DEBORA ROMEO BERTOLA
Projetos de Pesquisa
Unidades Organizacionais
Instituto da Criança, Hospital das Clínicas, Faculdade de Medicina - Médico
BIO, IB
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina
BIO, IB
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina
17 resultados
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conferenceObject Novel mutations in fibronectin associated with metaphyseal fractures - Expanding the phenotype of patients with a subtype of spondylomethaphyseal dysplasia with ""corner fractures""(2018) ALM, Jessica J.; COSTANTINI, Alice; VALTA, Helena; BARATANG, Nissan Vida; YAP, Patrick; BERTOLA, Debora; YAMAMOTO, Guilherme; KIM, Chong A.; CHEN, Jiani; WIERENGA, Klaas J.; FANNING, Elizabeth A.; ESCOBAR, Luis; MCWALTER, Kirsty; MCLAUGHLIN, Heather; WILLAERT, Rebecca; BEGTRUP, Amber; REINHARDT, Dieter P.; MAKITIE, Outi; CAMPEAU, Philippe M.- 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.
- Chromosomal microarray analysis in the genetic evaluation of 279 patients with syndromic obesity(2018) D'ANGELO, Carla Sustek; VARELA, Monica Castro; CASTRO, Claudia Irene Emilio de; OTTO, Paulo Alberto; PEREZ, Ana Beatriz Alvarez; LOURENCO, Charles Marques; KIM, Chong Ae; BERTOLA, Debora Romeo; KOK, Fernando; GARCIA-ALONSO, Luis; KOIFFMANN, Celia PriszkulnikBackground: Syndromic obesity is an umbrella term used to describe cases where obesity occurs with additional phenotypes. It often arises as part of a distinct genetic syndrome with Prader-Willi syndrome being a classical example. These rare forms of obesity provide a unique source for identifying obesity-related genetic changes. Chromosomal microarray analysis (CMA) has allowed the characterization of new genetic forms of syndromic obesity, which are due to copy number variants (CNVs); however, CMA in large cohorts requires more study. The aim of this study was to characterize the CNVs detected by CMA in 279 patients with a syndromic obesity phenotype. Results: Pathogenic CNVs were detected in 61 patients (22%) and, among them, 35 had overlapping/recurrent CNVs. Genomic imbalance disorders known to cause syndromic obesity were found in 8.2% of cases, most commonly deletions of 1p36, 2q37 and 17p11.2 (5.4%), and we also detected deletions at 1p21.3, 2p25.3, 6q16, 9q34, 16p11.2 distal and proximal, as well as an unbalanced translocation resulting in duplication of the GNB3 gene responsible for a syndromic for of childhood obesity. Deletions of 9p terminal and 22q11.2 proximal/distal were found in 1% and 3% of cases, respectively. They thus emerge as being new putative obesity-susceptibility loci. We found additional CNVs in our study that overlapped with CNVs previously reported in cases of syndromic obesity, including a new case of 13q34 deletion (CHAMP1), bringing to 7 the number of patients in whom such defects have been described in association with obesity. Our findings implicate many genes previously associated with obesity (e.g. PTBP2, TMEM18, MYT1L, POU3F2, SIM1, SH2B1), and also identified other potentially relevant candidates including TAS1R3, ALOX5AP, and GAS6. Conclusion: Understanding the genetics of obesity has proven difficult, and considerable insight has been obtained from the study of genomic disorders with obesity associated as part of the phenotype. In our study, CNVs known to be causal for syndromic obesity were detected in 8.2% of patients, but we provide evidence for a genetic basis of obesity in as many as 14% of cases. Overall, our results underscore the genetic heterogeneity in syndromic forms of obesity, which imposes a substantial challenge for diagnosis.
