DSpace Repository :: Browsing by Author "Repetto, Gabriela"

Browsing by Author "Repetto, Gabriela"

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A normative chart for cognitive development in a genetically selected population
(2021) Fiksinski, Ania; Bearden, Carrie; Bassett, Anne; Kahn, René; Zinkstok, Janneke; Hooper, Stephen R; Tempelaar, Wanda; McDonald, Donna; Swillen, Ann; Emanuel, Beverly; Morrow, Bernice; Gur, Raquel; Chow, Eva; Van den Bree, Marianne; Vermeesch, Joris; Warren, Stephen; Owen, Michael; Van Amelsvoort, Therese; Eliez, Stephan; Gothelf, Doron; Arango, Celso; Kates, Wendy; Simon, Tony; Murphy, Kieran; Repetto, Gabriela; Heine, Damian; Vicari, Stefano; Cubells, Joseph; Armando, Marco; Philip, Nicole; Campbell, Linda; García, Sixto; Schneider, Maude; Shashi, Vandana; 22q11DS International Consortium on Brain and Behavior; Vorstman, Jacob; Breetvelt, Elemi
Certain pathogenic genetic variants impact neurodevelopment and cause deviations from typical cognitive trajectories. Understanding variant-specific cognitive trajectories is clinically important for informed monitoring and identifying patients at risk for comorbid conditions. Here, we demonstrate a variant-specific normative chart for cognitive development for individuals with 22q11.2 deletion syndrome (22q11DS). We used IQ data from 1365 individuals with 22q11DS to construct variant-specific normative charts for cognitive development (Full Scale, Verbal, and Performance IQ). This allowed us to calculate Z-scores for each IQ datapoint. Then, we calculated the change between first and last available IQ assessments (delta Z-IQ-scores) for each individual with longitudinal IQ data (n = 708). We subsequently investigated whether using the variant-specific IQ-Z-scores would decrease required sample size to detect an effect with schizophrenia risk, as compared to standard IQ-scores. The mean Z-IQ-scores for FSIQ, VIQ, and PIQ were close to 0, indicating that participants had IQ-scores as predicted by the normative chart. The mean delta-Z-IQ-scores were equally close to 0, demonstrating a good fit of the normative chart and indicating that, as a group, individuals with 22q11DS show a decline in IQ-scores as they grow into adulthood. Using variant-specific IQ-Z-scores resulted in 30% decrease of required sample size, as compared to the standard IQ-based approach, to detect the association between IQ-decline and schizophrenia (p < 0.01). Our findings suggest that using variant-specific normative IQ data significantly reduces required sample size in a research context, and may facilitate a more clinically informative interpretation of IQ data. This approach allows identification of individuals that deviate from their expected, variant-specific, trajectory. This group may be at increased risk for comorbid conditions, such as schizophrenia in the case of 22q11DS.
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.
Abnormal nodal and global network organization in resting state functional MRI from subjects with the 22q11 deletion syndrome
(2021) Pelgrim, Teuntje A.D.; Bosson, Matthijs G.; Cuiza, Analía; Alliende, Luz María; Mena, Carlos; Tepper, Angeles; Ramirez‑Mahaluf, Juan Pablo; Iruretagoyena, Bárbara; Ornstein, Claudia; Fritsch, Rosemarie; Cruz, Juan Pablo; Tejos, Cristian; Repetto, Gabriela; Crossley, Nicolás
The 22q11 deletion syndrome is a genetic disorder associated with a high risk of developing psychosis, and is therefore considered a neurodevelopmental model for studying the pathogenesis of schizophrenia. Studies have shown that localized abnormal functional brain connectivity is present in 22q11 deletion syndrome like in schizophrenia. However, it is less clear whether these abnormal cortical interactions lead to global or regional network disorganization as seen in schizophrenia. We analyzed from a graph-theory perspective fMRI data from 40 22q11 deletion syndrome patients and 67 healthy controls, and reconstructed functional networks from 105 brain regions. Between-group differences were examined by evaluating edge-wise strength and graph theoretical metrics of local (weighted degree, nodal efficiency, nodal local efficiency) and global topological properties (modularity, local and global efficiency). Connectivity strength was globally reduced in patients, driven by a large network comprising 147 reduced connections. The 22q11 deletion syndrome network presented with abnormal local topological properties, with decreased local efficiency and reductions in weighted degree particularly in hub nodes. We found evidence for abnormal integration but intact segregation of the 22q11 deletion syndrome network. Results suggest that 22q11 deletion syndrome patients present with similar aberrant local network organization as seen in schizophrenia, and this network configuration might represent a vulnerability factor to psychosis.
