Repetto, Gabriela

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  • Publication
    Decoding complex inherited phenotypes in rare disorders: the DECIPHERD initiative for rare undiagnosed diseases in Chile
    (2024) Poli Harlowe, María Cecilia; Rebolledo Jaramillo, Boris; Lagos, Catalina; Orellana, Joan; Moreno, Gabriela; Martín, Luz M.; Encina, Gonzalo; Böhme, Daniela; Faundes, Víctor; Zavala, M. Jesús; Hasbún, María Trinidad; Fischer, Sara; Brito, Florencia; Araya, Diego; Lira, Manuel; Cruz, Javiera de la; Astudillo, Camila; Lay-Son, Guillermo; Cares, Carolina; Aracena, Mariana; San Martín, Esteban; Coban-Akdemir, Zeynep; Posey, Jennifer E.; Lupski, James R.; Repetto, Gabriela
    Rare diseases affect millions of people worldwide, and most have a genetic etiology. The incorporation of next-generation sequencing into clinical settings, particularly exome and genome sequencing, has resulted in an unprecedented improvement in diagnosis and discovery in the past decade. Nevertheless, these tools are unavailable in many countries, increasing health care gaps between high- and low-and-middle-income countries and prolonging the “diagnostic odyssey” for patients. To advance genomic diagnoses in a setting of limited genomic resources, we developed DECIPHERD, an undiagnosed diseases program in Chile. DECIPHERD was implemented in two phases: training and local development. The training phase relied on international collaboration with Baylor College of Medicine, and the local development was structured as a hybrid model, where clinical and bioinformatics analysis were performed in-house and sequencing outsourced abroad, due to lack of high-throughput equipment in Chile. We describe the implementation process and findings of the first 103 patients. They had heterogeneous phenotypes, including congenital anomalies, intellectual disabilities and/or immune system dysfunction. Patients underwent clinical exome or research exome sequencing, as solo cases or with parents using a trio design. We identified pathogenic, likely pathogenic or variants of unknown significance in genes related to the patients´ phenotypes in 47 (45.6%) of them. Half were de novo informative variants, and half of the identified variants have not been previously reported in public databases. DECIPHERD ended the diagnostic odyssey for many participants. This hybrid strategy may be useful for settings of similarly limited genomic resources and lead to discoveries in understudied populations.
  • Publication
    Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS
    (2023) Repetto, Gabriela; Zhao, Yingjie; Wang, Yujue; Shi, Lijie; McDonald, Donna; Crowley, Blaine; McGinn, Daniel; Tran, Oanh; Miller, Daniella; Lin, Jhih-Rong; Zacka, Elaine; Johnston, Richard; Chow, Eva; Vorstman, Jacob; Vingerhoets, Claudia; Van Amelsvoort, Therese; Gothelf, Doron; Swillen, Ann; Breckpot, Jeroen; Vermeesch, Joris; Eliez, Stephan; Schneider, Maude; Van den Bree, Marianne; Owen, Michael; Kates, Wendy; Shashi, Vandana; Schoch, Kelly; Bearden, Carrie; Digili, M. Cristina; Unolt, Marta; Putotto, Carolina; Marino, Bruno; Pontillo, Maria; Armando, Marco; Vicar, Stefano; Angkustsiri, Kathleen; Campbell, Linda; Busa, Tiffany; Heine, Damian; Murphy, Kieran; Murphy, Declan
    Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD
  • Publication
    Source-based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome
    (2024) Repetto, Gabriela; Ge, Ruiyang; Ching, Christopher; Bassett, Anne; Kushan, Leila; Antshe, Kevin; Van Amelsvoort, Therese; Bakker, Geor; Butcher, Nancy; Campbell, Linda; Chow, Eva; Craig, Michael; Crossley, Nicolas; Cunningham, Adam; Daly, Eileen; Doherty, Joanne; Durdle, Courtney; Emanuel, Beverly; Fiksinski, Ania; Forsyth, Jennifer; Fremont, Wanda; Goodrich-Hunsaker, Naomi; Gudbrandsen, Maria; Gur, Raquel; Jalbrzikowski, Maria; Kates, Wendy; Lin, Amy; Linden, David; McCabe, Kathryn; McDonald, Donna; Moss, Hayley; Murphy, Declan; Murphy, Kieran; Owen, Michael; Villalon, Julio; Roalf, David; Ruparel, Kosha; Schmitt, J. Eric; Schuite, Sanne; Angkustsiri, Kathleen
    22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.