- IHH Gene Mutations Causing Short Stature With Nonspecific Skeletal Abnormalities and Response to Growth Hormone Therapy(2018) VASQUES, Gabriela A.; FUNARI, Mariana F. A.; FERREIRA, Frederico M.; AZA-CARMONA, Miriam; SENTCHORDI-MONTANE, Lucia; BARRAZA-GARCIA, Jimena; LERARIO, Antonio M.; YAMAMOTO, Guilherme L.; NASLAVSKY, Michel S.; DUARTE, Yeda A. O.; BERTOLA, Debora R.; HEATH, Karen E.; JORGE, Alexander A. L.Context: Genetic evaluation has been recognized as an important tool to elucidate the causes of growth disorders. Objective: To investigate the cause of short stature and to determine the phenotype of patients with IHH mutations, including the response to recombinant human growth hormone (rhGH) therapy. Patients and Methods: We studied 17 families with autosomal-dominant short stature by using whole exome sequencing and screened IHH defects in 290 patients with growth disorders. Molecular analyses were performed to evaluate the potential impact of N-terminal IHH variants. Results: We identified 10 pathogenic or possibly pathogenic variants in IHH, an important regulator of endochondral ossification. Molecular analyses revealed a smaller potential energy of mutated IHH molecules. The allele frequency of rare, predicted to be deleterious IHH variants found in short-stature samples (1.6%) was higher than that observed in two control cohorts (0.017% and 0.08%; P < 0.001). Identified IHH variants segregate with short stature in a dominant inheritance pattern. Affected individuals typically manifest mild disproportional short stature with a frequent finding of shortening of the middle phalanx of the fifth finger. None of them have classic features of brachydactyly type A1, which was previously associated with IHH mutations. Five patients heterozygous for IHH variants had a good response to rhGH therapy. The mean change in height standard deviation score in 1 year was 0.6. Conclusion: Our study demonstrated the association of pathogenic variants in IHH with short stature with nonspecific skeletal abnormalities and established a frequent cause of growth disorder, with a preliminary good response to rhGH.
- KIF11 microdeletion is associated with microcephaly, chorioretinopathy and intellectual disability(2018) MALVEZZI, Joao V. M.; MAGALHAES, Ingrid H.; COSTA, Silvia S.; OTTO, Paulo A.; ROSENBERG, Carla; BERTOLA, Debora R.; FERNANDES, Walter L. M.; VIANNA-MORGANTE, Angela M.; KREPISCHI, Ana C. V.KIF11 mutations are known to cause autosomal dominant microcephaly-lymphedema-chorioretinopathy dysplasia syndrome, associated or not with intellectual disability. We report a father and two children presenting microcephaly, chorioretinopathy and mild intellectual disability associated with a 209-kb microdeletion at 10q23.33. This microdeletion encompasses the entire KIF11 gene. In addition to point mutations, KIF11 haploinsufficiency due to a deletion is causally associated with autosomal dominant microcephaly, chorioretinopathy and mild intellectual disability.
- Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848(2018) KOCZKOWSKA, Magdalena; CHEN, Yunjia; CALLENS, Tom; GOMES, Alicia; SHARP, Angela; JOHNSON, Sherrell; HSIAO, Meng-Chang; CHEN, Zhenbin; BALASUBRAMANIAN, Meena; BARNETT, Christopher P.; BECKER, Troy A.; BEN-SHACHAR, Shay; BERTOLA, Debora R.; BLAKELEY, Jaishri O.; BURKITT-WRIGHT, Emma M. M.; CALLAWAY, Alison; CRENSHAW, Melissa; CUNHA, Karin S.; CUNNINGHAM, Mitch; D'AGOSTINO, Maria D.; DAHAN, Karin; LUCA, Alessandro De; DESTREE, Anne; DHAMIJA, Radhika; EOLI, Marica; EVANS, D. Gareth R.; GALVIN-PARTON, Patricia; GEORGE-ABRAHAM, Jaya K.; GRIPP, Karen W.; GUEVARA-CAMPOS, Jose; HANCHARD, Neil A.; HERNANDEZ-CHICO, Concepcion; IMMKEN, LaDonna; JANSSENS, Sandra; JONES, Kristi J.; KEENA, Beth A.; KOCHHAR, Aaina; LIEBELT, Jan; MARTIR-NEGRON, Arelis; MAHONEY, Maurice J.; MAYSTADT, Isabelle; MCDOUGALL, Carey; MCENTAGART, Meriel; MENDELSOHN, Nancy; MILLER, David T.; MORTIER, Geert; MORTON, Jenny; PAPPAS, John; PLOTKIN, Scott R.; POND, Dinel; ROSENBAUM, Kenneth; RUBIN, Karol; RUSSELL, Laura; RUTLEDGE, Lane S.; SALETTI, Veronica; SCHONBERG, Rhonda; SCHREIBER, Allison; SEIDEL, Meredith; SIQVELAND, Elizabeth; STOCKTON, David W.; TREVISSON, Eva; ULLRICH, Nicole J.; UPADHYAYA, Meena; MINKELEN, Rick van; VERHELST, Helene; WALLACE, Margaret R.; YAP, Yoon-Sim; ZACKAI, Elaine; ZONANA, Jonathan; ZURCHER, Vickie; CLAES, Kathleen; MARTIN, Yolanda; KORF, Bruce R.; LEGIUS, Eric; MESSIAEN, Ludwine M.Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1: 2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p. Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect similar to 0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals.
conferenceObject Genetic Evaluation of Syndromic Short Stature Children Born Small for Gestational Age(2018) HOMMA, T.; FREIRE, B.; HONJO, R.; DAUBER, A.; FUNARI, M.; LERARIO, A.; ARNHOLD, I.; CANTON, A.; SUGAYAMA, S.; BERTOLA, D.; KIM, C.; MALAQUIAS, A.; JORGE, A.conferenceObject Genetic Investigation of Children with Syndromic Prenatal Onset Short Stature(2018) HOMMA, Thais; FREIRE, Bruna; RONJO, Rachel; DAUBER, Andrew; FUNARI, Mariana; LERARIO, Antonio; ARNHOLD, Ivo; CANTON, Ana; SUGAYAMA, Sofia; BERTOLA, Debora; KIM, Chong; MALAQUIAS, Alexsandra; JORGE, AlexanderconferenceObject 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- Richieri-Costa-Pereira syndrome: Expanding its phenotypic and genotypic spectrum(2018) BERTOLA, D. R.; HSIA, G.; ALVIZI, L.; GARDHAM, A.; WAKELING, E. L.; YAMAMOTO, G. L.; HONJO, R. S.; OLIVEIRA, L. A. N.; FRANCESCO, R. C. Di; PEREZ, B. A.; KIM, C. A.; PASSOS-BUENO, M. R.Richieri-Costa-Pereira syndrome is a rare autosomal recessive acrofacial dysostosis that has been mainly described in Brazilian individuals. The cardinal features include Robin sequence, cleft mandible, laryngeal anomalies and limb defects. A biallelic expansion of a complex repeated motif in the 5 untranslated region of EIF4A3 has been shown to cause this syndrome, commonly with 15 or 16 repeats. The only patient with mild clinical findings harbored a 14-repeat expansion in 1 allele and a point mutation in the other allele. This proband is described here in more details, as well as is his affected sister, and 5 new individuals with Richieri-Costa-Pereira syndrome, including a patient from England, of African ancestry. This study has expanded the phenotype in this syndrome by the observation of microcephaly, better characterization of skeletal abnormalities, less severe phenotype with only mild facial dysmorphisms and limb anomalies, as well as the absence of cleft mandible, which is a hallmark of the syndrome. Although the most frequent mutation in this study was the recurrent 16-repeat expansion in EIF4A3, there was an overrepresentation of the 14-repeat expansion, with mild phenotypic expression, thus suggesting that the number of these motifs could play a role in phenotypic delineation.