MICHELLE BUSCARILLI DE MORAES
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- Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome(2015) YAMAMOTO, Guilherme Lopes; AGUENA, Meire; GOS, Monika; HUNG, Christina; PILCH, Jacek; FAHIMINIYA, Somayyeh; ABRAMOWICZ, Anna; CRISTIAN, Ingrid; BUSCARILLI, Michelle; NASLAVSKY, Michel Satya; MALAQUIAS, Alexsandra C.; ZATZ, Mayana; BODAMER, Olaf; MAJEWSKI, Jacek; JORGE, Alexander A. L.; PEREIRA, Alexandre C.; KIM, Chong Ae; PASSOS-BUENO, Maria Rita; BERTOLA, Debora RomeoBackground Noonan syndrome is an autosomal dominant, multisystemic disorder caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. Heterozygous, pathogenic variants in 11 known genes account for approximately 80% of cases. The identification of novel genes associated with Noonan syndrome has become increasingly challenging, since they might be responsible for very small fractions of the cases. Methods A cohort of 50 Brazilian probands negative for pathogenic variants in the known genes associated with Noonan syndrome was tested through whole-exome sequencing along with the relatives in the familial cases. Families from the USA and Poland with mutations in the newly identified genes were included subsequently. Results We identified rare, segregating or de novo missense variants in SOS2 and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands. SOS2 and LZTR1 variants were also found to segregate in one American and one Polish family. Notably, SOS2 variants were identified in patients with marked ectodermal involvement, similar to patients with SOS1 mutations. Conclusions We identified two novel genes, SOS2 and LZTR1, associated with Noonan syndrome, thereby expanding the molecular spectrum of RASopathies. Mutations in these genes are responsible for approximately 3% of all patients with Noonan syndrome. While SOS2 is a natural candidate, because of its homology with SOS1, the functional role of LZTR1 in the RAS/MAPK pathway is not known, and it could not have been identified without the large pedigrees. Additional functional studies are needed to elucidate the role of LZTR1 in RAS/MAPK signalling and in the pathogenesis of Noonan syndrome.
conferenceObject Maxillary myxomas associated with MEN1 syndrome(2014) LOURENCO, D. M.; TOLEDO, R. A.; SEKIYA, T.; MORAES, M. B.; SANTANA, L. S.; TOLEDO, S. P. A.- Noonan syndrome patients beyond the obvious phenotype: A potential unfavorable metabolic profile(2021) NORONHA, Renata M.; VILLARES, Sandra M. F.; TORRES, Natalia; QUEDAS, Elisangela P. S.; HOMMA, Thais Kataoka; ALBUQUERQUE, Edoarda V. A.; MORAES, Michelle B.; FUNARI, Mariana F. A.; BERTOLA, Debora R.; JORGE, Alexander A. L.; MALAQUIAS, Alexsandra C.Noonan syndrome (NS) and NS related disorders (NRD) are frequent monogenic diseases. Pathogenic variants in PTPN11 are observed in approximately 50% of these NS patients. Several pleiotropic phenotypes have previously been described in this condition. This study aimed at characterizing glucose and lipid profiles in patients with NS/NRD. We assessed fasting blood glucose, insulin, cholesterol (total and fractions), and triglyceride (TG) levels in 112 prepubertal children and 73 adults. Additionally, an oral glucose tolerance test (OGTT) was performed in 40 children and 54 adults. Data were analyzed between age groups according to the presence (+) or absence (-) of PTPN11 mutation. Prepubertal patients with NS/NRD were also compared with a control group. Despite the lean phenotype of children with NS/NRD, they presented an increased frequency of low HDL-cholesterol (63% in PTPN11+, 59% in PTPN11- and 16% in control, p < .001) and high TG levels (29% in PTPN11+, 18% in PTPN11- and 2.3% in control). PTPN11+ patients had a higher median HOMA-IR (1.0, ranged from 0.3 to 3.2) in comparison with PTPN11- (0.6; 0.2 to 4.4) and controls (0.6; 0.4 to 1.4, p = .027). Impaired glucose tolerance was observed in 19% (10:54) of lean adults with NS/NRD assessed by OGTT. Moreover, women with PTPN11 mutations had lower HDL-cholesterol levels than those without. Our results suggest that children and young adult patients with NS/NRD have an unfavorable metabolic profile characterized by low HDL, a tendency of elevated TGs, and glucose metabolism impairment despite a lean phenotype.
