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
18 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 18
- 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 A NEW INSIGHT ON CFTR ALLELE FREQUENCY IN BRAZIL THROUGH NEXT GENERATION SEQUENCING(2016) NUNES, Luisa Mesquita; RIBEIRO, Roberto; SABINO, Ester; NIEWIANDONSKI, Vivian D. T.; YAMAMOTO, Guilherme Lopes; SILVA FILHO, Luiz Vicente Ribeiro F. da- Natural history of 39 patients with Achondroplasia(2018) CERONI, Jose Ricardo Magliocco; SOARES, Diogo Cordeiro de Queiroz; TESTAI, Larissa de Cassia; KAWAHIRA, Rachel Sayuri Honjo; YAMAMOTO, Guilherme Lopes; SUGAYAMA, Sofia Mizuho Miura; OLIVEIRA, Luiz Antonio Nunes de; BERTOLA, Debora Romeo; KIM, Chong AeOBJECTIVES: To characterize the natural history of 39 achondroplastic patients diagnosed by clinical, radiological and molecular assessments. METHODS: Observational and retrospective study of 39 patients who were attended at a public tertiary level hospital between 1995 and 2016. RESULTS: Diagnosis was made prenatally in 11 patients, at birth in 9 patients and within the first year of life in 13 patients. The most prevalent clinical findings were short stature, high forehead, trident hands, genu varum and macrocephaly. The most prevalent radiographic findings were rhizomelic shortening of the long bones and narrowing of the interpediculate distance of the caudal spine. There was motor developmental delay in 18 patients and speech delay in 16 patients. The most common clinical intercurrences were middle ear dysfunction, sleep apnea, limb pain and obesity from 2 to 9 years of age. One patient was large for the gestational age but did not develop obesity. One patient developed hydrocephalus at 10 years old. The current age of the patients varies from 15 months to 36 years. The molecular study performed by Sanger sequencing of the common heterozygous mutation 1138G >A in FGFR3 was positive in all patients. Four cases were inherited, and 35 were sporadic (paternal age from 19 to 66 years). CONCLUSIONS: The diagnoses were made early based on clinical and radiographic findings. All cases were confirmed molecularly. Despite presenting a benign course, it is necessary to establish a systematic protocol for the surveillance of these patients due to the common clinical intercurrences.
conferenceObject A MILD PANCREATIC SUFFICIENT CF-PHENOTYPE ON TWO UNRELATED PATIENTS WITH THE I148N;5T MUTATION(2016) NUNES, Luisa Mesquita; NIEWIANDONSKI, Vivian D. T.; GABURO, Nelson; YAMAMOTO, Guilherme Lopes; BERTOLA, Debora Romeu; SILVA FILHO, Luiz Vicente Ribeiro F. da- 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
- A dopamine receptor D2 genetic polymorphism associated with transition to mental disorders in a cohort of individuals with at-risk mental state for psychosis(2023) MARQUES, Julia Hatagami; TALIB, Leda Leme; HORTENCIO, Lucas; ANDRADE, Julio Cesar; ALVES, Tania Maria; SERPA, Mauricio Henriques; YAMAMOTO, Guilherme Lopes; BILT, Martinus Theodorus van de; ROSSLER, Wulf; GATTAZ, Wagner Farid; LOCH, Alexandre AndradeObjectives: To test the association of 45 single nucleotide polymorphisms (SNPs) with transition to psychiatric disorders in a cohort of individuals at ultrahigh risk (UHR) mental state for psychosis.Methods: Through general population screening, 88 non-help-seeking UHR subjects and 130 healthy control individuals were genotyped for 45 SNPs related to psychosis. They were followed for a mean of 2.5 years, and conversion to psychotic and to general psychiatric disorders was assessed. Genotype frequencies between controls, converters, and non-converters were analyzed.Results: There were no differences in sociodemographics between controls and UHR. Also, UHR converters and non-converters had no differences in their baseline symptoms scores. The dopamine receptor D2 gene (DRD2) SNP rs6277 was significantly more common among UHR who transitioned to psychosis (p o 0.001) and to UHR who transitioned to any psychiatric disorders (p = 0.001) when compared to UHR who did not transition. The rs6277 T allele was related to psychiatric morbidity in a dose-response fashion, being significantly more frequent in UHR converters than UHR non-converters and control subjects (p = 0.003).Conclusion: Our findings suggest that rs6277 could potentially constitute a genetic marker of transition to psychiatric disorders in subjects with at-risk mental states, warranting further investigation in larger samples.
