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
87 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 87
- Mucopolysaccharidosis Type IVA: Evidence of Primary and Secondary Central Nervous System Involvement(2014) BORLOT, Felippe; ARANTES, Paula Ricci; QUAIO, Caio Robledo; FRANCO, Jose Francisco da Silva; LOURENCO, Charles Marques; GOMY, Israel; BERTOLA, Debora Romeo; KIM, Chong AeMucopolysaccharidosis type IVA is a rare lysosomal storage disease caused by a deficiency of N-acetylgalactosamine 6-sulfatase. Studies usually focus on skeletal abnormalities and their consequences. This study explores the neurological manifestations in a cohort of mucopolysaccharidosis type IVA patients, with a detailed focus on brain and spinal magnetic resonance imaging (MRI) findings. We performed a cross-sectional study involving nine patients with a biochemical confirmation of mucopolysaccharidosis type IVA. The protocol consists of a comprehensive clinical examination and brain and spinal cord MRI analysis for all subjects. The mean age was 16.4 years (+/- 5.7) and the mean onset of symptoms was 11.5 months (+/- 6.3). Overall, cognition was spared in all but one patient and motor weakness was a constant finding in all patients. Deep sensation impairment was found in six patients. The brain MRIs showed non-specific white matter changes in two patients. Other abnormalities such as clival hypoplasia, basilar invagination, and arachnoid cists appeared in seven of the nine patients. Eight patients presented spinal cord compression, and in three of them, two spinal levels were compromised. Odontoid hypoplasia and degenerative features in the neuroaxis were present in all patients. Our experience with mucopolysaccharidosis type IVA patients supports the evidence of central nervous system involvement. We emphasize the importance of regular clinical assessments with complete MRI studies, as an attempt to detect the early signs of spinal cord compression. This evaluation may be especially important before surgical interventions, as occult lesions may become symptomatic and promote postoperative unfavorable outcomes. (c) 2014 Wiley Periodicals, Inc.
- Multiple, diffuse schwannomas in a RASopathy phenotype patient with germline KRAS mutation: a causal relationship?(2012) BERTOLA, D. R.; PEREIRA, A. C.; BRASIL, A. S.; SUZUKI, L.; LEITE, C.; FALZONI, R.; TANNURI, U.; POPLAWSKI, A. B.; JANOWSKI, K. M.; KIM, C. A.; MESSIAEN, L. M.
- Stuve-Wiedemann Syndrome: Update on Clinical and Genetic Aspects(2016) BERTOLA, Debora Romeo; HONJO, Rachel S.; BARATELA, Wagner A. R.Stuve-Wiedemann syndrome is a rare autosomal recessive disorder characterized by bowed long bones, joint restrictions, dysautonomia, and respiratory and feeding difficulties, leading to death in the neonatal period and infancy in several occasions. Since the first cases in 1971, much has been learned about this condition, including its molecular basis - mutations in the leukemia inhibitory factor receptor gene (LIFR) -, natural history and management possibilities. This review aims to highlight the clinical aspects, radiological features, molecular findings, and management strategies in Stuve-Wiedemann syndrome. (C) 2016 S. Karger AG, Basel
- Unexpected role of SIX1 variants in craniosynostosis: expanding the phenotype of SIX1-related disorders(2022) CALPENA, Eduardo; WURMSER, Maud; MCGOWAN, Simon J.; ATIQUE, Rodrigo; BERTOLA, Debora R.; CUNNINGHAM, Michael L.; GUSTAFSON, Jonas A.; JOHNSON, David; V, Jenny E. Morton; PASSOS-BUENO, Maria Rita; TIMBERLAKE, Andrew T.; LIFTON, Richard P.; WALL, Steven A.; TWIGG, Stephen R. F.; MAIRE, Pascal; WILKIE, Andrew O. M.Background Pathogenic heterozygous SIX1 variants (predominantly missense) occur in branchio-otic syndrome (BOS), but an association with craniosynostosis has not been reported. Methods We investigated probands with craniosynostosis of unknown cause using whole exome/genome (n=628) or RNA (n=386) sequencing, and performed targeted resequencing of SIX1 in 615 additional patients. Expression of SIX1 protein in embryonic cranial sutures was examined in the Six1 ( nLacZ/+ ) reporter mouse. Results From 1629 unrelated cases with craniosynostosis we identified seven different SIX1 variants (three missense, including two de novo mutations, and four nonsense, one of which was also present in an affected twin). Compared with population data, enrichment of SIX1 loss-of-function variants was highly significant (p=0.00003). All individuals with craniosynostosis had sagittal suture fusion; additionally four had bilambdoid synostosis. Associated BOS features were often attenuated; some carrier relatives appeared non-penetrant. SIX1 is expressed in a layer basal to the calvaria, likely corresponding to the dura mater, and in the mid-sagittal mesenchyme. Conclusion Craniosynostosis is associated with heterozygous SIX1 variants, with possible enrichment of loss-of-function variants compared with classical BOS. We recommend screening of SIX1 in craniosynostosis, particularly when sagittal +/- lambdoid synostosis and/or any BOS phenotypes are present. These findings highlight the role of SIX1 in cranial suture homeostasis.
