LESLIE DOMENICI KULIKOWSKI
Projetos de Pesquisa
Unidades Organizacionais
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina
LIM/03 - Laboratório de Medicina Laboratorial, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/03 - Laboratório de Medicina Laboratorial, Hospital das Clínicas, Faculdade de Medicina - Líder
10 resultados
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- Cri-du-Chat Syndrome: Revealing a Familial Atypical Deletion in 5p(2023) ALMEIDA, Vanessa T.; CHEHIMI, Samar N.; GASPARINI, Yanca; NASCIMENTO, Amom M.; CARVALHO, Gleyson F. S.; MONTENEGRO, Marilia M.; ZANARDO, Evelin Aline; DIAS, Alexandre T.; ASSUNCAO, Nilson A.; KIM, Chong A.; KULIKOWSKI, Leslie D.Introduction: Cri-du-chat syndrome is generally diagnosed when patients present a high-pitched cry at birth, microcephaly, ocular hypertelorism, and prominent nasal bridge. The karyotype is useful to confirm deletions in the short arm of chromosome 5 (5p-) greater than 10 Mb. In cases of smaller deletions, it is necessary to resort to other molecular techniques such as fluorescence in situ hybridization, multiplex ligation-dependent probe amplification (MLPA) or genomic array. Case Presentation: We report a family with an atypical deletion in 5p (mother and 2 children) and variable phenotypes compared with the literature. We applied a P064 MLPA kit to evaluate 5p- in the mother and the 2 children, and we used the Infinium CytoSNP-850K BeadChip genomic array to evaluate the siblings, an 11-year-old boy and a 13-year-old girl, to better define the 5p breakpoints. Both children presented a high-pitched cry at birth, but they did not present any of the typical physical features of 5p- syndrome. The MLPA technique with 5 probes for the 5p region revealed that the patients and their mother presented an atypical deletion with only 4 probes deleted (TERT_ex2, TERT_ex13, CLPTM1L, and IRX4). The genomic array performed in the siblings' samples revealed a 6.2-Mb terminal deletion in 5p15.33p15.32, which was likely inherited from their mother, who presented similar molecular features, seen in MLPA. Discussion: The sparing of the CTNND2 gene, which is associated with cerebral development, in both siblings may explain why these 2 patients had features such as better communication skills which most patients with larger 5p deletions usually do not present. In addition, both patients had smaller deletions than those found in patients with a typical 5p- phenotype. This report demonstrates the utility of genomic arrays as a diagnostic tool to better characterize atypical deletions in known syndromes such as 5p- syndrome, which will allow a better understanding of the genotype-phenotype correlations.
conferenceObject Pineal region high grade neuroepithelial tumors with NTRK fusions belonging to the novel methylation class ""diffuse high grade glioma, IDH-wildtype, subtype E"" (HGG_E)-A distinct clinicopathological and molecular presentation(2023) COSTA, F. D'Almeida; CASTRO, J. V. Alves de; KULIKOWSKI, L. Domenici; WOLFF, B.; GREGIANIN, L. J.; NETO, C. Scapulatempo; KOTIDIS, C.; DALAHMAH, O. Al; CANOLL, P.; BRUCE, J.; ALDAPE, K.; ABDULLAEV, Z.; NASRALLAH, M.; ZANAZZI, G.- Cytogenomic Investigation of Syndromic Brazilian Patients with Differences of Sexual Development(2023) JR, Jose Antonio Diniz Faria; MORAES, Daniela R.; KULIKOWSKI, Leslie Domenici; BATISTA, Rafael Loch; GOMES, Nathalia Lisboa; NISHI, Mirian Yumie; ZANARDO, Evelin; NONAKA, Carolina Kymie Vasques; SOUZA, Bruno Solano de Freitas; MENDONCA, Berenice Bilharinho; DOMENICE, SorahiaBackground: Cytogenomic methods have gained space in the clinical investigation of patients with disorders/differences in sexual development (DSD). Here we evaluated the role of the SNP array in achieving a molecular