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
Resultados de Busca
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- 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.
- 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.
- Atypical, severe hypertrophic cardiomyopathy in a newborn presenting Noonan syndrome harboring a recurrent heterozygous MRAS variant(2021) PIRES, Lucas Vieira Lacerda; BORDIM, Renata de Almeida; MACIEL, Maria Beatriz Rabelo; TANAKA, Ana Cristina Sayuri; YAMAMOTO, Guilherme Lopes; HONJO, Rachel Sayuri; KIM, Chong Ae; BERTOLA, Debora RomeoNoonan syndrome (NS) is a Mendelian phenotype, member of a group of disorders sharing neurocardiofaciocutaneous involvement, known as RASopathies, caused by germline variants in genes coding for components of the RAS/MAPK signaling pathway. Recently, a novel gene of the RAS family (MRAS) was reported to be associated with NS in five children, all of them presenting, among the cardinal features of NS, the same cardiac finding, hypertrophic cardiomyopathy (HCM). We report on a 2-month-old infant boy also presenting this cardiac anomaly that evolved to a fatal outcome after a surgical myectomy. In addition, a thick walled left ventricle apical aneurysm, rarely described in NS, was also disclosed. Next-generation sequencing revealed a missense, previously reported variant in MRAS (p.Thr68Ile). This report reinforces the high frequency of HCM among individuals harboring MRAS variants, contrasting to the 20% overall prevalence of this cardiac anomaly in NS. Thus, these preliminary data suggest that variants in MRAS per se are high risk factors for the development of an early, severe HCM, mostly of them with left ventricle outflow tract obstruction, with poor prognosis. Because of the severity of the cardiac involvement, other clinical findings could not be addressed in detail. Therefore, long-term follow-up of these individuals and further descriptions are required to fully understand the complete phenotypic spectrum of NS associated with MRAS germline variants, including if these individuals present an increased risk for cancer.
- Twenty-year follow-up of the facial phenotype of Brazilian patients with Sotos syndrome(2021) CASTRO, Matheus Augusto Araujo; SANTOS, Juliana Heather Vedovato dos; HONJO, Rachel Sayuri; YAMAMOTO, Guilherme Lopes; BERTOLA, Debora Romeo; HURST, Anna C.; CHORICH, Lynn P.; LAYMAN, Lawrence C.; KIM, Chong Ae; KIM, Hyung-GooSotos syndrome is characterized by overgrowth starting before birth through childhood with intellectual disability and craniofacial anomalies. The majority of patients are large for gestational age with developmental delay or intellectual disability. The majority of cases are caused by pathogenic variants in NSD1. The most consistent physical features in this disorder are facial dysmorphisms including prominent forehead, downslanted palpebral fissures, prognathism with a pointed chin, and a long and narrow face. We present a follow-up to a cohort of 11 individuals found to harbor heterozygous, pathogenic, or likely pathogenic variants in NSD1. We analyzed the facial dysmorphisms and the condition using retrospective over 20 years. Among these patients, followed in our medical genetics outpatient clinic for variable periods of time, all had a phenotype compatible with the characteristic Sotos syndrome facial features, which evolved with time and became superimposed with natural aging modifications. We present here a long-term follow-up of facial features of Brazilian patients with molecularly confirmed Sotos syndrome. In this largest Brazilian cohort of molecularly confirmed patients with Sotos syndrome to date, we provide a careful description of the facial phenotype, which becomes less pronounced with aging and possibly more difficult to recognize in adults. These results may have broad clinical implications for diagnosis and add to the global clinical delineation of this condition.
- Biased pathogenic assertions of loss of function variants challenge molecular diagnosis of admixed individuals(2021) NASLAVSKY, Michel S.; SCLIAR, Marilia O.; NUNES, Kelly; WANG, Jaqueline Y. T.; YAMAMOTO, Guilherme L.; GUIO, Heinner; TARAZONA-SANTOS, Eduardo; DUARTE, Yeda A. O.; PASSOS-BUENO, Maria Rita; MEYER, Diogo; ZATZ, MayanaDiagnosis of individuals affected by monogenic disorders was significantly improved by next-generation sequencing targeting clinically relevant genes. Whole exomes yield a large number of variants that require several filtering steps, prioritization, and pathogenicity classification. Among the criteria recommended by ACMG, those that rely on population databases critically affect analyses of individuals with underrepresented ancestries. Population-specific allelic frequencies need consideration when characterizing potential deleteriousness of variants. An orthogonal input for classification is annotation of variants previously classified as pathogenic as a criterion that provide supporting evidence widely sourced at ClinVar. We used a whole-genome dataset from a census-based cohort of 1,171 elderly individuals from Sao Paulo, Brazil, highly admixed, and unaffected by severe monogenic disorders, to investigate if pathogenic assertions in ClinVar are enriched with higher proportions of European ancestry, indicating bias. Potential loss of function (pLOF) variants were filtered from 4,250 genes associated with Mendelian disorders and annotated with ClinVar assertions. Over 1,800 single nucleotide pLOF variants were included, 381 had non-benign assertions. Among carriers (N = 463), average European ancestry was significantly higher than noncarriers (N = 708; p = .011). pLOFs in genomic contexts of non-European local ancestries were nearly three times less likely to have any ClinVar entry (OR = 0.353; p <.0001). Independent pathogenicity assertions are useful for variant classification in molecular diagnosis. However, European overrepresentation of assertions can promote distortions when classifying variants in non-European individuals, even in admixed samples with a relatively high proportion of European ancestry. The investigation and deposit of clinically relevant findings of diverse populations is fundamental improve this scenario.
- Germline variants of Brazilian women with breast cancer and detection of a novel pathogenic ATM deletion in early-onset breast cancer(2021) BANDEIRA, Gabriel; ROCHA, Katia; LAZAR, Monize; EZQUINA, Suzana; YAMAMOTO, Guilherme; VARELA, Monica; TAKAHASHI, Vanessa; AGUENA, Meire; GOLLOP, Thomaz; ZATZ, Mayana; PASSOS-BUENO, Maria Rita; KREPISCHI, Ana; OKAMOTO, Oswaldo KeithBackground It is estimated that 5-10% of breast cancer cases are hereditary. The identification of pathogenic germline variants allows individualized preventive health care, improvement of clinical management and genetic counseling. Studies in ethnically admixed Latin American populations have identified regions with increased frequency of deleterious variants in breast cancer predisposing genes. In this context, the Brazilian population exhibits great genetic heterogeneity, and is not well represented in international databases, which makes it difficult to interpret the clinical relevance of germline variants. Methods We evaluated the frequency of pathogenic/likely pathogenic (P/LP) germline variants in up to 37 breast cancer predisposing genes, in a cohort of 105 breast and/or ovarian cancer Brazilian women referred to two research centers between 2014 and 2019. Results A total of 22 patients (21%) were found to carry P/LP variants, and 16 VUS were detected in 15 patients (14.3%). Additionally, a novel pathogenicATMintragenic deletion was identified in an early-onset breast cancer. We also detected aBRCA1pathogenic variant (c.5074+2T>C) in higher frequency (10x) than in other studies with similar cohorts. Conclusions Our findings contribute to the characterization of the genetic background of breast cancer predisposition in the Brazilian population as a useful resource to discriminate between deleterious variants and VUS, thus enabling improvement in the preventive health care and clinical management of carriers.