Clinical and molecular study of patients with Noonan and Noonan-like syndromes: phenotypic characterization and searching for new mutations

• Grant number: 11/17299-3
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2012
• End date: August 31, 2014
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Débora Romeo Bertola
• Grantee: Débora Romeo Bertola
• Host Institution: Instituto da Criança Professor Doutor Pedro de Alcantara (ICR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Alexander Augusto de Lima Jorge ; Alexandre da Costa Pereira

Abstract

Noonan syndrome (NS) is one of the most frequent genetic diseases of autosomal dominant inheritance, with an estimated incidence between 1:1000 and 1:2500 live births (Nora et al., 1974). Clinical findings are characterized by short stature, facial dimorphisms, short and/or webbed neck, sternal deformity, congenital heart disease, mild mental retardation, cryptorchidism in boys and hematological disorders (Noonan, 1994). The extreme clinical variability inter- and intra-familial and the phenotypic age variability (Allanson, 1987) hinder the recognition of the syndrome. The NS patient's prognosis is good, except in cases with severe heart disease, when surgical correction of cardiac defect becomes necessary. The diagnosis is based primarily on a clinical findigs however the syndrome does not have a typical signal. Only a set of several signals lead to clinical diagnosis. The disease's molecular analysis is complex, since the involvement of several genes of the RAS/MAPK signaling pathway. Other rare syndromes have similar characteristics to NS, each one with its own peculiarities. These syndromes are called Noonan-like syndromes (NLS) and include: syndrome cardio-facio-cutaneous (CFC), Costello syndrome (CS), Neurofibromatosis with Noonan syndrome (NFNS) and LEOPARD syndrome (LS). For NLS the involvement of genes in the same signaling pathway was demonstrated. This complicates the confirmation diagnostic, which made it essential to attempt to establish a flowchart for the genes serial study. In addition, molecular diagnosis does not answer for all cases, suggesting that the involvement of one or more genes are still unknown. (AU)

Scientific publications

(5)

(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)

ALTMUELLER, FRANZISKA; LISSEWSKI, CHRISTINA; BERTOLA, DEBORA; FLEX, ELISABETTA; STARK, ZORNITZA; SPRANGER, STEPHANIE; BAYNAM, GARETH; BUSCARILLI, MICHELLE; DYACK, SARAH; GILLIS, JANE; et al. Genotype and phenotype spectrum of NRAS germline variants. European Journal of Human Genetics, v. 25, n. 7, p. 823-831, JUN 2017. (13/08028-1, 11/17299-3)

BERTOLA, DEBORA R.; CASTRO, MATHEUS A. A.; YAMAMOTO, GUILHERME L.; HONJO, RACHEL S.; CERONI, JOSE RICARDO; BUSCARILLI, MICHELE M.; FREITAS, AMANDA B.; MALAQUIAS, ALEXSANDRA C.; PEREIRA, ALEXANDRE C.; JORGE, ALEXANDER A. L.; et al. Phenotype-genotype analysis of 242 individuals with RASopathies: 18-year experience of a tertiary center in Brazil. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS, v. 184, n. 4, SI, p. 896-911, DEC 2020. (11/17299-3, 13/08028-1)

BERTOLA, DEBORA R.; YAMAMOTO, GUILHERME L.; ALMEIDA, TATIANA F.; BUSCARILLI, MICHELLE; JORGE, ALEXANDER A. L.; MALAQUIAS, ALEXSANDRA C.; KIM, CHONG A.; TAKAHASHI, VANESSA N. V.; PASSOS-BUENO, MARIA RITA; PEREIRA, ALEXANDRE C.. Further Evidence of the Importance of RIT1 in Noonan Syndrome. AMERICAN JOURNAL OF MEDICAL GENETICS PART A, v. 164, n. 11, p. 2952-2957, NOV 2014. (11/17299-3)

YAMAMOTO, GUILHERME LOPES; AGUENA, MEIRE; GOS, MONIKA; HUNG, CHRISTINA; PILCH, JACEK; FAHIMINIYA, SOMAYYEH; ABRAMOWICZ, ANNA; CRISTIAN, INGRID; BUSCARILLI, MICHELLE; NASLAVSKY, MICHEL SATYA; et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. JOURNAL OF MEDICAL GENETICS, v. 52, n. 6, p. 413-421, JUN 2015. (98/14254-2, 11/17299-3)

BERTOLA, DEBORA R.; CASTRO, MATHEUS A. A.; YAMAMOTO, GUILHERME L.; HONJO, RACHEL S.; CERONI, JOSE RICARDO; BUSCARILLI, MICHELE M.; FREITAS, AMANDA B.; MALAQUIAS, ALEXSANDRA C.; PEREIRA, ALEXANDRE C.; JORGE, ALEXANDER A. L.; et al. Phenotype-genotype analysis of 242 individuals with RASopathies: 18-year experience of a tertiary center in Brazil. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS, v. 184, n. 4, p. 16-pg., 2020-10-31. (13/08028-1, 11/17299-3)