with Ach, Leri‐Weill dyschondrosteosis, and TD (Mancilla et al, 2003; Poggi et al, 2015). Sequencing of selected exons of the FGFR3 gene and MLPA deletion/duplication analysis and sequencing of the SHOX gene are currently performed.…”

A Track Record on SHOX: From Basic Research to Complex Models and Therapy

“…Among individuals with the initial diagnosis of ISS, approximately 10% harbor SHOX mutations ( Table 2 ). The results vary considerably from cohort to cohort, and the prevalence of SHOX mutations has increased with more sensitive genetic tests that can detect small deletions (eg, MLPA vs fluorescence in situ hybridization [FISH]) and with the examination of SHOX enhancer regions that were omitted in early SHOX mutation screening ( 18 , 50 , 58 , 161 , 166 , 167 , 174 , 179 , 180 , 184 , 186 , 205 – 207 , 209 – 211 ).…”