  • Publication
    Genomic analysis in Chilean patients with suspected Rett syndrome: keep a broad differential diagnosis
    (2024) Brito, Florencia; Lagos, Catalina; Cubillos, Jessica; Orellana, Joan; Gajardo, Mallen; Böhme, Daniela; Encina, Gonzalo; Repetto, Gabriela
    Introduction: Rett syndrome (RTT, MIM #312750) is a rare genetic disorder that leads to developmental regression and severe disability and is caused by pathogenic variants in the MECP2 gene. The diagnosis of RTT is based on clinical features and, depending on resources and access, on molecular confirmation. There is scarce information on molecular diagnosis from patients in Latin America, mostly due to limited availability and coverage of genomic testing. This pilot study aimed to implement genomic testing and characterize clinical and molecular findings in a group of Chilean patients with a clinical diagnosis of RTT. Methods: Twenty-eight patients with suspected RTT underwent characterization of phenotypic manifestations and molecular testing using Clinical Exome SolutionTM CES_V2 by SOPHiA Genetics. Data was analyzed using the commercial bioinformatics platform, SOPHiA DDMTM. A virtual panel of 34 genes, including MECP2 and other genes that are in the differential diagnosis of RTT, was used to prioritize initial analyses, followed by evaluation of the complete exome sequence data. Results: Twelve patients (42.8% of participants) had variants in MECP2, of which 11 (39.2%) were interpreted as pathogenic/likely pathogenic (P/LP), thus confirming the diagnosis of RTT in them. Eight additional patients (28.5%) harbored ten variants in nine other genes. Four of these variants were interpreted as P/LP (14.2%) (GRIN2B, MADD, TRPM3 and ZEB2) resulting in alternative neurodevelopmental diagnoses, and six were considered of uncertain significance. No evident candidate variant was found for eight patients. Discussion: This study allowed to reach a diagnosis in half of the participants. The diagnosis of RTT was confirmed in over a third of them, while others were found to have alternative neurodevelopmental disorders. Further evaluation is needed to identify the cause in those with negative or uncertain results. This information is useful for the patients, families, and clinicians to guide clinical management,
  • Publication
    A Novel Gemcitabine-Resistant Gallbladder Cancer Model Provides Insights into Molecular Changes Occurring during Acquired Resistance
    (2023) Vergara, Luis; Bizama, Carolina; Zhong, Jun; Buchegger, Kurt; Suárez, Felipe; Rosa, Lorena; Ili, Carmen; Weber, Helga; Obreque, Javiera; Espinoza, Karena; Repetto, Gabriela; Roa, Juan; Leal, Pamela; García, Patricia
    Treatment options for advanced gallbladder cancer (GBC) are scarce and usually rely on cytotoxic chemotherapy, but the effectiveness of any regimen is limited and recurrence rates are high. Here, we investigated the molecular mechanisms of acquired resistance in GBC through the development and characterization of two gemcitabine-resistant GBC cell sublines (NOZ GemR and TGBC1 GemR). Morphological changes, cross-resistance, and migratory/invasive capabilities were evaluated. Then, microarray-based transcriptome profiling and quantitative SILAC-based phosphotyrosine proteomic analyses were performed to identify biological processes and signaling pathways dysregulated in gemcitabine-resistant GBC cells. The transcriptome profiling of parental and gemcitabine-resistant cells revealed the dysregulation of protein-coding genes that promote the enrichment of biological processes such as epithelial-to-mesenchymal transition and drug metabolism. On the other hand, the phosphoproteomics analysis of NOZ GemR identified aberrantly dysregulated signaling pathways in resistant cells as well as active kinases, such as ABL1, PDGFRA, and LYN, which could be novel therapeutic targets in GBC. Accordingly, NOZ GemR showed increased sensitivity toward the multikinase inhibitor dasatinib compared to parental cells. Our study describes transcriptome changes and altered signaling pathways occurring in gemcitabine-resistant GBC cells, which greatly expands our understanding of the underlying mechanisms of acquired drug resistance in GBC.
