SOLVING THE UNSOLVED: AN INTERDISCIPLINARY EVALUATION OF PERSONAL, SOCIAL AND HEALTH SYSTEM EFFECTS OF THE USE OF GENOMIC STRATEGIES FOR RARE UNDIAGNOSED DISORDERS

Project Title

Partner Organisations

Facultad de Medicina Clínica Alemana Universidad del Desarrollo

Internal ID

1211411

Principal Investigator

REPETTO LISBOA, MARIA GABRIELA

Start Date

2021

Publications

Now showing 1 - 9 of 9

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<i>PUF60</i>‐related developmental disorder: A case series and phenotypic analysis of 10 additional patients with monoallelic <i>PUF60</i> variants
(2023)
H. Grimes
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M. Ansari
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T. Ashraf
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Anna Mª. Cueto‐González
;
A. Calder
<jats:title>Abstract</jats:title><jats:p><jats:italic>PUF60</jats:italic>‐related developmental disorder (also referred to as Verheij syndrome), resulting from haploinsufficiency of <jats:italic>PUF60</jats:italic>, 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 <jats:italic>PUF60</jats:italic>‐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 <jats:italic>PUF60</jats:italic> 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 <jats:italic>PUF60</jats:italic> 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 <jats:italic>PUF60</jats:italic>‐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 <jats:italic>PUF60</jats:italic>‐related developmental disorder with a low threshold for endocrine investigations as hormone therapy may be indicated. Our study reports an inherited case with <jats:italic>PUF60</jats:italic>‐related developmental disorder which has important genetic counseling implications for families.</jats:p>
Scopus© Citations 5 1
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Enfermedades raras y trayectorias terapéuticas de pacientes: ¿qué sabemos hoy?
(Universidad de Chile, 2023-07-03)
CAMPAÑA, CARLA
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CABIESES VALDES, BALTICA BEATRIZ
<jats:p>Antecedentes y objetivos: Las enfermedades raras (ER) son un grupo de trastornos muy heterogéneos, definidos según su incidencia. Dada sus características singulares, las experiencias del paciente y la familia con ER son únicas. La investigación sobre trayectorias terapéuticas de pacientes (TTP) es importante para mejorar la atención médica, pero los estudios sobre TTP y ER son limitados. Nuestro objetivo fue desarrollar una síntesis narrativa de la evidencia científica para conocer la información disponible en la literatura sobre trayectorias terapéuticas de pacientes con enfermedades raras y contribuir como insumo a la creación de propuestas en el contexto del plan nacional y leyes específicas. Método(s) y resultados: Realizamos una revisión narrativa de literatura científica. La búsqueda se realizó en PubMed (2021), incluyendo estudios con TTP con ER, familiares o cuidadores, sin filtros. Identificamos seis temas principales en las TTP: diagnóstico, tratamiento, costo, calidad de vida, informante clave y aportes tecnológicos. Conclusiones: Los hallazgos sugieren que comprender las TTP podría ayudar a reconocer el tiempo efectivo para diagnósticos, tratamientos y capacidad de respuesta de los sistemas de salud. La perspectiva de pacientes y familias con ER debe incluirse como parte de la agenda de investigación y política.</jats:p>
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Source‐based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome
(2024)
Ruiyang Ge
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Christopher R. K. Ching
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Anne S. Bassett
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Leila Kushan
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Kevin M. Antshel
<jats:title>Abstract</jats:title><jats:p>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.</jats:p>
3Scopus© Citations 6
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Decoding complex inherited phenotypes in rare disorders: the DECIPHERD initiative for rare undiagnosed diseases in Chile
(2024)
POLI HARLOWE, MARIA CECILIA BERTA
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Boris Rebolledo-Jaramillo
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Víctor Faundes
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Catalina Lagos
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Joan Orellana
<jats:title>Abstract</jats:title><jats:p>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.</jats:p>
Scopus© Citations 13 6
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Discovery of novel genetic syndromes in Latin America: Opportunities and challenges
(2024)
Víctor Faundes
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REPETTO LISBOA, MARIA GABRIELA
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Leonardo E. Valdivia
Scopus© Citations 2 1
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Exome Sequencing Identifies Genetic Variants Associated with Extreme Manifestations of the Cardiovascular Phenotype in Marfan Syndrome
(2022)
Yanireth Jimenez
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Cesar Paulsen
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Eduardo Turner
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Sebastian Iturra
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Oscar Cuevas
