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
31 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 31
- Congenital Adrenal Hyperplasia, Ovarian Failure and Ehlers-Danlos Syndrome due to a 6p Deletion(2014) MOYSES-OLIVEIRA, Mariana; MANCINI, Tatiane I.; TAKENO, Sylvia S.; RODRIGUES, Andressa D. S.; BACHEGA, Tania A. S. S.; BERTOLA, Debora; MELARAGNO, Maria IsabelCryptic deletions in balanced de novo translocations represent a frequent cause of abnormal phenotypes, including Mendelian diseases. In this study, we describe a patient with multiple congenital abnormalities, such as late-onset congenital adrenal hyperplasia (CAH), primary ovarian failure and Ehlers-Danlos syndrome (EDS), who carries a de novo t(6;14)(p21;q32) translocation. Genomic array analysis identified a cryptic 1.1-Mb heterozygous deletion, adjacent to the breakpoint on chromosome 6, extending from 6p21.33 to 6p21.32 and affecting 85 genes, including CYP21A2,TNXB and MSH5. Multiplex ligation-dependent probe amplification analysis of the 6p21.3 region was performed in the patient and her family and revealed a 30-kb deletion in the patient's normal chromosome 6, inherited from her mother, resulting in homozygous loss of genes CYP21A1P and C4B. CYP21A2 sequencing showed that its promoter region was not affected by the 30-kb deletion, suggesting that the deletion of other regulatory sequences in the normal chromosome 6 caused a loss of function of the CYP21A2 gene. EDS and primary ovarian failure phenotypes could be explained by the loss of genes TNXB and MSH5, a finding that may contribute to the characterization of disease-causing genes. The detection of this de novo microdeletion drastically reduced the estimated recurrence risk for CAH in the family. (C) 2014 S. Karger AG, Basel
- Achondroplasia in Latin America: practical recommendations for the multidisciplinary care of pediatric patients(2022) LLERENA JR., Juan; KIM, Chong Ae; FANO, Virginia; ROSSELLI, Pablo; COLLETT-SOLBERG, Paulo Ferrez; MEDEIROS, Paula Frassinetti Vasconcelos de; PINO, Mariana del; BERTOLA, Debora; LOURENCO, Charles Marques; CAVALCANTI, Denise Pontes; FELIX, Temis Maria; ROSA-BELLAS, Antonio; ROSSI, Norma Teresa; CORTES, Fanny; ABREU, Flavia; CAVALCANTI, Nicolette; RUZ, Maria Cecilia Hervias; BARATELA, WagnerBackground Achondroplasia is the most common bone dysplasia associated with disproportionate short stature, and other comorbidities, such as foramen magnum stenosis, thoracolumbar kyphosis, lumbar hyperlordosis, genu varum and spinal compression. Additionally, patients affected with this condition have higher frequency of sleep disorders, ear infections, hearing loss and slowed development milestones. Considering these clinical features, we aimed to summarize the regional experts' recommendations for the multidisciplinary management of patients with achondroplasia in Latin America, a vast geographic territory with multicultural characteristics and with socio-economical differences of developing countries. Methods Latin American experts (from Argentina, Brazil, Chile and Colombia) particiated of an Advisory Board meeting (October 2019), and had a structured discussion how patients with achondroplasia are followed in their healthcare centers and punctuated gaps and opportunities for regional improvement in the management of achondroplasia. Results Practical recommendations have been established for genetic counselling, prenatal diagnosis and planning of delivery in patients with achondroplasia. An outline of strategies was added as follow-up guidelines to specialists according to patient developmental phases, amongst them neurologic, orthopedic, otorhinolaryngologic, nutritional and anthropometric aspects, and related to development milestones. Additionally, the role of physical therapy, physical activity, phonoaudiology and other care related to the quality of life of patients and their families were discussed. Preoperative recommendations to patients with achondroplasia were also included. Conclusions This study summarized the main expert recommendations for the health care professionals management of achondroplasia in Latin America, reinforcing that achondroplasia-associated comorbidities are not limited to orthopedic concerns.
