Browsing by Author "Posey, Jennifer E."
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Item 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, DariusBi‐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.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, GabrielaRare 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.