<jats:p>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.</jats:p>
37Scopus© Citations 4
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Genomic analysis in Chilean patients with suspected Rett syndrome: keep a broad differential diagnosis
(2024)
Florencia Brito
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Catalina Lagos
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Jessica Cubillos
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Joan Orellana
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Mallen Gajardo
<jats:p><jats:bold>Introduction:</jats:bold> 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 <jats:italic>MECP2</jats:italic> 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.</jats:p><jats:p><jats:bold>Methods:</jats:bold> Twenty-eight patients with suspected RTT underwent characterization of phenotypic manifestations and molecular testing using Clinical Exome Solution<jats:sup>TM</jats:sup> CES_V2 by SOPHiA Genetics. Data was analyzed using the commercial bioinformatics platform, SOPHiA DDM<jats:sup>TM</jats:sup>. A virtual panel of 34 genes, including <jats:italic>MECP2</jats:italic> 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.</jats:p><jats:p><jats:bold>Results:</jats:bold> Twelve patients (42.8% of participants) had variants in <jats:italic>MECP2</jats:italic>, 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%) (<jats:italic>GRIN2B, MADD, TRPM3</jats:italic> and <jats:italic>ZEB2</jats:italic>) resulting in alternative neurodevelopmental diagnoses, and six were considered of uncertain significance. No evident candidate variant was found for eight patients.</jats:p><jats:p><jats:bold>Discussion:</jats:bold> 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, even more so since the development of novel therapies for RTT. We also show the feasibility of implementing a step-wide approach to genomic testing in a setting with limited resources.</jats:p>
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Challenges for gene therapy in the financial sustainability of health systems: a scoping review
(2024)
Hugo Ossandon
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Nicolás Armijo
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Constanza Vargas
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REPETTO LISBOA, MARIA GABRIELA
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Manuel Antonio Espinoza
<jats:title>Abstract</jats:title><jats:sec> <jats:title>Aim</jats:title> <jats:p>To review the available evidence about the strategies implemented or proposed for coverage or reimbursement for currently approved gene therapies.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusion</jats:title> <jats:p>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.</jats:p> </jats:sec>
Scopus© Citations 4 1
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Therapeutic trajectories of families with rare diseases in Chile from the perspectives of patients, carers, and healthcare workers: a qualitative study
(Springer Science and Business Media LLC, 2025-02-25)
CABIESES VALDES, BALTICA BEATRIZ
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OBACH KING, ALEXANDRA ALICE
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Antonia Roberts
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REPETTO LISBOA, MARIA GABRIELA
Background Rare diseases are conditions that have a low prevalence in the population and a high disease burden and are often chronic and progressive. International evidence concerning the experience of people and families living with rare diseases is scarce, leading to late and erroneous diagnoses, as well as non-specific treatments. This study explored the therapeutic trajectories of people and families living with rare diseases within Chile’s public and private healthcare systems from the perspective of patients, caregivers, and medical teams, including the initial symptoms, first consultation, testing, diagnosis, treatment, and follow-up. Methods A qualitative exploratory study was conducted through multiple case studies. Sixty participants were interviewed in person and/or virtually: patients (n = 16), caregivers (n = 22), healthcare workers (n = 20), and two patient organisation leaders. The material was analysed using thematic analysis. The project was approved by the Scientific Ethics Committee of Facultad de Medicina Clínica Alemana, Universidad del Desarrollo. Results After similar initial symptoms and first consultation, three main types of trajectories were identified: (i) the path taken by those who reach a diagnosis for a disease that has specific treatment available; (ii) the journey of those who reach a diagnosis for their health condition, but their disease does not have a specific treatment available; and (iii) the trajectory of those who have not reached a diagnosis and receive symptomatic treatments for symptoms. Conclusions The therapeutic trajectories of patients with rare symptoms are similar in terms of initial symptoms and first consultation. However, their paths diverge at the diagnostic stage, with diverse experiences related to these journeys, largely based on having a diagnosis and whether there is a specific treatment. Rare conditions in Chile requires further attention and urgent action that considers those who live with them and their families.
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