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.- Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with ""Corner Fractures''(2017) LEE, Chae Syng; FU, He; BARATANG, Nissan; ROUSSEAU, Justine; KUMRA, Heena; SUTTON, V. Reid; NICETA, Marcello; CIOLFI, Andrea; YAMAMOTO, Guilherme; BERTOLA, Debora; MARCELIS, Carlo L.; LUGTENBERG, Dorien; BARTULI, Andrea; KIM, Choel; HOOVER-FONG, Julie; SOBREIRA, Nara; PAULI, Richard; BACINO, Carlos; KRAKOW, Deborah; PARBOOSINGH, Jillian; YAP, Patrick; KARIMINEJAD, Ariana; MCDONALD, Marie T.; ARACENA, Mariana I.; LAUSCH, Ekkehart; UNGER, Sheila; SUPERTI-FURGA, Andrea; LU, James T.; COHN, Dan H.; TARTAGLIA, Marco; LEE, Brendan H.; REINHARDT, Dieter P.; CAMPEAU, Philippe M.Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylo-metaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of ""corner fractures'' at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70 kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.
- Recurrence of Frontometaphyseal Dysplasia in Two Sisters With a Mutation in FLNA and an Atypical Paternal Phenotype: Insights Into Genotype-Phenotype Correlation(2015) BERTOLA, Debora; PASSOS-BUENO, Maria Rita; PEREIRA, Alexandre; KIM, Chong; MORGAN, Tim; ROBERTSON, Stephen P.
- Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface(2023) MARTINS, Luciane; LESSA, Luis Gustavo F.; ALI, Taccyanna M. M.; LAZAR, Monize; KIM, Chong A. A.; KANTOVITZ, Kamila R. R.; SANTAMARIA, Mauro P. P.; ARAUJO, Cassia F.; RAMOS, Carolina J. J.; FOSTER, Brian L. L.; FRANCO, Jose Francisco S.; BERTOLA, Debora; JR, Francisco H. H. NocitiThe goal of this study was to perform a clinical and molecular investigation in an eight-year-old female child diagnosed with hypophosphatasia (HPP). The proband and her family were evaluated by medical and dental histories, biochemical analyses, radiographic imaging, and genetic analysis of the tissue-nonspecific alkaline phosphatase (ALPL) gene. A bioinformatic analysis was performed to predict the structural and functional impact of the point mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) molecule and to define their potential contribution to the phenotype. We identified a novel combination of heterozygous ALPL missense variants in the proband, p.Ala33Val and p.Asn47His, compatible with an autosomal recessive mode of inheritance and resulting in skeletal and dental phenotypes. Computational modeling showed that the affected Asn47 residue is located in the coil structure close to the N-terminal alpha-helix, whereas the affected Ala33 residue is localized in the N-terminal alpha-helix. Both affected residues are located close to the homodimer interface, suggesting they may impair TNSALP dimer formation and stability. Clinical and biochemical follow-up revealed improvements after six years of ERT. Reporting this novel combination of ALPL variants in childhood HPP provides new insights into genotype-phenotype associations for HPP and specific sites within the TNSALP molecule potentially related to a childhood-onset HPP and skeletal and dental manifestations. Beneficial effects of ERT are implicated in skeletal and dental tissues.
