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Project Title
Prodromal manifestations of Parkinson´s disease in a high-risk population: 22q11.2 microdeletion syndrome
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Internal ID
1171014
Principal Investigator
Status
TERMINADO
Start Date
2017
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Publication

Rare diseases in Chile: challenges and recommendations in universal health coverage context

2019 , Gonzalo Encina , CASTILLO LABORDE, CARLA CECILIA , LECAROS URZUA, JUAN ALBERTO , Karen Dubois-Camacho , CALDERON GIADROSIC, JUAN FRANCISCO , AGUILERA SANHUEZA, XIMENA PAZ , KLEIN POSTERNACK, ANDRES DAVID , REPETTO LISBOA, MARIA GABRIELA

AbstractRare diseases (RDs) are a large number of diverse conditions with low individual prevalence, but collectively may affect up to 3.5–5.9% of the population. They have psychosocial and economic impact on patients and societies, and are a significant problem for healthcare systems, especially for countries with limited resources. In Chile, financial protection exists for 20 known RDs through different programs that cover diagnosis and treatments. Although beneficial for a number of conditions, most RD patients are left without a proper legal structure that guarantees a financial coverage, and in a vulnerable situation. In this review, we present and analyze the main challenges of the Chilean healthcare system and legislation on RDs, and other ambits of the RD ecosystem, including patient advocacy groups and research. Finally, we propose a set of policy recommendations that includes creating a patient registry, eliciting social preferences on health and financial coverage, improving access to clinical genetic services and therapies, promoting research on RDs and establishing a Latin-American cooperation network, all aimed at promoting equitable quality healthcare access for people living with RDs.

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Publication

Barriers and Considerations for Diagnosing Rare Diseases in Indigenous Populations

2020 , Carla S. D'Angelo , Azure Hermes , Christopher R. McMaster , Elissa Prichep , Étienne Richer , Francois H. van der Westhuizen , REPETTO LISBOA, MARIA GABRIELA , Gong Mengchun , Helen Malherbe , Juergen K. V. Reichardt , Laura Arbour , Maui Hudson , Kelly du Plessis , Melissa Haendel , Phillip Wilcox , Sally Ann Lynch , Shamir Rind , Simon Easteal , Xavier Estivill , Yarlalu Thomas , Gareth Baynam

Advances in omics and specifically genomic technologies are increasingly transforming rare disease diagnosis. However, the benefits of these advances are disproportionately experienced within and between populations, with Indigenous populations frequently experiencing diagnostic and therapeutic inequities. The International Rare Disease Research Consortium (IRDiRC) multi-stakeholder partnership has been advancing toward the vision of all people living with a rare disease receiving an accurate diagnosis, care, and available therapy within 1 year of coming to medical attention. In order to further progress toward this vision, IRDiRC has created a taskforce to explore the access barriers to diagnosis of rare genetic diseases faced by Indigenous peoples, with a view of developing recommendations to overcome them. Herein, we provide an overview of the state of play of current barriers and considerations identified by the taskforce, to further stimulate awareness of these issues and the passage toward solutions. We focus on analyzing barriers to accessing genetic services, participating in genomic research, and other aspects such as concerns about data sharing, the handling of biospecimens, and the importance of capacity building.

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Publication

Prevalence of filaggrin loss‐of‐function variants in Chilean population with and without atopic dermatitis

2021 , Geovanna V. Cárdenas , Carolina Iturriaga , Caroll D. Hernández , Macarena Tejos‐Bravo , Guillermo Pérez‐Mateluna , Carolina Cabalin , Marcela Urzúa , Luis F. Venegas‐Salas , Juan P. Fraga , REBOLLEDO JARAMILLO, BORIS EDUARDO , Maria C. Poli , REPETTO LISBOA, MARIA GABRIELA , Paola Casanello , José A. Castro‐Rodríguez , Arturo Borzutzky

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Publication

Sleep architecture in 22q11.2 microdeletion syndrome patients: polysomnographic study of prodromal signs of Parkinson's Disease and obstructive sleep apnea

2019 , A. Ocampo-Garcés , M. Diaz , K. Villanueva , T. Córdova , J. Mauro , T. Cáceres , A. Bassi , REPETTO LISBOA, MARIA GABRIELA