Accuracy of a Genetic Test for the Diagnosis of Hypolactasia in Chilean Children: Comparison With the Breath Test.
(Philadelphia, PA : Lippincott Williams & Wilkins, 2016) Alliende, Francisco; Vial, Cecilia; Espinoza, Karen; Schnettle, Daniela; Romero, Victoria; Miquel, Isabel; Arancibia, María Eugenia; Ríos, Gloria; Rodríguez, Lorena; Quesada, Soledad; Lucero, Yalda; Repetto, Gabriela
BACKGROUND: Lactase nonpersistence (LNP) in humans is a genetically determined trait. This age-dependent decrease of lactase expression is most frequently caused by single nucleotide polymorphisms in the regulatory region of the lactase (LCT) gene. The homozygous LCT-13,910C/C genotype (rs 4988235) predominates in Caucasian adults with LNP, and is useful for its diagnosis in this population. The accuracy of this genetic test (GT) has not been completely established in children or in a Latin-American population. OBJECTIVES: The aim of the study was to determine diagnostic accuracy of GT for LNP in Chilean children using the lactose breath test (BT) as a reference, and to compare diagnostic yield in preschool- (<6 years) and in school-age (≥6 years) children. METHODS: Children referred for BT for diagnosis of lactose malabsorption to the Gastroenterology Laboratory at Clínica Alemana, Santiago, from October 2011 to March 2012 were invited to participate. After informed consent, symptom questionnaires, both historic and post lactose ingestion were completed. H2 and CH4 in expired air and -13,910 C>T single nucleotide polymorphism by polymerase chain reaction, restriction enzyme analysis, and/or Sanger sequencing were determined. GT accuracy was calculated compared to BT as reference method. Diagnostic yield of GT in preschool- and school-age children was compared. RESULTS: Lactose malabsorption was detected by BT in 42 of 60 children (70%). Genotype -13,910C/C was identified in 41 of 60 patients (68%). GT showed 80% sensitivity, 63% specificity, and 74% accuracy for LNP in the preschool population. In school-age children values were higher, 85%, 80%, and 84%, respectively. CONCLUSIONS: GT results were significantly concordant with BT results for hypolactasia detection in Chilean children, particularly in those of age 6 years and older.
Alta prevalencia de hernias abdominales en pacientes con síndrome velocardiofacial
(2012) justiniano D., José Andrés; Guzmán G., María Luisa; Astete A., Carmen Paz; Aravena C., Teresa; Arriaza Z., Marta; Aracena A., Mariana; Repetto, Gabriela
El síndrome velocardiofacial (SVCF) se debe a una microdeleción en la región cromosómica 22q11.2. Clínicamente, se caracteriza por anomalías congénitas y manifestaciones siquiátricas y cognitivas. Entre las malformaciones más comunes, están las cardiopatías congénitas y anomalías palatinas, por defectos en el desarrollo de las bolsas faríngeas. Otra manifestación menos estudiada son las hernias de la pared abdominal. Objetivo: Caracterizar la frecuencia y tipos de hernias en pacientes con SVCF y su asociación con cardiopatías congénitas y anomalías del paladar. Pacientes y Método: Evaluamos 202 pacientes mediante un examen clínico directo y un cuestionario sobre sus características fenotípicas. Comparamos los resultados con la información de la literatura. Resultados: El rango de edad fue de 0,5 a 48,4 años (media de 11,9 años), 50,4% de sexo femenino. El 22% de los pacientes presentó hernias de la pared abdominal. De estas, el 49,1% fueron inguinales y el 40,3%, umbilicales. La frecuencia de hernias en los pacientes con SVCF es significativamente mayor que la descrita para la población general, aproximadamente un 5%. Esta es una manifestación común del síndrome, que no es atribuible a defectos del desarrollo de las bolsas faríngeas y cuya patogenia no ha sido definida.
