GUILHERME LOPES YAMAMOTO
Projetos de Pesquisa
Unidades Organizacionais
Instituto da Criança, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina
6 resultados
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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.
- Intragenic Deletion in the LIFR Gene in a Long-Term Survivor with Stuve-Wiedemann Syndrome(2015) MARQUES, Julia Hatagami; YAMAMOTO, Guilherme Lopes; TESTAI, Larissa de Cassia; PEREIRA, Alexandre da Costa; KIM, Chong Ae; PASSOS-BUENO, Maria R.; BERTOLA, Debora RomeoStuve-Wiedemann syndrome (SWS, OMIM 601559) is a rare autosomal recessive bent-bone dysplasia, caused by loss-offunction mutations in the leukemia inhibitory factor receptor (LIFR) gene, which usually leads to early death. Only few patients with long-term survival have been described in the literature. We report on a 5-year-old boy from a consanguineous marriage with molecular analysis for the LIFR gene. Sanger and next-generation sequencing (NGS) of LIFR were performed. Copy number variation analysis with NGS showed a novel mutation as the cause for the syndrome: an intragenic homozygous deletion in LIFR, involving exons 1520. Bridging PCR was carried out to confirm the intragenic deletion. This is the first description of a large deletion in LIFR, broadening the spectrum of mutations in SWS. Besides the reported allelic heterogeneity, further studies such as exome sequencing are required to identify a novel gene in order to confirm the locus heterogeneity in SWS. (C) 2015 S. Karger AG, Basel
- Nutritional Aspects of Noonan Syndrome and Noonan-Related Disorders(2016) SILVA, Fernanda Marchetto da; JORGE, Alexander Augusto; MALAQUIAS, Alexandra; PEREIRA, Alexandre da Costa; YAMAMOTO, Guilherme Lopes; KIM, Chong Ae; BERTOLA, DeboraRasopathies are a group of rare disorders characterized by neurocardiofaciocutaneous involvement, and caused by mutations in several genes of the RAS/MAPK pathway. In the present study, we characterized growth parameters, body composition, and nutritional aspects of children and adults (n = 62) affected by these disorders, mainly Noonan syndrome, using an indirect method-anthropometry-and a 24-hr recall questionnaire. The growth parameters in our cohort showed short stature, especially in individuals with RAF1 and SHOC2 mutations, lower obesity rates compared to the control population, and BMI scores highest in individuals with BRAF mutations and lowest in individuals with SHOC2. Body composition showed a compromise in the upper arm muscle circumference, with a statistically significant difference in the z-score of triceps skin-fold (P = 0.0204) and upper arm fat area (P = 0.0388) between BRAF and SHOC2 groups and in the z-score of triceps skinfold between RAF1 and SHOC2 (P = 0.0218). The pattern of macro-nutrient consumption was similar to the control population. Our study is the first to address body composition in RASopathy individuals and the data indicate a compromise not only in adipose tissue, but also in muscle mass. Studies using different techniques, such as dual-energy X-ray absorptiometry or imaging studies, which give a more precise delineation of fat and non-fat mass, are required to confirm our results, ultimately causing an impact on management strategies. (C) 2016 Wiley Periodicals, Inc.