- 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.
- Deletion 5q12: Delineation of a Phenotype Including Mental Retardation and Ocular Defects(2011) JAILLARD, Sylvie; ANDRIEUX, Joris; PLESSIS, Ghislaine; KREPISCHI, Ana C. V.; LUCAS, Josette; DAVID, Veronique; BRUN, Marine Le; BERTOLA, Debora R.; DAVID, Albert; BELAUD-ROTUREAU, Marc-Antoine; MOSSER, Jean; LAZARO, Leila; TREGUIER, Catherine; ROSENBERG, Carla; ODENT, Sylvie; DUBOURG, ChristeleArray-CGH enables the detection of submicroscopic chromosomal deletions and duplications and leads to an accurate delineation of the imbalances, raising the possibility of correlating genotype to phenotype and mapping minimal critical regions associated with particular patterns of clinical features. We report here on four patients sharing common clinical features (psychomotor retardation, coarse facies and ocular anomalies), with proximal 5q deletions identified by oligo array-CGH. The deletions range from 5.75 to 17.26-Mb in size and occurred de novo. A common 2.63-Mb region between the deletions described here can be defined in 5q12.1 (59,390,122-62,021,754 bp bp from 5pter, hg18) and includes 12 genes. Among them, KIF2A, which encodes a kinesin superfamily protein, is a particularly interesting candidate for the phenotype, as it suppresses the growth of axonal collateral branches and is involved in normal brain development. Ocular defects, albeit unspecific, seem to be common in the 5q12.1 deletion. Identification of additional cases of deletions involving the 5q12.1 region will allow more accurate genotype-phenotype correlations. (C) 2011 Wiley-Liss, Inc.
- Six Additional Cases of SEDC Due to the Same and Recurrent R989C Mutation in the COL2A1 Gene-the Clinical and Radiological Follow-up(2015) SILVEIRA, Karina C.; BONADIA, Luciana C.; SUPERTI-FURGA, Andrea; BERTOLA, Debora R.; JORGE, Alexander A. L.; CAVALCANTI, Denise P.
- Nosology of genetic skeletal disorders: 2023 revision(2023) UNGER, Sheila; FERREIRA, Carlos R. R.; MORTIER, Geert R. R.; ALI, Houda; BERTOLA, Debora R.; CALDER, Alistair; COHN, Daniel H. H.; CORMIER-DAIRE, Valerie; GIRISHA, Katta M. M.; HALL, Christine; KRAKOW, Deborah; MAKITIE, Outi; MUNDLOS, Stefan; NISHIMURA, Gen; ROBERTSON, Stephen P. P.; SAVARIRAYAN, Ravi; SILLENCE, David; SIMON, Marleen; SUTTON, V. Reid; WARMAN, Matthew L. L.; SUPERTI-FURGA, AndreaThe ""Nosology of genetic skeletal disorders"" has undergone its 11th revision and now contains 771 entries associated with 552 genes reflecting advances in molecular delineation of new disorders thanks to advances in DNA sequencing technology. The most significant change as compared to previous versions is the adoption of the dyadic naming system, systematically associating a phenotypic entity with the gene it arises from. We consider this a significant step forward as dyadic naming is more informative and less prone to errors than the traditional use of list numberings and eponyms. Despite the adoption of dyadic naming, efforts have been made to maintain strong ties to the MIM catalog and its historical data. As with the previous versions, the list of disorders and genes in the Nosology may be useful in considering the differential diagnosis in the clinic, directing bioinformatic analysis of next-generation sequencing results, and providing a basis for novel advances in biology and medicine.
- 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.
- Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu-Cheney syndrome(2012) GRAY, Mary J.; KIM, Chong Ae; BERTOLA, Debora Romeo; ARANTES, Paula Ricci; STEWART, Helen; SIMPSON, Michael A.; IRVING, Melita D.; ROBERTSON, Stephen P.Serpentine fibula polycystic kidney syndrome (SFPKS; MIM600330) is a rare skeletal dysplasia that has polycystic kidneys and dysmorphic facies as additional defining phenotypic components. The nosological classification of this disease has been debated as the condition shares features common to other skeletal dysplasias such as Melnick Needles syndrome (MNS; MIM309350) and Hajdu-Cheney Syndrome (HCS; MIM102500). Here, two previously reported cases of SFPKS are presented with emphasis on their phenotypic evolution. With the recent discovery that HCS is caused by mutations in NOTCH2, DNA from the both cases was examined and both were found to have truncating mutations in exon 34 of NOTCH2. The phenotypic evolution of SFPKS and this molecular analysis strongly suggest that SFPKS is part of the phenotypic spectrum of HCS and should no longer be classified as a distinct disease entity. European Journal of Human Genetics (2012) 20, 122-124; doi:10.1038/ejhg.2011.125; published online 29 June 2011