Analysis of REM sleep without atonia in 22q11.2 deletion syndrome determined by domiciliary polysomnography: a cross sectional study
(2022) Mauro, Jorge; Díaz, Mario; Córdova, Teresa; Villanueva, Katiuska; Cáceres, Tania; Bassi, Alejandro; Fritsch, Rosemarie; Repetto, Gabriela; Ocampo, Adrián
Study objectives: Our aim is to evaluate the presence of REM sleep without atonia (RWA), the objective hallmark of REM sleep Behaviour Disorder (RBD), as prodromal marker of Parkinson's disease (PD), in an adult cohort of 22q11.2 deletion syndrome (22qDS). Methods: Sleep quality was assessed by means of Pittsburgh quality scale index (PSQI), and RBD symptoms by means of RBD questionnaire-Hong-Kong (RBDQ-HK). Attended domiciliary video-Polysomnography (v-PSG) were performed in 26 adults (18-51 years, 14 females) 22qDS patients. Electromyogram during REM sleep was analyzed by means of SINBAR procedure at 3-second time resolution (miniepochs). Results: An overall poor sleep quality was observed in the cohort and high RBDQ-HK score in 7 of the 26 patients, two additional patients with positive dream enactment reported by close relatives had low score of RBDQ-HK. Nevertheless, SINBAR RWA scores were lower than cut-off threshold for RWA (mean 5.5%, range 0-12.2%). TST and the percentage of light sleep (N1) were increased, with preserved proportions of N2 and N3. Participants reported poor quality of sleep (mean PSQI > 5), with prolonged sleep latency in the v-PSG. No subjects exhibit evident dream enactment episodes during recording sessions. Conclusions: RWA was absent in the studied cohort of 22qDS adult volunteers according to validated polysomnographic criteria. High RBDQ-HK scores do not correlate with v-PSG results among 22qDS individuals.
Angiotensin-converting enzyme insertion/deletion polymorphism is associated with severe hypoxemia in pediatric ARDS
(Springer, 2012) Cruces, Pablo; Puga, Alonso; Erranz, Benjamín; Donoso, Alejandro; Carvajal, Cristobal; Wilhelm, Jan; Repetto, Gabriela
PURPOSE: The D allele of the insertion/deletion (I/D) polymorphism of a 287-bp sequence in the angiotensin-converting enzyme (ACE) gene has been associated with an increased activity of this enzyme. Its role in susceptibility to acute respiratory distress syndrome (ARDS) has not been well defined. We hypothesized that ACE I/D genotype in pediatrics is associated with ARDS and plasma levels of angiotensin II. METHODS: Prospective case-control study in patients under 15 years of age from a mixed Chilean population. Sixty patients with ARDS and 60 controls were included. Association between ACE genotype and ARDS was evaluated as the primary outcome; mortality and severe hypoxemia were examined as secondary outcomes. Plasma angiotensin-II concentration was measured by immunoassay at admission. RESULTS: Frequency of ACE I/D genotype was similar in ARDS and control groups (p = 0.18). In the ARDS group, severe hypoxemia was less frequent in D allele carriers (p < 0.05). Plasma angiotensin-II levels were associated with genotype in the ARDS group, but not controls, being higher in D allele carriers (p = 0.016). CONCLUSION: These data do not support the association between ACE I/D genotype and ARDS, although severe hypoxemia was less frequent in D allele carriers. ACE I/D polymorphism modified angiotensin-II levels in pediatric ARDS, but its pathogenic role is not well understood and needs to be addressed in future studies.
Association between phenotype and deletion size in 22q11.2 microdeletion syndrome: systematic review and meta-analysis
(2019) Rozas, M. Fernanda; Benavides, Felipe; León, Luis; Repetto, Gabriela
Background: Chromosome 22q11.2 microdeletion syndrome, a disorder caused by heterozygous loss of genetic material in chromosome region 22q11.2, has a broad range of clinical symptoms. The most common congenital anomalies involve the palate in 80% of patients, and the heart in 50–60% of them. The cause of the phenotypic variability is unknown. Patients usually harbor one of three common deletions sizes: 3, 2 and 1.5 Mb, between low copy repeats (LCR) designated A-D, A-C and A-B, respectively. This study aimed to analyze the association between these 3 deletion sizes and the presence of congenital cardiac and/or palatal malformations in individuals with this condition. A systematic review and meta-analysis were conducted, merging relevant published studies with data from Chilean patients to increase statistical power. Results: Eight articles out of 432 were included; the data from these studies was merged with our own, achieving a total of 1514 and 487 patients to evaluate cardiac and palate malformations, respectively. None of the compared deleted chromosomal segments were statistically associated with cardiac defects (ORAB v/s AC-AD: 0.654 [0.408–1.046]; OR AD v/s AB-AC: 1.291 [0.860–1.939]) or palate anomalies (ORAB v/s AC-AD: 1.731 [0.708–4.234]; OR AD v/s AB-AC: 0.628 [0.286–1.382]). Conclusions: The lack of association between deletion size and CHD or PA found in this meta-analysis suggests that deletion size does not explain the incomplete penetrance of these 2 major manifestations, and that the critical region for the development of heart and palatal abnormalities is within LCR A-B, the smallest region of overlap among the three deletion sizes.
