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
14 resultados
Resultados de Busca
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- Cross-national harmonization of cognitive measures across HRS HCAP (USA) and LASI-DAD (India)(2022) VONK, Jet M. J.; GROSS, Alden L.; ZAMMIT, Andrea R.; BERTOLA, Laiss; AVILA, Justina F.; JUTTEN, Roos J.; GAYNOR, Leslie S.; SUEMOTO, Claudia K.; KOBAYASHI, Lindsay C.; O'CONNELL, Megan E.; ELUGBADEBO, Olufisayo; AMOFA, Priscilla A.; STAFFARONI, Adam M.; RENTERIA, Miguel Arce; TURNEY, Indira C.; JONES, Richard N.; MANLY, Jennifer J.; LEE, Jinkook; ZAHODNE, Laura B.Background As global populations age, cross-national comparisons of cognitive health and dementia risk are increasingly valuable. It remains unclear, however, whether country-level differences in cognitive function are attributable to population differences or bias due to incommensurate measurement. To demonstrate an effective method for cross-national comparison studies, we aimed to statistically harmonize measures of episodic memory and language function across two population-based cohorts of older adults in the United States (HRS HCAP) and India (LASI-DAD). Methods Data for 3,496 HRS HCAP (>= 65 years) and 3,152 LASI-DAD (>= 60 years) participants were statistically harmonized for episodic memory and language performance using confirmatory factor analysis (CFA) methods. Episodic memory and language factor variables were investigated for differential item functioning (DIF) and precision. Results CFA models estimating episodic memory and language domains based on a priori adjudication of comparable items fit the data well. DIF analyses revealed that four out of ten episodic memory items and five out of twelve language items measured the underlying construct comparably across samples. DIF-modified episodic memory and language factor scores showed comparable patterns of precision across the range of the latent trait for each sample. Conclusions Harmonization of cognitive measures will facilitate future investigation of cross-national differences in cognitive performance and differential effects of risk factors, policies, and treatments, reducing study-level measurement and administrative influences. As international aging studies become more widely available, advanced statistical methods such as those described in this study will become increasingly central to making universal generalizations and drawing valid conclusions about cognitive aging of the global population.
- 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.
- 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.
- Impact of ERT and follow-up of 17 patients from the same family with a mild form of MPS II(2022) STEPHAN, Bruno de Oliveira; QUAIO, Caio Robledo; SPOLADOR, Gustavo Marquezani; PAULA, Ana Carolina de; CURIATI, Marco Antonio; MARTINS, Ana Maria; LEAL, Gabriela Nunes; TENORIO, Artur; FINZI, Simone; CHIMELO, Flavia Teixeira; MATAS, Carla Gentile; HONJO, Rachel Sayuri; BERTOLA, Debora Romeo; KIM, Chong AeBackground: Mucopolysaccharidosis type II, also known as Hunter syndrome, is a rare X-linked recessive disorder caused by deficiency of the lysosomal enzyme Iduronate-2-Sulfatase (IDS), leading to progressive accumulation of Glycosaminoglycans (GAGs) in several organs. Over the years, Enzyme Replacement Therapy (ERT) has provided significant benefits for patients, retarding the natural progression of the disease. Results: The authors evaluated 17 patients from the same family with a mild form of MPS type II; the proband had developed acute decompensated heart failure refractory to clinical measurements at 23 years and needed a rather urgent heart transplant; however, he died from surgical complications shortly after the procedure. Nevertheless, subsequent to his tragic death, 16 affected male relatives were detected after biochemical tests identifying the low or absent activity of the IDS enzyme and confirmed by molecular analysis of the IDS gene. Following diagnosis, different options of treatment were chosen: 6 patients started ERT with Elaprase (R) (Idursulfase) soon after, while the other 10 remained without ERT. Eventually, 4 patients in the latter group began ERT with Hunterase (R) (Idursulfase Beta). None presented adverse effects to either form of the enzyme. Among the 6 individuals without any ERT, two died of natural causes, after reaching 70 years. Despite the variable phenotype within the same family (mainly heart dysfunctions and carpal tunnel syndrome), all 14 remaining patients were alive with an independent lifestyle. Conclusion: Here, the authors report the variable progress of the disease with and without ERT in a large Brazilian family with a slowly progressive form of MPS II, harboring the same missense variant in the IDS gene.