diagnosis in Brazilian patients with syndromic DSD of unknown etiology. Methods: Twenty-two patients with DSD and syndromic features were included in the study and underwent SNP-array analysis. Results: In two patients, the diagnosis of 46,XX SRY + DSD was established. Additionally, two deletions were revealed (3q29 and Xp22.33), justifying the syndromic phenotype in these patients. Two pathogenic CNVs, a 10q25.3-q26.2 and a 13q33.1 deletion encompassing the FGFR2 and the EFNB2 gene, were associated with genital atypia and syndromic characteristics in two patients with 46,XY DSD. In a third 46,XY DSD patient, we identified a duplication in the 14q11.2-q12 region of 6.5 Mb associated with a deletion in the 21p11.2-q21.3 region of 12.7 Mb. In a 46,XY DSD patient with delayed neuropsychomotor development and congenital cataracts, a 12 Kb deletion on chromosome 10 was found, partially clarifying the syndromic phenotype, but not the genital atypia. Conclusions: The SNP array is a useful tool for DSD patients, identifying the molecular etiology in 40% (2/5) of patients with 46,XX DSD and 17.6% (3/17) of patients with 46,XY DSD.
- Association between adult and child behavioral interactions with preoperative anxiety and emergence delirium(2023) QUINTAO, Vinicius Caldeira; CARLOS, Ricardo Vieira; KULIKOWSKI, Leslie Domenici; LEE-ARCHER, Paul; CARMONA, Maria Jose Carvalho
- Comparison of intravenous and inhalation anesthesia on postoperative behavior changes in children undergoing ambulatory endoscopic procedures: A randomized clinical trial(2023) QUINTAO, Vinicius Caldeira; CARLOS, Ricardo Vieira; CARDOSO, Priscilla Ferreira Neto; ZEFERINO, Suely Pereira; KULIKOWSKI, Leslie Domenici; LEE-ARCHER, Paul; CARMONA, Maria Jose CarvalhoBackgroundEarly and delayed behavioral changes are well recognized after anesthesia. Intravenous anesthesia may prevent emergence delirium. However, it has not been evaluated as a preventive strategy for delayed postoperative behavior changes. AimsWe aimed to determine whether intravenous anesthesia is effective at reducing postoperative behavior changes in children undergoing ambulatory endoscopic procedures when compared to inhalation anesthesia. MethodsThis randomized, double-blinded controlled trial was approved by the local IRB. Children aged 1-12 years who underwent ambulatory endoscopic procedures were recruited. Preoperative anxiety was evaluated through the modified Yale Preoperative Anxiety Scale. All children underwent face mask inhalation induction with sevoflurane. After a peripheral line was placed, each child was allocated to sevoflurane or propofol maintenance. Emergence delirium was evaluated through the Pediatric Anesthesia Emergence Delirium scale. The child was discharged home, and behavioral changes were assessed through the Posthospitalization Behavior Questionnaire for Ambulatory Surgery on Days 1, 7, and 14. ResultsOverall, 175 children were enrolled. On Day 1 after the procedure, 57 children presented at least one negative behavior. On Days 7 and 14, 49 and 44 children presented at least one negative behavior, respectively. The median number of negative behaviors was similar between the groups. Post hoc analyses showed a moderate correlation between emergence delirium and negative postoperative behavior on Day 7 (r = .34; p = <.001) and an increase of 3.31 (95% CI 1.90; 4.36 p < .001) points in the mean summed score of new negative behaviors for individuals with emergence delirium. ConclusionThe incidence of postoperative behavior changes in children undergoing ambulatory endoscopic procedures was similar when comparing intravenous with inhalation anesthesia. Children who experience emergence delirium might show a greater incidence of negative postoperative behavior changes.