- Impact of Growth Hormone Therapy on Adult Height in Patients with PTPN11 Mutations Related to Noonan Syndrome(2019) MALAQUIAS, Alexsandra C.; NORONHA, Renata M.; SOUZA, Thaiana T. O.; HOMMA, Thais K.; FUNARI, Mariana F. A.; YAMAMOTO, Guilherme L.; SILVA, Fernanda Viana; MORAES, Michelle B.; HONJO, Rachel S.; KIM, Chong A.; NESI-FRANCA, Suzana; CARVALHO, Julienne A. R.; QUEDAS, Elisangela P. S.; BERTOLA, Debora R.; JORGE, Alexander A. L.Objectives: The aim of this study was to evaluate the response to recombinant human growth hormone (rhGH) treatment in patients with Noonan syndrome (NS). Materials and Methods: Forty-two patients (35 PTPN11+) were treated with rhGH, and 17 were followed-up until adult height. The outcomes were changes in growth velocity (GV) and height standard deviation scores (SDS) for normal (height-CDC SDS) and Noonan standards (height-NS SDS). Results: The pretreatment chronological age was 10.3 +/- 3.5 years. Height-CDC SDS and height-NS SDS were -3.1 +/- 0.7 and -0.5 +/- 0.6, respectively. PTPN11+ patients had a better growth response than PTPN11- patients. GV SDS increased from -1.2 +/- 1.8 to 3.1 +/- 2.8 after the first year of therapy in PTPN11+ patients, and from -1.9 +/- 2.6 to -0.1 +/- 2.6 in PTPN11- patients. The gain in height-CDC SDS during the first year was higher in PTPN11+ than PTPN11- (0.6 +/- 0.4 vs. 0.1 +/- 0.2, p = 0.008). Similarly, the gain was observed in height-NS SDS (0.6 +/- 0.3 vs. 0.2 +/- 0.2, respectively, p < 0.001). Among the patients that reached adult height (n = 17), AH-CDC SDS and AH-NS SDS were -2.1 +/- 0.7 and 0.7 +/- 0.8, respectively. The total increase in height SDS was 1.3 +/- 0.7 and 1.5 +/- 0.6 for normal and NS standards, respectively. Conclusions: This study supports the advantage of rhGH therapy on adult height in PTPN11+ patients. In comparison, PTPN11- patients showed a poor response to rhGH. However, this PTPN11- group was small, preventing an adequate comparison among different genotypes and no guarantee of response to therapy in genes besides PTPN11. (C) 2019 S. Karger AG, Basel
conferenceObject Targeted High-Throughput Sequencing of RAS/MAPK Pathway Genes for Diagnosis of Noonan Syndrome (NS) and Noonan-Related Disorders (NRD)(2014) MALAQUIAS, Alexsandra C.; MORAES, Michelle B.; LERARIO, Antonio M.; TRARBACH, Ericka Barbosa; MITNE-NETO, Miguel; PEREIRA, Alexandre; BERTOLA, Debora R.; TELES, Milena Gurgel; JORGE, Alexander Augusto Lima- The Recurrent PPP1CB Mutation p. Pro49Arg in an Additional Noonan- Like Syndrome Individual: Broadening the Clinical Phenotype(2017) BERTOLA, Debora; YAMAMOTO, Guilherme; BUSCARILLI, Michelle; JORGE, Alexander; PASSOS-BUENO, Maria Rita; KIM, ChongWe report on a 12-year-old Brazilian boy with the p.Pro49Arg mutation in PPP1CB, a novel gene associated with RASopathies. This is the fifth individual described, and the fourth presenting the same variant, suggesting a mutational hotspot. Phenotypically, he also showed the same hair pattern-sparse, thin, and with slow growing-, similar to the typical ectodermal finding observed in Noonan syndrome-like disorder with loose anagen hair. Additionally, he presented craniosynostosis, a rare clinical finding in RASopathies. This report gives further support that this novel RASopathy-PPP1CB-related Noonan syndrome with loose anagen hair-shares great similarity to Noonan syndrome-like disorder with loose anagen hair, and expands the phenotypic spectrum by adding the cranial vault abnormality. (C) 2017 Wiley Periodicals, Inc.
