Browsing by Author "Mencacci, Niccolò E."

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    International Genetic Testing and Counseling Practices for Parkinson's Disease
    (Wiley, 2023) Saunders-Pullman, Rachel; Raymond, Deborah; Ortega, Roberto A.; Shalash, Ali; Gatto, Emilia; Salari, Mehri; Markgraf, Maggie; Alcalay, Roy N.; Mascalzoni, Deborah; Mencacci, Niccolò E.; Bonifati, Vincenzo; Merello, Marcelo; Chung, Sun Ju; Novakovic, Ivana; Bardien, Soraya; Pal, Gian; Hall, Anne; Hattori, Nobutaka; Lynch, Timothy; Thaler, Avner; Sue, Carolyn M.; Foroud, Tatiana; Verbrugge, Jennifer; Schulze, Jeanine; Cook, Lola; Marder, Karen; Suchowersky, Oksana; Klein, Christine; Simuni, Tatyana; Medical and Molecular Genetics, School of Medicine
    Background: There is growing clinical and research utilization of genetic testing in Parkinson's disease (PD), including direct-to-consumer testing. Objectives: The aim is to determine the international landscape of genetic testing in PD to inform future worldwide recommendations. Methods: A web-based survey assessing current practices, concerns, and barriers to genetic testing and counseling was administered to the International Parkinson and Movement Disorders Society membership. Results: Common hurdles across sites included cost and access to genetic testing, and counseling, as well as education on genetic counseling. Region-dependent differences in access to and availability of testing and counseling were most notable in Africa. High-income countries also demonstrated heterogeneity, with European nations more likely to have genetic testing covered through insurance than Pan-American and Asian countries. Conclusions: This survey highlights not only diversity of barriers in different regions but also the shared and highly actionable needs for improved education and access to genetic counseling and testing for PD worldwide. © 2023 International Parkinson and Movement Disorder Society.
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    MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia
    (Wiley, 2021) Meng, Linyan; Isohanni, Pirjo; Shao, Yunru; Graham, Brett H.; Hickey, Scott E.; Brooks, Stephanie; Suomalainen, Anu; Joset, Pascal; Steindl, Katharina; Rauch, Anita; Hackenberg, Annette; High, Frances A.; Armstrong-Javors, Amy; Mencacci, Niccolò E.; Gonzàlez-Latapi, Paulina; Kamel, Walaa A.; Al-Hashel, Jasem Y.; Bustos, Bernabé I.; Hernandez, Alejandro V.; Krainc, Dimitri; Lubbe, Steven J.; Van Esch, Hilde; De Luca, Chiara; Ballon, Katleen; Ravelli, Claudia; Burglen, Lydie; Qebibo, Leila; Calame, Daniel G.; Mitani, Tadahiro; Marafi, Dana; Pehlivan, Davut; Saadi, Nebal W.; Sahin, Yavuz; Maroofian, Reza; Efthymiou, Stephanie; Houlden, Henry; Maqbool, Shazia; Rahman, Fatima; Gu, Shen; Posey, Jennifer E.; Lupski, James R.; Hunter, Jill V.; Wangler, Michael F.; Carroll, Christopher J.; Yang, Yaping; Medical and Molecular Genetics, School of Medicine
    The Mediator multiprotein complex functions as a regulator of RNA polymerase II-catalyzed gene transcription. In this study, exome sequencing detected biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome. Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia. Seizures and cataracts were noted in severely affected individuals. Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum.
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    Parkinson's disease variant detection and disclosure: PD GENEration, a North American study
    (Oxford University Press, 2024) Cook, Lola; Verbrugge, Jennifer; Schwantes-An, Tae-Hwi; Schulze, Jeanine; Foroud, Tatiana; Hall, Anne; Marder, Karen S.; Mata, Ignacio F.; Mencacci, Niccolò E.; Nance, Martha A.; Schwarzschild, Michael A.; Simuni, Tanya; Bressman, Susan; Wills, Anne-Marie; Fernandez, Hubert H.; Litvan, Irene; Lyons, Kelly E.; Shill, Holly A.; Singer, Carlos; Tropea, Thomas F.; Vanegas Arroyave, Nora; Carbonell, Janfreisy; Cruz Vicioso, Rossy; Katus, Linn; Quinn, Joseph F.; Hodges, Priscila D.; Meng, Yan; Strom, Samuel P.; Blauwendraat, Cornelis; Lohmann, Katja; Casaceli, Cynthia; Rao, Shilpa C.; Ghosh Galvelis, Kamalini; Naito, Anna; Beck, James C.; Alcalay, Roy N.; Medical and Molecular Genetics, School of Medicine
    Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinson's disease; however, individuals with Parkinson's disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinson's disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinson's disease. PD GENEration is an ongoing multi-centre, observational study (NCT04057794, NCT04994015) offering genetic testing with results disclosure and genetic counselling to those in the US (including Puerto Rico), Canada and the Dominican Republic, through local clinical sites or remotely through self-enrolment. DNA samples are analysed by next-generation sequencing including deletion/duplication analysis (Fulgent Genetics) with targeted testing of seven major Parkinson's disease-related genes. Variants classified as pathogenic/likely pathogenic/risk variants are disclosed to all tested participants by either neurologists or genetic counsellors. Demographic and clinical features are collected at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59% male; 86% White, 2% Asian, 4% Black/African American, 9% Hispanic/Latino; mean age 67.4 ± 10.8 years. Reportable genetic variants were observed in 13% of all participants, including 18% of participants with one or more 'high risk factors' for a genetic aetiology: early onset (<50 years), high-risk ancestry (Ashkenazi Jewish/Basque/North African Berber), an affected first-degree relative; and, importantly, in 9.1% of people with none of these risk factors. Reportable variants in GBA1 were identified in 7.7% of all participants; 2.4% in LRRK2; 2.1% in PRKN; 0.1% in SNCA; and 0.2% in PINK1, PARK7 or VPS35 combined. Variants in more than one of the seven genes were identified in 0.4% of participants. Approximately 13% of study participants had a reportable genetic variant, with a 9% yield in people with no high-risk factors. This supports the promotion of universal access to genetic testing for Parkinson's disease, as well as therapeutic trials for GBA1 and LRRK2-related Parkinson's disease.