- Developmental genomics of limb malformations: Allelic series in association with gene dosage effects contribute to the clinical variability(2022) DUAN, Ruizhi; HIJAZI, Hadia; GULEC, Elif Yilmaz; EKER, Hatice Kocak; COSTA, Silvia R.; SAHIN, Yavuz; OCAK, Zeynep; ISIKAY, Sedat; OZALP, Ozge; BOZDOGAN, Sevcan; ASLAN, Huseyin; ELCIOGLU, Nursel; BERTOLA, Debora R.; GEZDIRICI, Alper; DU, Haowei; FATIH, Jawid M.; GROCHOWSKI, Christopher M.; AKAY, Gulsen; JHANGIANI, Shalini N.; KARACA, Ender; GU, Shen; COBAN-AKDEMIR, Zeynep; POSEY, Jennifer E.; BAYRAM, Yavuz; SUTTON, V. Reid; CARVALHO, Claudia M. B.; PEHLIVAN, Davut; GIBBS, Richard A.; LUPSKI, James R.Genetic heterogeneity, reduced penetrance, and variable expressivity, the latter including asymmetric body axis plane presentations, have all been described in families with congenital limb malformations (CLMs). Interfamilial and intrafamilial heterogeneity highlight the complexity of the underlying genetic pathogenesis of these developmental anomalies. Family-based genomics by exome sequencing (ES) and rare variant analyses combined with whole-genome array-based comparative genomic hybridization were implemented to investigate 18 families with limb birth defects. Eleven of 18 (61%) families revealed explanatory variants, including 7 single-nucleotide variant alleles and 3 copy number variants (CNVs), at previously reported ""disease trait associated loci"": BHLHA9, GLI3, HOXD cluster, HOXD13, NPR2, and WNT10B. Breakpoint junction analyses for all three CNV alleles revealed mutational signatures consistent with microhomology-mediated break-induced replication, a mechanism facilitated by Alu/Alu-mediated rearrangement. Homozygous duplication of BHLHA9 was observed in one Turkish kindred and represents a novel contributory genetic mechanism to Gollop-Wolfgang Complex (MIM: 228250), where triplication of the locus has been reported in one family from Japan (i.e., 4n = 2n + 2n versus 4n = 3n + 1n allelic configurations). Genes acting on limb patterning are sensitive to a gene dosage effect and are often associated with an allelic series. We extend an allele-specific gene dosage model to potentially assist, in an adjuvant way, interpretations of interconnections among an allelic series, clinical severity, and reduced penetrance of the BHLHA9-related CLM spectrum.
- Chromosomal microarray analyses from 5778 patients with neurodevelopmental disorders and congenital anomalies in Brazil(2022) V, Ana C. Krepischi; VILLELA, Darine; COSTA, Silvia Souza da; MAZZONETTO, Patricia C.; MIGLIAVACCA, Michele P.; MILANEZI, Fernanda; SANTOS, Juliana G.; GUARISCHI-SOUSA, Rodrigo; CAMPANA, Gustavo; KOK, Fernando; SCHLESINGER, David; KITAJIMA, Joao Paulo; CAMPAGNARI, Francine; BERTOLA, Debora R.; VIANNA-MORGANTE, Angela M.; PEARSON, Peter L.; ROSENBERG, CarlaChromosomal microarray analysis (CMA) has been recommended and practiced routinely since 2010 both in the USA and Europe as the first-tier cytogenetic test for patients with unexplained neurodevelopmental delay/intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies. However, in Brazil, the use of CMA is still limited, due to its high cost and complexity in integrating the results from both the private and public health systems. Although Brazil has one of the world's largest single-payer public healthcare systems, nearly all patients referred for CMA come from the private sector, resulting in only a small number of CMA studies in Brazilian cohorts. To date, this study is by far the largest Brazilian cohort (n = 5788) studied by CMA and is derived from a joint collaboration formed by the University of Sao Paulo and three private genetic diagnostic centers to investigate the genetic bases of neurodevelopmental disorders and congenital abnormalities. We identified 2,279 clinically relevant CNVs in 1886 patients, not including the 26 cases of UPD found. Among detected CNVs, the corresponding frequency of each category was 55.6% Pathogenic, 4.4% Likely Pathogenic and 40% VUS. The diagnostic yield, by taking into account Pathogenic, Likely Pathogenic and UPDs, was 19.7%. Since the rational for the classification is mostly based on Mendelian or highly penetrant variants, it was not surprising that a second event was detected in 26% of those cases of predisposition syndromes. Although it is common practice to investigate the inheritance of VUS in most laboratories around the world to determine the inheritance of the variant, our results indicate an extremely low cost-benefit of this approach, and strongly suggest that in cases of a limited budget, investigation of the parents of VUS carriers using CMA should not be prioritized.