- Establishment and Comprehensive Molecular Characterization of an Immortalized Glioblastoma Cell Line from a Brazilian Patient(2023) SILVA, Fernanda F. da; LUPINACCI, Fernanda C. S.; ELIAS, Bruno D. S.; BESERRA, Adriano O.; SANEMATSU, Paulo; ROFFE, Martin; KULIKOWSKI, Leslie D.; COSTA, Felipe D'almeida; SANTOS, Tiago G.; HAJJ, Glaucia N. M.Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with few effective treatment strategies. The research on the development of new treatments is often constrained by the limitations of preclinical models, which fail to accurately replicate the disease's essential characteristics. Herein, we describe the obtention, molecular, and functional characterization of the GBM33 cell line. This cell line belongs to the GBM class according to the World Health Organization 2021 Classification of Central Nervous System Tumors, identified by methylation profiling. GBM33 expresses the astrocytic marker GFAP, as well as markers of neuronal origin commonly expressed in GBM cells, such as beta III-tubulin and neurofilament. Functional assays demonstrated an increased growth rate when compared to the U87 commercial cell line and a similar sensitivity to temozolamide. GBM33 cells retained response to serum starvation, with reduced growth and diminished activation of the Akt signaling pathway. Unlike LN-18 and LN-229 commercial cell lines, GBM33 is able to produce primary cilia upon serum starvation. In summary, the successful establishment and comprehensive characterization of this GBM cell line provide researchers with invaluable tools for studying GBM biology, identifying novel therapeutic targets, and evaluating the efficacy of potential treatments.
- SIN3A defects associated with syndromic congenital hypogonadotropic hypogonadism: an overlap with Witteveen-Kolk syndrome(2023) SCHNOLL, Caroline; KREPISCHI, Ana Cristina Victorino; RENCK, Alessandra Covallero; AMATO, Lorena Guimaraes Lima; KULIKOWSKI, Leslie Domenici; DANTAS, Naiara Castelo Branco; COSTA, Elaine Maria Frade; MENDONCA, Berenice Bilharinho; LATRONICO, Ana Claudia; JORGE, Alexander Augusto de Lima; SILVEIRA, Leticia Ferreira GontijoIntroduction: Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. More than 40 genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. Mutations involving the same gene (e.g. FGFR1, PROK2/PROKR2, CHD7) were found to cause normosmic CHH and Kallmann syndrome, with and without associated phenotypes, illustrating the coexistence of CHH with signs of other complex syndromes. The Witteveen-Kolk syndrome (WITKOS), caused by defects of the SIN3A gene, is a heterogeneous disorder characterized by distinctive facial features, microcephaly, short stature, delayed cognitive and motor development. Although micropenis and cryptorchidism have been reported in this syndrome, WITKOS has not been formally associated with CHH so far. Patients and Methods: A man with Kallmann syndrome (KS) associated with mild syndromic features (S1) and a boy with global developmental delay, syndromic short stature, micropenis and cryptorchidism (S2), in whom common genetic defects associated with CHH and short stature had been previously excluded, were studied by either chromosomal microarray analysis (CMA) or whole exome sequencing (WES). Results: Rare SIN3A pathogenic variants were identified in these two unrelated patients with CHH phenotypic features. A 550 kb deletion at 15q24.1, including the whole SIN3A gene, was identified in S1, and a SIN3A nonsense rare variant (p.Arg471*) was detected in S2. Conclusion: These findings lead us to propose a link between SIN3A defects and CHH, especially in syndromic cases, based on these two patients with overlapping phenotypes of WITKOS and CHH.