Barriers and Considerations for Diagnosing Rare Diseases in Indigenous Populations
(2020-12) D'Angelo, Carla S.; Hermes, Azure; McMaster, Christopher R.; Prichep, Elissa; Richer, Etienne; Van der Westhuizen, Francois H.; Repetto, Gabriela; Mengchun, Gong; Malherbe, Helen; Reichardt, Juergen K.V.; Arbour, Laura; Hudson, Maui; Plessis, Kelly du; Haendel, Melissa; Wilcox, Phillip; Lynch, Sally Ann; Rind, Shamir; Easteal, Simon; Estivill, Xavier; Thomas, Yarlalu; Baynam, Gareth
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.
Case fatality rate and associated factors in patients with 22q11 microdeletion syndrome: a retrospective cohort study
(BMJ Publishing Group, 2014) Repetto, Gabriela; Guzmán, Maria Luisa; Delgado, Iris; Loyola, Hugo; Palomares, Mirta; Lay-Son, Guillermo; Vial, Cecilia; Benavides, Felipe; Espinoza, Karena; Alvarez, Patricia
OBJECTIVE: Chromosome 22q11.2 deletion is the most commonly occurring known microdeletion syndrome. Deaths related to the syndrome have been reported, but the magnitude of death has not been quantified. This study evaluated the deletion's impact on survival and its clinical manifestations in a large cohort of Chilean patients. DESIGN: Demographic and clinical data of individuals with 22q11 deletions diagnosed between 1998 and 2013 were collected from medical records and death certificates. Case fatality rate was calculated and compared with national vital statistics. OR with 95% CI analysis was used to assess the association between clinical manifestations and death. SETTING: Genetic services in tertiary care centres in Chile, following patients with 22q11.2 deletion. OUTCOMES: Fatality rate and associated factors. RESULTS: 59 of 419 patients (14.1%) died during the study period at a median of 3.4 months (range 0 to 32 years of age). Factors associated with death included congenital heart disease (OR 5.27; 95% CI 2.06 to 13.99; p<0.0001), hypocalcaemia (OR 4.27; 95% CI 1.67 to 11.15; p<0.002) and airway malacia (OR 13.37; 95% CI 1.19 to 110.51; p<0.002). Patients with deletions and defects such as tetralogy of Fallot with or without pulmonary atraesia, truncus arteriosus or ventricular septal defect, had a 2.6-fold to 4.6-fold higher death rate compared with nationwide reports for the same types of defects. CONCLUSIONS: In this cohort, we observed a death rate of 14.1%, implying that one in seven patients with 22q11 deletion died during the study period. Significant associations with cardiac defects, hypocalcaemia and airway malacia were observed. Furthermore, the death risk in patients with 22q11 deletion and cardiac defects exceeded the global figures observed in Chile for infants with structurally similar but apparently isolated anomalies. These observations indicate a need to identify patients who may require specific perioperative management to improve survival.
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.
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
Chromosomal microarrays testing in children with developmental disabilities and congenital anomalies
(Sociedad Brasileira de Pediatria with Elsevier, 2015) Lay-Son, Guillermo; Espinoza, Karena; Vial, Cecilia; Rivera, Juan; Guzmán, María; Repetto, Gabriela
Objectives Clinical use of microarray-based techniques for the analysis of many developmental disorders has emerged during the last decade. Thus, chromosomal microarray has been positioned as a first-tier test. This study reports the first experience in a Chilean cohort. Methods Chilean patients with developmental disabilities and congenital anomalies were studied with a high-density microarray (CytoScan™ HD Array, Affymetrix, Inc., Santa Clara, CA, USA). Patients had previous cytogenetic studies with either a normal result or a poorly characterized anomaly. Results This study tested 40 patients selected by two or more criteria, including: major congenital anomalies, facial dysmorphism, developmental delay, and intellectual disability. Copy number variants (CNVs) were found in 72.5% of patients, while a pathogenic CNV was found in 25% of patients and a CNV of uncertain clinical significance was found in 2.5% of patients. Conclusion Chromosomal microarray analysis is a useful and powerful tool for diagnosis of developmental diseases, by allowing accurate diagnosis, improving the diagnosis rate, and discovering new etiologies. The higher cost is a limitation for widespread use in this setting.