- Phenotype-genotype analysis of 242 individuals with RASopathies: 18-year experience of a tertiary center in Brazil(2020) 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.; PASSOS-BUENO, Maria Rita; KIM, Chong A.We report the clinical and molecular data of a large cohort comprising 242 individuals with RASopathies, from a single Tertiary Center in Brazil, the largest study from Latin America. Noonan syndrome represented 76% of the subjects, with heterozygous variants in nine different genes, mainly PTPN11, SOS1, RAF1, LZTR1, and RIT1, detected by Sanger and next-generation sequencing. The latter was applied to 126 individuals, with a positive yield of 63% in genes of the RAS/MAPK cascade. We present evidence that there are some allelic differences in PTPN11 across distinct populations. We highlight the clinical aspects that pose more medical concerns, such as the cardiac anomalies, bleeding diathesis and proliferative lesions. The genotype-phenotype analysis between the RASopathies showed statistically significant differences in some cardinal features, such as craniofacial and cardiac anomalies, the latter also statistically significant for different genes in Noonan syndrome. We present two individuals with a Noonan syndrome phenotype, one with an atypical, structural cardiac defect, harboring variants in genes mainly associated with isolated hypertrophic cardiomyopathy and discuss the role of these variants in their phenotype.
- Genotype and phenotype spectrum of NRAS germline variants(2017) ALTMUELLER, Franziska; LISSEWSKI, Christina; BERTOLA, Debora; FLEX, Elisabetta; STARK, Zornitza; SPRANGER, Stephanie; BAYNAM, Gareth; BUSCARILLI, Michelle; DYACK, Sarah; GILLIS, Jane; YNTEMA, Helger G.; PANTALEONI, Francesca; LOON, Rosa L. E. van; MACKAY, Sara; MINA, Kym; SCHANZE, Ina; TAN, Tiong Yang; WALSH, Maie; WHITE, Susan M.; NIEWISCH, Marena R.; GARCIA-MINAUR, Sixto; PLAZA, Diego; AHMADIAN, Mohammad Reza; CAVE, Helene; TARTAGLIA, Marco; ZENKER, MartinRASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly conserved RAS-MAPK signalling pathway that lead to dysregulation of cell signal transmission. Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants). A small number of RASopathy cases with disease-causing germline NRAS alterations have been reported. Affected individuals exhibited features fitting Noonan syndrome, and the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours. Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS. Importantly, four of them harbored missense changes affecting Gly12, which was previously described to occur exclusively in cancer. The phenotype in our cohort was variable but well within the RASopathy spectrum. Further, one of the patients (c. 35G > A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c. 34G > C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour. With this report, we expand the genotype and phenotype spectrum of RASopathy-associated germline NRAS variants and provide evidence that NRAS variants do not spare the cancer-associated mutation hotspots.
conferenceObject The Metabolic Profile Associated with RASopathies(2018) NORONHA, Renata; HOMMA, Thais; MORAES, Michelle; ALBUQUERQUE, Edoarda; FUNARI, Mariana; PEREIRA, Alexandre; VILLARES, Sandra; BERTOLA, Debora; JORGE, Alexander; MALAQUIAS, Alexsandra- Phenotypic spectrum of Costello syndrome individuals harboring the rare HRAS mutation p.Gly13Asp(2017) BERTOLA, Debora; BUSCARILLI, Michelle; STABLEY, Deborah L.; BAKER, Laura; DOYLE, Daniel; BARTHOLOMEW, Dennis W.; SOL-CHURCH, Katia; GRIPP, Karen W.Costello syndrome is part of the RASopathies, a group of neurocardiofaciocutaneous syndromes caused by deregulation of the RAS mitogen-activated protein kinase pathway. Heterozygous mutations in HRAS are responsible for Costello syndrome, with more than 80% of the patients harboring the specific p.Gly12Ser variant. These individuals show a homogeneous phenotype. The clinical characteristics of the Costello syndrome individuals harboring rarer HRAS mutations are less understood, due to the small number of reported cases. Here, we describe the phenotypic spectrum of five additional individuals with HRAS c.38G>A; p.Gly13Asp, including one with somatic mosaicism, and review five previously described cases. The facial and hair abnormalities of the HRAS p.Gly13Asp individuals differ from the typical pattern observed in those showing the common HRAS (p.Gly12Ser) mutation, with less coarse facial features and slow growing, sparse hair with abnormal texture, the latter resembling the pattern observed in Noonan syndrome-like disorder with loose anagen hair and individuals harboring another amino acid substitution in HRAS (p.Gly13Cys). Although some individuals with HRAS p.Gly13Asp developed papillomata and vascular proliferation lesions, no malignant tumors occurred, similar to what was reported for individuals harboring the HRAS p.Gly13Cys. The fact that no malignant tumors were described in these individuals does not allow definitive conclusions about the risk for cancer development. It remains to be determined if substitutions of amino acid 13 in HRAS (p.Gly13Asp and p.Gly13Cys) increase the risk of tumor development.