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Publication

Contribution of Mitochondrial DNA Heteroplasmy to the Congenital Cardiac and Palatal Phenotypic Variability in Maternally Transmitted 22q11.2 Deletion Syndrome

2021 , REBOLLEDO JARAMILLO, BORIS EDUARDO , Maria Gabriela Obregon , Victoria Huckstadt , Abel Gomez , REPETTO LISBOA, MARIA GABRIELA

Congenital heart disease (CHD) and palatal anomalies (PA), are among the most common characteristics of 22q11.2 deletion syndrome (22q11.2DS), but they show incomplete penetrance, suggesting the presence of additional factors. The 22q11.2 deleted region contains nuclear encoded mitochondrial genes, and since mitochondrial function is critical during development, we hypothesized that changes in the mitochondrial DNA (mtDNA) could be involved in the intrafamilial variability of CHD and PA in cases of maternally inherited 22q11.2DS. To investigate this, we studied the transmission of heteroplasmic mtDNA alleles in seventeen phenotypically concordant and discordant mother-offspring 22q11.2DS pairs. We sequenced their mtDNA and identified 26 heteroplasmic variants at >1% frequency, representing 18 transmissions. The median allele frequency change between a mother and her child was twice as much, with a wider distribution range, in PA discordant pairs, p-value = 0.039 (permutation test, 11 concordant vs. 7 discordant variants), but not in CHD discordant pairs, p-value = 0.441 (9 vs. 9). Only the variant m.9507T>C was considered to be pathogenic, but it was unrelated to the structural phenotypes. Our study is novel, yet our results are not consistent with mtDNA variation contributing to PA or CHD in 22q11.2DS. Larger cohorts and additional factors should be considered moving forward.

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Exome Sequencing Identifies Genetic Variants Associated with Extreme Manifestations of the Cardiovascular Phenotype in Marfan Syndrome

2022 , Yanireth Jimenez , Cesar Paulsen , Eduardo Turner , Sebastian Iturra , Oscar Cuevas , Guillermo Lay-son , REPETTO LISBOA, MARIA GABRIELA , Marcelo Rojas , CALDERON GIADROSIC, JUAN FRANCISCO

Marfan Syndrome (MFS) is an autosomal dominant condition caused by variants in the fibrillin-1 (FBN1) gene. Cardinal features of MFS include ectopia lentis (EL), musculoskeletal features and aortic root aneurysm and dissection. Although dissection of the ascending aorta is the main cause of mortality in MFS, the clinical course differs considerably in age of onset and severity, even among individuals who share the same causative variant, suggesting the existence of additional genetic variants that modify the severity of the cardiovascular phenotype in MFS. We recruited MFS patients and classified them into severe (n = 8) or mild aortic phenotype (n = 14) according to age of presentation of the first aorta-related incident. We used Exome Sequencing to identify the genetic variants associated with the severity of aortic manifestations and we performed linkage analysis where suitable. We found five genes associated with severe aortic phenotype and three genes that could be protective for this phenotype in MFS. These genes regulate components of the extracellular matrix, TGFβ pathway and other signaling pathways that are involved in the maintenance of the ECM or angiogenesis. Further studies will be required to understand the functional effect of these variants and explore novel, personalized risk management and, potentially, therapies for these patients.

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Pharmacogenetics in Psychiatry: Perceived Value and Opinions in a Chilean Sample of Practitioners

2021 , UNDURRAGA FOURCADE, JUAN PABLO , Ignacio Bórquez-Infante , Nicolás A. Crossley , Miguel L. Prieto , REPETTO LISBOA, MARIA GABRIELA