Cleft Palate, Interdisciplinary Diagnosis, and Treatment
(2015) Ysunza, Pablo Antonio; Pamplona, María Carmen; Repetto, Gabriela
Cleft lip and palate is the 4th most common congenital malformation and the 1st most common craniofacial anomaly. The incidence of cleft lip and palate varies from 1 per 750 live births to 1 per 650 live births depending on the geographical area. Cleft palate is a feature of over 200 well defined syndromes of congenital malformations. Although at the present time it is still not feasible to completely prevent the occurrence of cleft palate, the consequences of this major malformation on maxillary structure, esthetic appearance, speech, feeding, and swallowing can be appropriately addressed and corrected by the intervention of an interdisciplinary team.
Clinical, neuroimaging, and molecular spectrum of TECPR2‐associated hereditary sensory and autonomic neuropathy with intellectual disability
(2021) Neuser, Sonja; Brechmann, Barbara; Heimer, Gali; Brösse, Ines; Schubert, Susanna; O'Grady, Lauren; Zech, Michael; Srivastava, Siddharth; Sweetser, David A.; Dincer, Yasemin; Mall, Volker; Winkelmann, Juliane; Behrends, Christian; Darras, Basil T.; Graham, Robert J.; Jayakar, Parul; Byrne, Barry; Bar‐Aluma, Bat El; Haberman, Yael; Szeinberg, Amir; Aldhalaan, Hesham M.; Hashem, Mais; Tenaiji, Amal Al; Ismayl, Omar; Al Nuaimi, Asma E.; Maher, Karima; Ibrahim, Shahnaz; Khan, Fatima; Houlden, Henry; Ramakumaran, Vijayalakshmi S.; Pagnamenta, Alistair T.; Posey, Jennifer E.; Lupski, James R.; Tan, Wen‐Hann; ElGhazali, Gehad; Herman, Isabella; Muñoz, Tatiana; Repetto, Gabriela; Seitz, Angelika; Krumbiegel, Mandy; Poli, Cecilia; Kini, Usha; Efthymiou, Stephanie; Meiler, Jens; Maroofian, Reza; Alkuraya, Fowzan S.; Jamra, Rami Abou; Popp, Bernt; Ben‐Zeev, Bruria; Ebrahimi‐Fakhari, Darius
Bi‐allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi‐allelic TECPR2‐variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross‐ sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N‐ and C‐terminal regions containing β‐propeller repeats. Despite constituting nearly half of disease‐associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging, and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/ treatment of individuals with TECPR2‐associated disorder. This sets the stage for future prospective natural history studies.
Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects
(American Society of Human Genetics by Elsevier Inc., 2020-01) Zhao, Yingjie; Diacou, Alexander; Johnston, Richard; Musfee, Fadi; McDonald-McGinn, Donna; McGinn, Daniel; Crowley, Blaine; Repetto, Gabriela; Swillen, Ann; Breckpot, Jeroen; Vermeesch, Joris; Kates, Wendy; Digilio, Cristina; Unolt, Marta; Marino, Bruno; Pontillo, Maria; Armando, Marco; Di Fabio, Fabio; Vicari, Stefano; van den Bree, Marianne; Moss, Hayley; Owen, Michael; Murphy, Kieran; Murphy, Clodagh; Murphy, Declan; Schoch, Kelly; Shashi, Vandana; Tassone, Flora
The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.
Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects
(2020) Zhao, Yingjie; Diacou, Alexander; Johnston, H. Richard; Musfee, Fadi I; McDonald-McGinn, Donna M.; McGinn, Daniel; Crowley, T. Blaine; Repetto, Gabriela; Swillen, Ann; Breckpot, Jeroen; Vermeesch, Joris R; Kates, Wendy R.; Digilio, M. Cristina; Unolt, Marta; Marino, Bruno; Pontillo, Maria; Armando, Marco; Di Fabio, Fabio; Vicari, Stefano; Bree, Marianne van den; Moss, Hayley; Owen, Michael J.; Murphy, Kieran C.; Murphy, Clodagh M.; Murphy, Declan; Schoch, Kelly; Shashi, Vandana; Tassone, Flora; Simon, Tony J.; Shprintzen, Robert J.; Campbell, Linda; Philip, Nicole; Heine-Suñer, Damian; García-Miñaúr, Sixto; Fernández, Luis; Bearden, Carrie E.; Vingerhoets, Claudia; Amelsvoort, Therese van; Eliez, Stephan; Schneider, Maude; Vorstman, Jacob A. S.; Gothelf, Doron; Zackai, Elaine; Agopian, A. J.; Gur, Raquel E.; Bassett, Anne S.; Emanuel, Beverly S.; Goldmuntz, Elizabeth; Mitchell, Laura E.; Wang, Tao; Morrow, Bernice E.
The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.
Consenso chileno para la atención integral de niños y adultos con fibrosis Quística
(2020) Navarro D., Elizabeth; Parra O., Genoveva; Pavez A., Daniela; Pérez O., María Eugenia; Pinochet N., María José; Repetto, Gabriela; Slaibe C., Lisset; Soto B., Julio; Vega M., Adriana; Wong L., Carolina
La Fibrosis Quística (FQ) es la enfermedad hereditaria de pronóstico reservado más frecuente en raza blanca. Desde el año 2003, Chile inicia un Programa Nacional de Fibrosis Quística, de carácter integral, dirigido por la Unidad de Salud Respiratoria del Ministerio de Salud. Hasta la fecha, los principales resultados del Programa registran una significativa mayor sobrevida (promedio 27 años) y una significativa reducción en la edad de diagnóstico de los pacientes ingresados desde 2006 en adelante. El acceso a la canasta GES (Garantías Explícitas en Salud), la implementación del tamizaje neonatal en algunas regiones del país, la organización y la constitución de equipos entrenados en FQ de diversas especialidades, ha contribuido a mejorar los resultados. Si bien las principales manifestaciones son del aparato respiratorio y digestivo, el carácter multisistémico de la FQ obliga a conocer los distintos aspectos involucrados en su manejo, a fin de optimizar los resultados del tratamiento y los recursos invertidos, tanto en el sector público como privado. Este documento es una revisión y actualización sobre los principales aspectos del diagnóstico, seguimiento y tratamiento de las manifestaciones respiratorias y no respiratorias de la FQ.
Contribution of Mitochondrial DNA Heteroplasmy to the Congenital Cardiac and Palatal Phenotypic Variability in Maternally Transmitted 22q11.2 Deletion Syndrome
(2021) Rebolledo-Jaramillo, Boris; Huckstadt, Victoria; Gómez, Abel; Repetto, Gabriela; Obregón, María 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.
Current Controversies in Diagnosis and Management of Cleft Palate and Velopharyngeal Insufficiency.
(2015 Pablo Antonio Ysunza et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., 2015) Ysunza, Pablo; Repetto, Gabriela; Pamplona, María; Calderón, Juan Francisco; Shaheen, Kenneth; Chaiyasate, Konkgrit; Rontal, Matthew
Abstract BACKGROUND: One of the most controversial topics concerning cleft palate is the diagnosis and treatment of velopharyngeal insufficiency (VPI). OBJECTIVE: This paper reviews current genetic aspects of cleft palate, imaging diagnosis of VPI, the planning of operations for restoring velopharyngeal function during speech, and strategies for speech pathology treatment of articulation disorders in patients with cleft palate. MATERIALS AND METHODS: An updated review of the scientific literature concerning genetic aspects of cleft palate was carried out. Current strategies for assessing and treating articulation disorders associated with cleft palate were analyzed. Imaging procedures for assessing velopharyngeal closure during speech were reviewed, including a recent method for performing intraoperative videonasopharyngoscopy. RESULTS: Conclusions from the analysis of genetic aspects of syndromic and nonsyndromic cleft palate and their use in its diagnosis and management are presented. Strategies for classifying and treating articulation disorders in patients with cleft palate are presented. Preliminary results of the use of multiplanar videofluoroscopy as an outpatient procedure and intraoperative endoscopy for the planning of operations which aimed to correct VPI are presented. CONCLUSION: This paper presents current aspects of the diagnosis and management of patients with cleft palate and VPI including 3 main aspects: genetics and genomics, speech pathology and imaging diagnosis, and surgical management.

Browsing by Author "Repetto, Gabriela"

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