  • Publication
    Gathering the Stakeholder’s Perspective: Experiences and Opportunities in Rare Genetic Disease Research
    (2023) White, Lauren; Crowley, Blaine; Finucane, Brenda; McClellan, Emily; Donoghue, Sarah; Garcia, Sixto; Repetto, Gabriela; Fischer, Matthias; Jacquemont, Sebastien; Gur, Raquel; Maillard, Anne; Donald, Kirsten; Bassett, Anne; Swillen, Ann; McDonald, Donna
    Background: Research participant feedback is rarely collected; therefore, investigators have limited understanding regarding stakeholders’ (affected individuals/caregivers) motivation to participate. Members of the Genes to Mental Health Network (G2MH) surveyed stakeholders affected by copy number variants (CNVs) regarding perceived incentives for study participation, opinions concerning research priorities, and the necessity for future funding. Respondents were also asked about feelings of preparedness, research burden, and satisfaction with research study participation. Methods: Modified validated surveys were used to assess stakeholders´ views across three domains: (1) Research Study Enrollment, Retainment, Withdrawal, and Future Participation; (2) Overall Research Experience, Burden, and Preparedness; (3) Research Priorities and Obstacles. Top box score analyses were performed. Results: A total of 704 stakeholders´ responded from 29 countries representing 55 CNVs. The top reasons for initial participation in the research included reasons related to education and altruism. The top reasons for leaving a research study included treatment risks and side effects. The importance of sharing research findings and laboratory results with stakeholders was underscored by participants. Most stakeholders reported positive research experiences. Conclusions: This study provides important insight into how individuals and families affected with a rare CNV feel toward research participation and their overall experience in rare disease research. There are clear targets for areas of improvement for study teams, although manystakeholders reported positive research experiences. Key findings from this international survey may help advance collaborative research and improve the experience of participants, investigators, and other stakeholders moving forward.
  • Publication
    Updated clinical practice recommendations for managing adults with 22q11.2 deletion syndrome
    (2023) Boot, Erik; Óskarsdóttir, Sólveig; C Y Loo, Joanne; Crowley, Terrence; Orchanian, Ani; Andrade, Danielle; Arganbright, Jill; Castelein, René; Cserti-Gazdewich, Christine; De Reuver, Steven; Fiksinski, Ania; Klingberg, Gunilla; Lang, Anthony; Mascarenhas, Maria; Moss, Edward; Anna, Beata; Oechslin, Erwin; Palmer, Lisa; Repetto, Gabriela; D Reyes, Nikolai; Schneider, Maude; Silversides, Candice; Sullivan, Kathleen; Swillen, Ann; Van Amelsvoort, Therese; Van Batavia, Jason; Vingerhoets, Claudia; McDonald, Donna; Bassett, Anne
    This review aimed to update the clinical practice guidelines for managing adults with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society recruited expert clinicians worldwide to revise the original clinical practice guidelines for adults in a stepwise process according to best practices: (1) a systematic literature search (1992-2021), (2) study selection and synthesis by clinical experts from 8 countries, covering 24 subspecialties, and (3) formulation of consensus recommendations based on the literature and further shaped by patient advocate survey results. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text review, with 2318 meeting inclusion criteria (clinical care relevance to 22q11.2DS) including 894 with potential relevance to adults. The evidence base remains limited. Thus multidisciplinary recommendations represent statements of current best practice for this evolving field, informed by the available literature. These recommendations provide guidance for the recognition, evaluation, surveillance, and management of the many emerging and chronic 22q11.2DS-associated multisystem morbidities relevant to adults. The recommendations also address key genetic counseling and psychosocial considerations for the increasing numbers of adults with this complex condition.
