Prospective evaluation of exome sequencing in the etiological investigation of syndromic short stature patients without clinical diagnosis

• Grant number: 18/10893-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: May 01, 2019
• End date: July 31, 2021
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Alexander Augusto de Lima Jorge
• Grantee: Bruna Lucheze Freire
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 13/03236-5 - New approaches and methodologies in molecular-genetic studies of growth and pubertal development disorders, AP.TEM

Abstract

The word syndrome is used to define a set of medical signs, symptoms and characteristics correlated with a particular condition. Short stature is one of the main features found in many known syndromes, and when it is associated with others signs such as, facial dimorphisms, NPMD and/or intellectual disabilities, major malformations (ex: cardiac defects, CNS malformation, renal agenesis, midline facial defects), we classify as a syndromic short stature, that is frequently result of a genetic defect. As a majority of the genetic syndromes related to the growth disorder are rare and/or phenotypically heterogeneous diseases, clinical diagnosis is a great challenge, making the molecular diagnosis important for therapeutic decision, in addition to genetic counseling of the family. The aim of this project is to study the molecular etiology of patients with syndromic short stature without a clinical diagnosis, through the exomic sequencing technology (n=50). In this way we hope to identify new genes responsible for syndromic short stature and to expand the phenotype associated to genes already implicated in syndromic short stature by describing atypical cases. Therefore, we intend to develop strategies for clinical investigation of these patients and to develop and implement a telemedicine platform for the evaluation of patients with syndromic growth disorder. We will use Agilent`s Sure Select system to prepare the exomes libraries. The bioinformatics analysis of the data will follow a flow previously established by the laboratory, and the variants found will be analyzed in relation to population frequency, position of the variant, in silico predisposition of pathogenicity, inheritance compatibility, biological plausibility, and subsequent segregation in relatives. (AU)

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)

FREIRE, BRUNA LUCHEZE; HOMMA, THAIS KATAOKA; LERARIO, ANTONIO MARCONDES; SEO, GO HUN; HAN, HEONJONG; DE ASSIS FUNARI, MARIANA FERREIRA; GOMES, NATHALIA LISBOA; ROSEMBERG, CARLA; VICTORINO KREPISCHI, ANA CRISTINA; VASQUES, GABRIELA DE ANDRADE; et al. High frequency of genetic/epigenetic disorders in short stature children born with very low birth weight. AMERICAN JOURNAL OF MEDICAL GENETICS PART A, v. 188, n. 9, p. 6-pg., 2022-07-06. (18/10893-6, 13/03236-5)

LIN, YUH-CHARN; NICETA, MARCELLO; MUTO, VALENTINA; VONA, BARBARA; PAGNAMENTA, ALISTAIR T.; MAROOFIAN, REZA; BEETZ, CHRISTIAN; VAN DUYVENVOORDE, HERMINE; DENTICI, MARIA LISA; LAUFFER, PETER; et al. SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling. American Journal of Human Genetics, v. 108, n. 1, p. 115-133, JAN 7 2021. (13/03236-5, 18/10893-6)

HARRIS, SARAH C.; CHONG, KAREN; CHITAYAT, DAVID; GILMORE, KELLY L.; JORGE, ALEXANDER A. L.; FREIRE, BRUNA L.; LERARIO, ANTONIO; SHANNON, PATRICK; COPE, HEIDI; GALLENTINE, WILLIAM B.; et al. Diagnosis of TBC1D32-associated conditions: Expanding the phenotypic spectrum of a complex ciliopathy. AMERICAN JOURNAL OF MEDICAL GENETICS PART A, v. 191, n. 5, p. 11-pg., 2023-02-24. (18/10893-6, 13/03236-5)

MAGRINO, JOSEPH; MUNFORD, VERIDIANA; MARTINS, DAVI JARDIM; HOMMA, THAIS K.; PAGE, BRENDAN; GAUBITZ, CHRISTL; FREIRE, BRUNA L.; LERARIO, ANTONIO M.; VILAR, JULIANA BRANDSTETTER; AMORIN, ANTONIO; et al. A thermosensitive PCNA allele underlies an ataxia- telangiectasia-like disorder. Journal of Biological Chemistry, v. 299, n. 5, p. 16-pg., 2023-04-26. (18/10893-6, 13/03236-5)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

FREIRE, Bruna Lucheze. Whole exome sequencing should be the first genetic-molecular approach for children with syndromic short stature without clinical diagnosis. 2021. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) São Paulo.