- Admixture/fine-mapping in Brazilians reveals a West African associated potential regulatory variant (rs114066381) with a strong female-specific effect on body mass and fat mass indexes(2021) SCLIAR, Marilia O.; SANT'ANNA, Hanaisa P.; SANTOLALLA, Meddly L.; LEAL, Thiago P.; ARAUJO, Nathalia M.; ALVIM, Isabela; BORDA, Victor; MAGALHAES, Wagner C. S.; GOUVEIA, Mateus H.; LYRA, Ricardo; MACHADO, Moara; MICHELIN, Lucas; RODRIGUES, Maira R.; ARAUJO, Gilderlanio S.; KEHDY, Fernanda S. G.; ZOLINI, Camila; PEIXOTO, Sergio V.; LUIZON, Marcelo R.; LOBO, Francisco; NASLAVSKY, Michel S.; YAMAMOTO, Guilherme L.; DUARTE, Yeda A. O.; HANSEN, Matthew E. B.; NORRIS, Shane A.; GILMAN, Robert H.; GUIO, Heinner; HSING, Ann W.; MBULAITEYE, Sam M.; MENSAH, James; DUTIL, Julie; YEAGER, Meredith; YEBOAH, Edward; TISHKOFF, Sarah A.; CHOUDHURY, Ananyo; RAMSAY, Michele; PASSOS-BUENO, Maria Rita; ZATZ, Mayana; O'CONNOR, Timothy D.; PEREIRA, Alexandre C.; BARRETO, Mauricio L.; LIMA-COSTA, Maria Fernanda; HORTA, Bernardo L.; TARAZONA-SANTOS, EduardoBackground/objectives Admixed populations are a resource to study the global genetic architecture of complex phenotypes, which is critical, considering that non-European populations are severely underrepresented in genomic studies. Here, we study the genetic architecture of BMI in children, young adults, and elderly individuals from the admixed population of Brazil. Subjects/methods Leveraging admixture in Brazilians, whose chromosomes are mosaics of fragments of Native American, European, and African origins, we used genome-wide data to perform admixture mapping/fine-mapping of body mass index (BMI) in three Brazilian population-based cohorts from Northeast (Salvador), Southeast (Bambui), and South (Pelotas). Results We found significant associations with African-associated alleles in children from Salvador (PALD1 and ZMIZ1 genes), and in young adults from Pelotas (NOD2 and MTUS2 genes). More importantly, in Pelotas, rs114066381, mapped in a potential regulatory region, is significantly associated only in females (p = 2.76e-06). This variant is rare in Europeans but with frequencies of similar to 3% in West Africa and has a strong female-specific effect (95% CI: 2.32-5.65 kg/m(2) per each A allele). We confirmed this sex-specific association and replicated its strong effect for an adjusted fat mass index in the same Pelotas cohort, and for BMI in another Brazilian cohort from Sao Paulo (Southeast Brazil). A meta-analysis confirmed the significant association. Remarkably, we observed that while the frequency of rs114066381-A allele ranges from 0.8 to 2.1% in the studied populations, it attains similar to 9% among women with morbid obesity from Pelotas, Sao Paulo, and Bambui. The effect size of rs114066381 is at least five times higher than the FTO SNPs rs9939609 and rs1558902, already emblematic for their high effects. Conclusions We identified six candidate SNPs associated with BMI. rs114066381 stands out for its high effect that was replicated and its high frequency in women with morbid obesity. We demonstrate how admixed populations are a source of new relevant phenotype-associated genetic variants.
- 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.
- Further Evidence of the Importance of RIT1 in Noonan Syndrome(2014) 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.Noonan syndrome (NS) is an autosomal dominant disorder consisting of short stature, short and/or webbed neck, distinctive facial features, cardiac abnormalities, cryptorchidism, and coagulation defects. NS exhibits genetic heterogeneity, associated with mutated genes that participate in RAS-mitogen-activated protein kinase signal transduction. Recently, a new gene (RIT1) was discovered as the causative gene in 17 of 180 Japanese individuals who were negative for the previously known genes for NS and were studied using exome sequencing (four patients), followed by Sanger sequencing (13 patients). The present study used the same technique in 70 Brazilian patients with NS and identified six with RIT1 missense mutations. Thus, we confirm that RIT1 is responsible for approximately 10% of the patients negative for mutations in the previously known genes. The phenotype includes a high frequency of high birth weight, relative macrocephaly, left ventricular hypertrophy, and ectodermal findings, such as curly hair, hyperpigmentation, and wrinkled palms and soles. Short stature and pectus deformity were less frequent. The majority of patients with a RIT1 mutation did not show apparent intellectual disability. Because of the relatively high frequency of mutations in RIT1 among patients with NS and its occurrence in different populations, we suggest that it should be added to the list of genes included in panels for the molecular diagnosis of NS through targeted next-generation sequencing. (c) 2014 Wiley Periodicals, Inc.