  • Publication
    Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome
    (2023) Óskarsdóttir, Sólveig; Boot, Erik; Blaine Crowley, Terrence; Loo, Joanne; Arganbright, Jill; Armando, Marco; Baylis, Adriane; Breetvelt, Elemi; Castelein, René; Chadehumbe, Madeline; Cielo, Christopher; De Reuver, Steven; Eliez, Stephan; Fiksinsk, Ania; Forbes, Brian; Gallagher, Emily; Hopkins, Sarah; Jackson, Oksana; Levitz-Katz, Lorraine; Klingberg, Gunilla; Lambert, Michele; Marino, Bruno; Mascarenhas, Maria; Moldenhauer, Julie; Moss, Edward; Nowakowska, Beata; Orchanian-Cheff, Ani; Putotto, Carolina; Repetto, Gabriela; Schindewolf, Erica; Schneider, Maude; Solot, Cynthia; Sullivan, Kathleen; Swillen, Ann; Unolt, Marta; Van Batavia, Jason; Vingerhoets, Claudia; Vorstman, Jacob; Bassett, Anne; McDonald, Donna
    This review aimed to update the clinical practice guidelines for managing children and adolescents with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society, the international scientific organization studying chromosome 22q11.2 differences and related conditions, recruited expert clinicians worldwide to revise the original 2011 pediatric clinical practice guidelines in a stepwise process: (1) a systematic literature search (1992-2021), (2) study selection and data extraction by clinical experts from 9 different countries, covering 24 subspecialties, and (3) creation of a draft consensus document based on the literature and expert opinion, which was further shaped by survey results from family support organizations regarding perceived needs. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text reviews, including 1545 meeting criteria for potential relevance to clinical care of children and adolescents. Informed by the available literature, recommendations were formulated. Given evidence base limitations, multidisciplinary recommendations represent consensus statements of good practice for this evolving field. These recommendations provide contemporary guidance for evaluation, surveillance, and management of the many 22q11.2DS-associated physical, cognitive, behavioral, and psychiatric morbidities while addressing important genetic counseling and psychosocial issues.
  • Publication
    PUF60-related developmental disorder: A case series and phenotypic analysis of 10 additional patients with monoallelic PUF60 variants
    (2023) Grimes, H.; Ansari, M.; Ashraf, T.; Cueto, Anna; Calder, A.; Day, M.; Fernandez, P.; Foster, A.; Lahiri, N.; Repetto, Gabriela; Scurr, I.; Varghese, V.; Low, Karen; Varghese, V.
    PUF60-related developmental disorder (also referred to as Verheij syndrome), resulting from haploinsufficiency of PUF60, is associated with multiple congenital anomalies affecting a wide range of body systems. These anomalies include ophthalmic coloboma, and congenital anomalies of the heart, kidney, and musculoskeletal system. Behavioral and intellectual difficulties are also observed. While less common than other features associated with PUF60-related developmental disorder, for instance hearing impairment and short stature, identification of specific anomalies such as ophthalmic coloboma can aid with diagnostic identification given the limited spectrum of genes linked with this feature. We describe 10 patients with PUF60 gene variants, bringing the total number reported in the literature, to varying levels of details, to 56 patients. Patients were recruited both via locally based exome sequencing from international sites and from the DDD study in the United Kingdom. Eight of the variants reported were novel PUF60 variants. The addition of a further patient with a reported c449-457del variant to the existing literature highlights this as a recurrent variant. One variant was inherited from an affected parent. This is the first example in the literature of an inherited variant resulting in PUF60-related developmental disorder. Two patients (20%) were reported to have a renal anomaly consistent with 22% of cases in previously reported literature. Two patients received specialist endocrine treatment. More commonly observed were clinical features such as: cardiac anomalies (40%), ocular abnormalities (70%), intellectual disability (60%), and skeletal abnormalities (80%). Facial features did not demonstrate a recognizable gestalt. Of note, but remaining of unclear causality, we describe a single pediatric patient with pineoblastoma. We recommend that stature and pubertal progress should be monitored in PUF60-related developmental disorder with a low threshold for endocrine investigations as hormone therapy may be indicated. Our study reports an inherited case with PUF60-related developmental disorder which has important genetic counseling implications for families
  • Publication
    Challenges for gene therapy in the financial sustainability of health systems: a scoping review
    (2024) Ossandon, Hugo; Armijo, Nicolás; Vargas, Constanza; Repetto, Gabriela; Espinoza, Manuel
    Aim: To review the available evidence about the strategies implemented or proposed for coverage or reimbursement for currently approved gene therapies. Methods: A scoping review was conducted to analyze the evidence published during the years 2016 to 2023. The main search criteria were coverage or reimbursement of gene therapy by healthcare systems. The eligible articles were those that described or proposed a financing model used to provide coverage in the various systems around the world. Results: The study identified 279 publications, and after removing duplicates and screening for eligibility, 10 were included in the study. The results show that various financing models have been proposed, including subscription-based payment models, outcome-based payment models, and amortization strategies. However, several barriers to implementing these models were identified, such as deficiencies in informatics systems for data collection, changes in laws or regulations, the lack of accessible clinical endpoints and administrative costs. Conclusion: This scoping review provides an overview of financing strategies for gene therapies. Gene therapies can cure rare or previously intractable diseases, but their high cost can make access difficult. Publishing experiences with these models can help evaluate their use and gather more evidence for their effectiveness.