bookPart Avaliação do número e da estrutura dos cromossomos(2023) KULIKOWSKI, Leslie Domenici; MONTENEGRO, Marília Moreira- Expanding the Phenotype of 8p23.1 Deletion Syndrome: Eight New Cases Resembling the Clinical Spectrum of 22q11.2 Microdeletion(2023) MONTENEGRO, Marilia Moreira; CAMILOTTI, Debora; QUAIO, Caio Robledo D'Anglioli Costa; GASPARINI, Yanca; ZANARDO, Evelin Aline; RANGEL-SANTOS, Andreia; NOVO-FILHO, Gil Monteiro; FRANCISCO, Gleyson; LIRO, Lucas; NASCIMENTO, Amom; CHEHIMI, Samar Nasser; SOARES, Diogo Cordeiro Queiroz; KREPISCHI, Ana C. V.; GRASSI, Marcilia Sierro; HONJO, Rachel Sayuri; PALMEIRA, Patricia; KIM, Chong Ae; CARNEIRO-SAMPAIO, Magda Maria Sales; ROSENBERG, Carla; KULIKOWSKI, Leslie DomeniciObjective To report the effectiveness of early molecular diagnosis in the clinical management of rare diseases, presenting 8 patients with 8p23.1DS who have clinical features that overlap the phenotypic spectrum of 22q11.2DS. Study design This report is part of a previous study that aims to provide a precocious molecular diagnosis of the 22q11.2 deletion syndrome in 118 infants with congenital heart disease. To confirm the clinical diagnosis, patients underwent comparative genomic screening by the multiplex ligation-dependent probe amplification (MLPA) assay with the SALSA MLPA probemix kits P064-B2, P036-E1, P070-B2, P356-A1, and P250-B1. Subsequently, the patients performed the genomic microarray using the Infinium CytoSNP-850K BeadChip to confirm the deletion, determine the breakpoints of the deletion, and search for genomic copy number variations. Results MLPA performed with 3 different kits revealed the 8p23.1 typical deletion involving the PPP1R3B, MSRA, and GATA4 genes in the 5 patients. The array analysis was performed on these 5 patients and 3 other patients (8 patients) who also had clinical suspicion of 22q11 deletion (8 patients) allowed a precise definition of the breakpoints and excluded other genomic abnormalities. Conclusions Cytogenomic screening was efficient in establishing a differential diagnosis and ruling out the presence of other concomitant syndromes. The clinical picture of the 8p23.1 deletion syndrome is challenging; however, cytogenomic tools can provide an exact diagnosis and help to clarify the genotype-phenotype complexity of these patients. Our reports underline the importance of early diagnosis and clinical follow-up of microdeletion syndromes.
- DNA methylation epi-signature and biological age in attention deficit hyperactivity disorder patients(2023) CARVALHO, Gleyson Francisco da Silva; COSTA, Thais Virginia Moura Machado; NASCIMENTO, Amom Mendes; WOLFF, Beatriz Martins; DAMASCENO, Julian Gabriel; VIEIRA, Lucas Liro; ALMEIDA, Vanessa Tavares; OLIVEIRA, Yanca Gasparini de; MELLO, Claudia Berlim de; MUSZKAT, Mauro; KULIKOWSKI, Leslie DomeniciObjective: Attention Deficit/Hyperactivity Disorder (ADHD) is a common behavioral syndrome that begins in childhood and affects 3.4% of children worldwide. Due to its etiological complexity, there are no consistent biomarkers for ADHD, however the high heritability presented by the disorder indicates a genetic/epigenetic influence. The main epigenetic mechanism is DNA methylation, a process with an important role in gene expression and in many psychiatric disorders. Thus, our study sought to identify epi-signatures biomarkers in 29 children clinically diagnosed with ADHD.Methods: After DNA extraction and bisulfite conversion, we performed methylation array experiment for dif-ferential methylation, ontological and biological age analysis.Results: The biological response in ADHD patients was not sufficient to determine a conclusive epi-signature in our study. However, our results highlighted the interaction of energy metabolism and oxidative stress pathways in ADHD patients detected by differential methylation patterns. Furthermore, we were able to identify a marginal association between the DNAmAge and ADHD. Conclusion: Our study present new methylation biomarkers findings associated with energy metabolism and oxidative stress pathways, in addition to DNAmAge in ADHD patients. However, we propose that further multiethnic studies, with larger cohorts and including maternal conditions, are necessary to demonstrate a definitive association between ADHD and these methylation biomarkers.