Use of pharmacogenetics (PGx) testing to guide clinical decisions is growing in developed countries. Published guidelines for gene–drug pair analysis are available for prescriptions in psychiatry, but information on their utilization, barriers, and health outcomes in Latin America is limited. As a result, this work aimed at exploring current use, opinions, and perceived obstacles on PGx testing among psychiatrists in Chile, via an online, anonymous survey. Among 123 respondents (5.9% of registered psychiatrists in the country), 16.3% reported ever requesting a PGx test. The vast majority (95%) of tests were ordered by clinicians practicing in the Metropolitan Region of Santiago. Having more than 20 years in practice was positively associated with prior use of PGx (p 0.02, OR 3.74 (1.19–11.80)), while working in the public health system was negatively associated (OR 0.30 (0.10–0.83)). Perceived barriers to local implementation included insufficient evidence of clinical utility, limited clinicians’ knowledge on PGx and on test availability, and health systems’ issues, such as costs and reimbursement. Despite the recognition of these barriers, 80% of respondents asserted that it is likely that they will incorporate PGx tests in their practice in the next five years. Given these results, we propose next steps to facilitate implementation such as further research in health outcomes and clinical utility of known and novel clinically actionable variants, growth in local sequencing capabilities, education of clinicians, incorporation of clinical decision support tools, and economic evaluations, all in local context.

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Publication

Somatic Mosaicism for Paternal Uniparental Disomy of 11p15.5 Region in Adrenal and Liver Tissues in a Newborn with Atypical Beckwith–Wiedemann Syndrome

2019 , Abraham Urzua , Sofia Burattini , Constanza Pinochet , BENAVIDES GONZALEZ, FELIPE ORLANDO , REPETTO LISBOA, MARIA GABRIELA

AbstractBeckwith–Wiedemann syndrome (BWS) is characterized by overgrowth and increased risk of embryonic tumors. It results from alterations in genes controlled by imprinting centers H19DMR (Imprinting Center [IC] 1) and KvDMR (IC2). Strategies for diagnostic confirmation include methylation analysis and CDKN1C sequencing. We present a newborn with placentomegaly, hyperinsulinism and adrenal cytomegaly, but no typical external features of BWS. The patient had normal genetic studies in blood. However, adrenal and liver tissues showed hypermethylation of IC1 and hypomethylation of IC2. Microsatellite analysis confirmed mosaic paternal uniparental disomy. This study demonstrates the importance of analyzing additional tissues to reduce underdiagnosis of somatic mosaicism in BWS.

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Publication

Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects

2018 , Yingjie Zhao , Tingwei Guo , Ania Fiksinski , Elemi Breetvelt , Donna M. McDonald-McGinn , Terrence B. Crowley , Alexander Diacou , Maude Schneider , Stephan Eliez , Ann Swillen , Jeroen Breckpot , Joris Vermeesch , Eva W. C. Chow , Doron Gothelf , Sasja Duijff , Rens Evers , Thérèse A. van Amelsvoort , Marianne van den Bree , Michael Owen , Maria Niarchou , Carrie E. Bearden , Claudia Ornstein , Maria Pontillo , Antonino Buzzanca , Stefano Vicari , Marco Armando , Kieran C. Murphy , Clodagh Murphy , Sixto Garcia-Minaur , Nicole Philip , Linda Campbell , Jaume Morey-Cañellas , Jasna Raventos , Jordi Rosell , Damian Heine-Suner , Robert J. Shprintzen , Raquel E. Gur , Elaine Zackai , Beverly S. Emanuel , Tao Wang , Wendy R. Kates , Anne S. Bassett , Jacob A. S. Vorstman , Bernice E. Morrow , REPETTO LISBOA, MARIA GABRIELA

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Publication

Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome

2020 , Robert W. Davies , Ania M. Fiksinski , Elemi J. Breetvelt , Nigel M. Williams , Stephen R. Hooper , Thomas Monfeuga , Anne S. Bassett , Michael J. Owen , Raquel E. Gur , Bernice E. Morrow , Donna M. McDonald-McGinn , Ann Swillen , Eva W. C. Chow , Marianne van den Bree , Beverly S. Emanuel , Joris R. Vermeesch , Therese van Amelsvoort , Celso Arango , Marco Armando , Linda E. Campbell , Joseph F. Cubells , Stephan Eliez , Sixto Garcia-Minaur , Doron Gothelf , Wendy R. Kates , Kieran C. Murphy , Clodagh M. Murphy , Declan G. Murphy , Nicole Philip , REPETTO LISBOA, MARIA GABRIELA , Vandana Shashi , Tony J. Simon , Damiàn Heine Suñer , Stefano Vicari , Stephen W. Scherer , Carrie E. Bearden , Jacob A. S. Vorstman

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