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Analysis of genetic variants in rare osteochondrodysplasias using whole exome sequencing

Grant number: 15/21783-9
Support type:Regular Research Grants
Duration: August 01, 2016 - July 31, 2018
Field of knowledge:Health Sciences - Medicine - Maternal and Child Health
Principal researcher:Débora Romeo Bertola
Grantee:Débora Romeo Bertola
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers:Chong Ae Kim ; Maria Rita dos Santos e Passos Bueno


The skeletal dysplasias or osteochondrodysplasias are a heterogeneous group of disorders that affect the formation, growth, and/or development of the skeletal system. Most of these disorders are caused by variants in the exonic region of genes. In the last review of the Nosology and Classification of Genetic Skeletal Disorders from 2015 there were 436 conditions, allocated in 42 groups accordingly to clinical, molecular and/or radiologic criteria. The discovery of the molecular basis of monogenic disorders in the last decade was leveraged by the usage of a new technique of massive parallel sequencing, also referred as next generation sequencing, that allows the analysis of large number of genomic regions, for instance the complete exome which harbors most of the pathogenic variants associated with skeletal dysplasias, for a reasonable cost. Presently, approximately 80 out of 436 (20%) of these disorders still have an unknown genetic etiology.In the last three years our group has followed individuals with skeletal dysplasia in a specific out-patient clinic (ambulatório de displasias esqueléticas da Unidade de Genética do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo), weekly. Many different skeletal dysplasias are followed, including the most common ones such as the FGFR3 related osteochondrodysplasias (achondroplasia, hypochondroplasia and thanatophoric dysplasia) and osteogenesis imperfecta, rare disorders such as spondylo-epiphyseal dysplasia with cone-rod dystrophy, in which our group has identified the associated gene (PCYT1A) in 2014, and also disorders without known associated genes such as a Grebe-like dysplasia which has only two cases reported in the literature.The follow up of these individuals includes clinical history, detailed clinical examination and x-rays. Based upon the findings in each individual the genetic molecular testing is directed to the the best candidate gene or genes. The molecular testing may be performed by conventional Sanger sequencing (in the cases of small genes or site specific mutations) or by next generation sequencing with a panel of more than 80 genes associated with skeletal dysplasias that was developed in association with the Centro para Pesquisa sobre o Genoma Humano e Células-Tronco do Instituto de Biociências da Universidade de São Paulo, coordinated by Prof. Dra. Maria Rita dos Santos e Passos Bueno. Since the beginning of the project, 60 patients have already been sequenced with this NGS panel, and a pathogenic variant was identified in 38 of them (a sensibility of 63%). The clinical, radiological, and molecular investigation of the patients is fundamental not only for the clinical management of the patient himself, but also for the appropriate counseling for family members, for the possibility of early treatment in relatives, and for the acquisition of scientific medical knowledge in several biological pathways in which single mutations lead to many variable and complex phenotypes.This project aims to perform whole exome sequencing in the osteocondrodisplasia individuals and families in which the genetic etiology is unknown, or that remains unknown after the investigation with the NGS panel for skeletal dysplasias, in order to identify genes that were not previously associated with skeletal dysplasia. (AU)

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Scientific publications (4)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
GUO, LONG; BERTOLA, DEBORA ROMEO; TAKANOHASHI, ASAKO; SAITO, ASUKA; SEGAWA, YUKO; YOKOTA, TAKANORI; ISHIBASHI, SATORU; NISHIDA, YOICHIRO; YAMAMOTO, GUILHERME LOPES; DA SILVA FRANCO, JOSE FRANCISCO; et al. Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation. American Journal of Human Genetics, v. 104, n. 5, p. 925-935, . (13/08028-1, 15/21783-9)
BERTOLA, D. R.; HSIA, G.; ALVIZI, L.; GARDHAM, A.; WAKELING, E. L.; YAMAMOTO, G. L.; HONJO, R. S.; OLIVEIRA, L. A. N.; DI FRANCESCO, R. C.; PEREZ, B. A.; et al. Richieri-Costa-Pereira syndrome: Expanding its phenotypic and genotypic spectrum. Clinical Genetics, v. 93, n. 4, p. 800-811, . (15/21783-9)
BURRAGE, LINDSAY C.; REYNOLDS, JOHN J.; BARATANG, NISSAN VIDA; PHILLIPS, JENNIFER B.; WEGNER, JEREMY; MCFARQUHAR, ASHLEY; HIGGS, MARTIN R.; CHRISTIANSEN, AUDREY E.; LANZA, DENISE G.; SEAVITT, JOHN R.; et al. Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes. American Journal of Human Genetics, v. 104, n. 3, p. 422-438, . (13/08028-1, 15/21783-9)
LEE, CHAE SYNG; FU, HE; BARATANG, NISSAN; ROUSSEAU, JUSTINE; KUMRA, HEENA; SUTTON, V. REID; NICETA, MARCELLO; CIOLFI, ANDREA; YAMAMOTO, GUILHERME; BERTOLA, DEBORA; et al. Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with ``Corner Fractures''. American Journal of Human Genetics, v. 101, n. 5, p. 815-823, . (13/08028-1, 15/21783-9)

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