- Exomic variants of an elderly cohort of Brazilians in the ABraOM database(2017) NASLAVSKY, Michel Satya; YAMAMOTO, Guilherme Lopes; ALMEIDA, Tatiana Ferreira de; EZQUINA, Suzana A. M.; SUNAGA, Daniele Yumi; PHO, Nam; BOZOKLIAN, Daniel; SANDBERG, Tatiana Orli Milkewitz; BRITO, Luciano Abreu; LAZAR, Monize; BERNARDO, Danilo Vicensotto; AMARO JR., Edson; DUARTE, Yeda A. O.; LEBRAO, Maria Lucia; PASSOS-BUENO, Maria Rita; ZATZ, MayanaBrazilians are highly admixed with ancestry from Europe, Africa, America, and Asia and yet still underrepresented in genomic databanks. We hereby present a collection of exomic variants from 609 elderly Brazilians in a census-based cohort (SABE609) with comprehensive phenotyping. Variants were deposited in ABraOM (Online Archive of Brazilian Mutations), a Web-based public database. Population representative phenotype and genotype repositories are essential for variant interpretation through allele frequency filtering; since elderly individuals are less likely to harbor pathogenic mutations for early- and adult-onset diseases, such variant databases are of great interest. Among the over 2.3 million variants from the present cohort, 1,282,008 were high-confidence calls. Importantly, 207,621 variants were absent from major public databases. We found 9,791 potential loss-of-function variants with about 300 mutations per individual. Pathogenic variants on clinically relevant genes (ACMG) were observed in 1.15% of the individuals and were correlated with clinical phenotype. We conducted incidence estimation for prevalent recessive disorders based upon heterozygous frequency and concluded that it relies on appropriate pathogenicity assertion. These observations illustrate the relevance of collecting demographic data from diverse, poorly characterized populations. Census-based datasets of aged individuals with comprehensive phenotyping are an invaluable resource toward the improved understanding of variant pathogenicity.
- Congenital limb deficiency: Genetic investigation of 44 individuals presenting mainly longitudinal defects in isolated or syndromic forms(2021) ROCHA, Leticia Alves da; PIRES, Lucas Vieira Lacerda; YAMAMOTO, Guilherme Lopes; CERONI, Jose Ricardo Magliocco; HONJO, Rachel Sayuri; BISNETO, Edgard de Novaes Franca; OLIVEIRA, Luiz Antonio Nunes; ROSENBERG, Carla; KREPISCHI, Ana Cristina Victorino; PASSOS-BUENO, Maria Rita; KIM, Chong Ae; BERTOLA, Debora RomeoCongenital limb deficiency (CLD), one of the most common congenital anomalies, is characterized by hypoplasia/aplasia of one or more limb bones and can be isolated or syndromic. The etiology in CLD is heterogeneous, including environmental and genetic factors. A fraction remains with no etiological factor identified. We report the study of 44 Brazilian individuals presenting isolated or syndromic CLD, mainly with longitudinal defects. Genetic investigation included particularly next-generation sequencing (NGS) and/or chromosomal microarray. The overall diagnostic yield was 45.7%, ranging from 60.9% in the syndromic to 16.7% in the non-syndromic group. In TAR syndrome, a common variant in 3 ' UTR of RBM8A, in trans with 1q21.1 microdeletion, was detected, corroborating the importance of this recently reported variant in individuals of African ancestry. NGS established a diagnosis in three individuals in syndromes recently reported or still under delineation (an acrofacial dysostosis, Coats plus and Verheij syndromes), suggesting a broader phenotypic spectrum in these disorders. Although a low rate of molecular detection in non-syndromic forms was observed, it is still possible that variants in non-coding regions and small CNVs, not detected by the techniques applied in this study, could play a role in the etiology of CLD.
- 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.
- Manifesting carriers of X-linked myotubular myopathy Genetic modifiers modulating the phenotype(2020) SOUZA, Lucas Santos; ALMEIDA, Camila Freitas; YAMAMOTO, Guilherme Lopes; PAVANELLO, Rita de Cassia Mingroni; GURGEL-GIANNETTI, Juliana; COSTA, Silvia Souza da; ANEQUINI, Isabela Pessa; CARMO, Silvana Amanda do; WANG, Jaqueline Yu Ting; SCLIAR, Marilia de Oliveira; CASTELLI, Erick C.; OTTO, Paulo Alberto; ZANOTELI, Edmar; VAINZOF, MarizObjective To analyze the modulation of the phenotype in manifesting carriers of recessive X-linked myotubular myopathy (XLMTM), searching for possible genetic modifiers. Methods Twelve Brazilian families with XLMTM were molecularly and clinically evaluated. In 2 families, 4 of 6 and 2 of 5 manifesting female carriers were identified. These females were studied for X chromosome inactivation. In addition, whole-exome sequencing was performed, looking for possible modifier variants. We also determined the penetrance rate among carriers of the mutations responsible for the condition. Results Mutations in the MTM1 gene were identified in all index patients from the 12 families, being 4 of them novel. In the heterozygotes, X chromosome inactivation was random in 3 of 4 informative manifesting carriers. The disease penetrance rate was estimated to be 30%, compatible with incomplete penetrance. Exome comparative analyses identified variants within a segment of 4.2 Mb on chromosome 19, containing the killer cell immunoglobulin-like receptor cluster of genes that were present in all nonmanifesting carriers and absent in all manifesting carriers. We hypothesized that these killer cell immunoglobulin-like receptor variants may modulate the phenotype, acting as a protective factor in the nonmanifesting carriers. Conclusions Affected XLMTM female carriers have been described with a surprisingly high frequency for a recessive X-linked disease, raising the question about the pattern of inheritance or the role of modifier factors acting on the disease phenotype. We demonstrated the possible existence of genetic mechanisms and variants accountable for the clinical manifestation in these women, which can become future targets for therapies.