- Investigation of 15q11-q13, 16p11.2 and 22q13 CNVs in Autism Spectrum Disorder Brazilian Individuals with and without Epilepsy(2014) MOREIRA, Danielle P.; GRIESI-OLIVEIRA, Karina; BOSSOLANI-MARTINS, Ana L.; LOURENCO, Naila C. V.; TAKAHASHI, Vanessa N. O.; ROCHA, Katia M. da; MOREIRA, Eloisa S.; VADASZ, Estevao; MEIRA, Joanna Goes Castro; BERTOLA, Debora; HALLORAN, Eoghan O'; MAGALHAES, Tiago R.; FETT-CONTE, Agnes C.; PASSOS-BUENO, Maria RitaCopy number variations (CNVs) are an important cause of ASD and those located at 15q11-q13, 16p11.2 and 22q13 have been reported as the most frequent. These CNVs exhibit variable clinical expressivity and those at 15q11-q13 and 16p11.2 also show incomplete penetrance. In the present work, through multiplex ligation-dependent probe amplification (MLPA) analysis of 531 ethnically admixed ASD-affected Brazilian individuals, we found that the combined prevalence of the 15q11-q13, 16p11.2 and 22q13 CNVs is 2.1% (11/531). Parental origin could be determined in 8 of the affected individuals, and revealed that 4 of the CNVs represent de novo events. Based on CNV prediction analysis from genome-wide SNP arrays, the size of those CNVs ranged from 206 kb to 2.27 Mb and those at 15q11-q13 were limited to the 15q13.3 region. In addition, this analysis also revealed 6 additional CNVs in 5 out of 11 affected individuals. Finally, we observed that the combined prevalence of CNVs at 15q13.3 and 22q13 in ASD-affected individuals with epilepsy (6.4%) was higher than that in ASD-affected individuals without epilepsy (1.3%; p < 0.014). Therefore, our data show that the prevalence of CNVs at 15q13.3, 16p11.2 and 22q13 in Brazilian ASD-affected individuals is comparable to that estimated for ASD-affected individuals of pure or predominant European ancestry. Also, it suggests that the likelihood of a greater number of positive MLPA results might be found for the 15q13.3 and 22q13 regions by prioritizing ASD-affected individuals with epilepsy.
conferenceObject Characterization of puberty development in a large cohort of patients with Noonan syndrome with molecular diagnosis(2021) REZENDE, Raissa; JORGE, Alexander; NORONHA, Renata; KESELMAN, Ana; ANDRADE, Nathalia; DANTAS, Naiara; BERTOLA, Debora; MALAQUIAS, Alexsandra- Vertebral segmentation defects in a Brazilian cohort: Clinical and molecular analysis focused on spondylocostal dysostosis(2022) LINNENKAMP, Bianca; GIRARDI, Raissa; ROCHA, Leticia; YAMAMOTO, Guilherme; CERONI, Jose Ricardo; MENDES, Antonia Elisabeth Cristhina; HONJO, Rachel; OLIVEIRA, Luiz Antonio; AMEMIYA, Raphael Bruno; QUAIO, Caio; OLIVEIRA FILHO, Joao Bosco de; KIM, Chong Ae; BERTOLA, Debora
- Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases(2015) VERLOES, Alain; DONATO, Nataliya Di; MASLIAH-PLANCHON, Julien; JONGMANS, Marjolijn; ABDUL-RAMAN, Omar A.; ALBRECHT, Beate; ALLANSON, Judith; BRUNNER, Han; BERTOLA, Debora; CHASSAING, Nicolas; DAVID, Albert; DEVRIENDT, Koen; EFTEKHARI, Pirayeh; DROUIN-GARRAUD, Valerie; FARAVELLI, Francesca; FAIVRE, Laurence; GIULIANO, Fabienne; ALMEIDA, Leina Guion; JUNCOS, Jorge; KEMPERS, Marlies; EKER, Hatice Kocak; LACOMBE, Didier; LIN, Angela; MANCINI, Grazia; MELIS, Daniela; LOURENCO, Charles Marques; SIU, Victoria Mok; MORIN, Gilles; NEZARATI, Marjan; NOWACZYK, Malgorzata J. M.; RAMER, Jeanette C.; OSIMANI, Sara; PHILIP, Nicole; PIERPONT, Mary Ella; PROCACCIO, Vincent; ROSELI, Zeichi-Seide; ROSSI, Massimiliano; RUSU, Cristina; SZNAJER, Yves; TEMPLIN, Ludivine; ULIANA, Vera; KLAUS, Mirjam; BON, Bregje Van; RAVENSWAAIJ, Conny Van; WAINER, Bruce; FRY, Andrew E.; RUMP, Andreas; HOISCHEN, Alexander; DRUNAT, Severine; RIVIERE, Jean-Baptiste; DOBYNS, William B.; PILZ, Daniela T.Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode beta-and gamma-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Progressive, severe dystonia was seen in one family. Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma, indicating that actinopathies may be cancer-predisposing disorders. Considering the multifaceted role of actins in cell physiology, we hypothesize that some clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial syndrome is our suggested designation for this clinical entity.