Open AccessAnalysis of mutations in EXT 1 and EXT 2 in Brazilian patients with multiple osteochondromas
Author(s) -
Santos Savana C. L.,
Rizzo Isabela M. P. O.,
Takata Reinaldo I.,
SpeckMartins Carlos E.,
Brum Jaime M.,
Sollaci Claudio
Publication year - 2018
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.382
Subject(s) - frameshift mutation , missense mutation , genetics , sanger sequencing , genotype , allele , biology , gene , population , mutation , medicine , environmental health
Abstract Background Multiple osteochondromas is a dysplasia characterized by growth of two or more osteochondromas. It is genetically heterogeneous, caused by pathogenic variants in EXT 1 or EXT 2 genes in 70%–90% of patients. The EXT 1 is more often mutated than EXT 2 gene, with a variable prevalence between populations. There are no data about EXT 1 and EXT 2 pathogenic variants in patients with multiple osteochondromas in Brazilian population. The aim of this survey is to characterize these to determine the genotype profile of this population. Methods DNA sequencing (Sanger Method) and MLPA analysis were performed to identify point mutations and deletions/duplications in the sample of 153 patients in 114 families. Results Germline variants were identified in 83% of families in which EXT 2 variants were detected in 46% and EXT 1 in 37% of cases. No variants were detected in 17% of them. We identified 50 different variants, 33 (13 frameshift, 11 nonsense, 5 missense, 2 splice site mutation, and 2 large deletions) in EXT 1 and 17 (6 frameshift, 6 splice site mutation, 3 nonsense, 1 missense, and 1 large deletion) in EXT 2 . Of all 50 variants, 31 (62%) were novel, including 20 out of 33 (60,6%) EXT 1 and 11 out of 17 (64.7%) EXT 2 alleles. The vast majority of variants (88%) were “loss‐of‐function” and two novel hotspots in EXT 2 gene were observed in our study. Conclusion The prevalence of variants detected in the EXT 2 gene differs from other researches from Latin America, European, and Asian population. This uncommon prevalence could be related with the newly characterized variant hotspot sites detected in EXT 2 gene (p.Ala409Profs*26 and p.Ser290*). A high number of novel variants were also identified indicating that Brazilian population has a unique genetic profile. Characterizing this population and establishing its genotype is essential to understand the molecular pathogenesis of this disease in Brazil.