- 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
- Neuroprogenitor Cells From Patients With TBCK Encephalopathy Suggest Deregulation of Early Secretory Vesicle Transport(2022) MOREIRA, Danielle de Paula; SUZUKI, Angela May; SILVA, Andre Luiz Teles e; VARELLA-BRANCO, Elisa; MENEGHETTI, Maria Cecilia Zorel; KOBAYASHI, Gerson Shigeru; FOGO, Mariana; FERRARI, Merari de Fatima Ramires; CARDOSO, Rafaela Regina; LOURENCO, Naila Cristina Vilaca; GRIESI-OLIVEIRA, Karina; ZACHI, Elaine Cristina; BERTOLA, Debora Romeo; WEINMANN, Karina de Souza; LIMA, Marcelo Andrade de; NADER, Helena Bonciani; SERTIE, Andrea Laurato; PASSOS-BUENO, Maria RitaBiallelic pathogenic variants in TBCK cause encephaloneuropathy, infantile hypotonia with psychomotor retardation, and characteristic facies 3 (IHPRF3). The molecular mechanisms underlying its neuronal phenotype are largely unexplored. In this study, we reported two sisters, who harbored biallelic variants in TBCK and met diagnostic criteria for IHPRF3. We provided evidence that TBCK may play an important role in the early secretory pathway in neuroprogenitor cells (iNPC) differentiated from induced pluripotent stem cells (iPSC). Lack of functional TBCK protein in iNPC is associated with impaired endoplasmic reticulum-to-Golgi vesicle transport and autophagosome biogenesis, as well as altered cell cycle progression and severe impairment in the capacity of migration. Alteration in these processes, which are crucial for neurogenesis, neuronal migration, and cytoarchitecture organization, may represent an important causative mechanism of both neurodevelopmental and neurodegenerative phenotypes observed in IHPRF3. Whether reduced mechanistic target of rapamycin (mTOR) signaling is secondary to impaired TBCK function over other secretory transport regulators still needs further investigation.
- The recurrent homozygous translation start site variant in CCDC134 in an individual with severe osteogenesis imperfecta of non-Morrocan ancestry(2022) ALI, Taccyanna M.; LINNENKAMP, Bianca D. W.; YAMAMOTO, Guilherme L.; HONJO, Rachel S.; MENEZES FILHO, Hamilton Cabral de; KIM, Chong Ae; BERTOLA, Debora R.Osteogenesis imperfecta (OI) is a rare low-bone mass skeletal Mendelian disorder characterized by bone fragility leading to bone fractures, with deformities and stunted growth in the more severe phenotypes. Other common, nonskeletal findings include blue sclerae and dentinogenesis imperfecta. It is caused mainly by quantitative or structural defects in type I collagen, although dysregulation of different signaling pathways that play a role in bone morphogenesis has been described to be associated with a small fraction of individuals with OI. Recently, a homozygous variant in the translation start site of CCDC134, showing increased activation of the RAS/MAPK signaling pathway, has been reported in three families of Moroccan origin with a severe, deforming form of OI. We report on a 9-year-old Brazilian boy, harboring the same homozygous variant in CCDC134, also presenting severe bone involvement. This report contributes to the phenotypic delineation of this novel autosomal recessive form of OI, which presents with high prevalence of nonunion fractures considered rare events in OI in general. In addition, it expands the phenotype to include base skull anomalies, potentially leading to serious complications, as seen in severe forms of OI. A poor response to bisphosphonate therapy was observed in these individuals. As the variant in CCDC134 leads to dysregulation of the RAS/MAPK signaling pathway, drugs targeted to this pathway could be an alternative to achieve a better management of these individuals.
- Phenotypic and mutational spectrum of ROR2-related Robinow syndrome(2022) LIMA, Ariadne R.; FERREIRA, Barbara M.; ZHANG, Chaofan; JOLLY, Angad; DU, Haowei; WHITE, Janson J.; DAWOOD, Moez; LINS, Tulio C.; CHIABAI, Marcela A.; BEUSEKOM, Ellen; CORDOBA, Mara S.; ROSA, Erica C. C. Caldas; KAYSERILI, Hulya; KIMONIS, Virginia; WU, Erica; MELLADO, Cecilia; AGGARWAL, Vineet; RICHIERI-COSTA, Antonio; BRUNONI, Decio; CANO, Talyta M.; JORGE, Alexander A. L.; KIM, Chong A.; HONJO, Rachel; BERTOLA, Debora R.; DANDALO-GIRARDI, Raissa M.; BAYRAM, Yavuz; GEZDIRICI, Alper; YILMAZ-GULEC, Elif; GUMUS, Evren; YILMAZ, Gulay C.; OKAMOTO, Nobuhiko; OHASHI, Hirofumi; COBAN-AKDEMIR, Zeynep; MITANI, Tadahiro; JHANGIANI, Shalini N.; MUZNY, Donna M.; REGATTIERI, Neysa A. P.; POGUE, Robert; PEREIRA, Rinaldo W.; OTTO, Paulo A.; GIBBS, Richard A.; ALI, Bassam R.; BOKHOVEN, Hans; BRUNNER, Han G.; SUTTON, V. Reid; LUPSKI, James R.; VIANNA-MORGANTE, Angela M.; CARVALHO, Claudia M. B.; MAZZEU, Juliana F.Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable autosomal recessive trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation of this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome.