Peter Balicza1, Zoltan Grosz1, Michael A Gonzalez2, Renata Bencsik1, Klara Pentelenyi1, Aniko Gal1, Edina Varga3, Peter Klivenyi3, Julia Koller1, Stephan Züchner2, Judit Maria Molnar4. 1. Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Tömő Street 25-29, 1083 Budapest, Hungary. 2. Dr John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, 1501 NW 10 Ave, Miami, FL 33136, USA. 3. Department of Neurology, University of Szeged, Semmelweis street 6, 6720 Szeged, Hungary. 4. Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Tömő Street 25-29, 1083 Budapest, Hungary. Electronic address: molnar.mariajudit@med.semmelweis-univ.hu.
Abstract
BACKGROUND: Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases with progressive lower limb spasticity and weakness. The aim of this study is to determine the frequency of different SPG mutations in Hungarian patients, and to provide further genotype-phenotype correlations for the known HSP causing genes. METHODS: We carried out genetic testing for 58 probands with clinical characteristics of HSP. For historical reasons, three different approaches were followed in different patients: 1) Sanger sequencing of ATL1 and SPAST genes, 2) whole exome, and 3) targeted panel sequencing by next generation sequencing. RESULTS: Genetic diagnosis was established for 20 probands (34.5%). We detected nine previously unreported mutations with high confidence for pathogenicity. The most frequently affected gene was SPAST with pathogenic or likely pathogenic mutations in 10 probands. The most frequently detected variant in our cohort was the SPG7 p.Leu78*, observed in four probands. Altogether five probands were diagnosed with SPG7. Additional mutations were detected in SPG11, ATL1, NIPA1, and ABCD1. CONCLUSION: This is the first comprehensive genetic epidemiological study of patients with HSP in Hungary. Next generation sequencing improved the yield of genetic diagnostics in this disease group even when the phenotype was atypical. However, considering the frequency of the HSP-causing gene defects, SPG4, the most common form of the disease, should be tested first to be cost effective in this economic region.
BACKGROUND:Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases with progressive lower limb spasticity and weakness. The aim of this study is to determine the frequency of different SPG mutations in Hungarian patients, and to provide further genotype-phenotype correlations for the known HSP causing genes. METHODS: We carried out genetic testing for 58 probands with clinical characteristics of HSP. For historical reasons, three different approaches were followed in different patients: 1) Sanger sequencing of ATL1 and SPAST genes, 2) whole exome, and 3) targeted panel sequencing by next generation sequencing. RESULTS: Genetic diagnosis was established for 20 probands (34.5%). We detected nine previously unreported mutations with high confidence for pathogenicity. The most frequently affected gene was SPAST with pathogenic or likely pathogenic mutations in 10 probands. The most frequently detected variant in our cohort was the SPG7 p.Leu78*, observed in four probands. Altogether five probands were diagnosed with SPG7. Additional mutations were detected in SPG11, ATL1, NIPA1, and ABCD1. CONCLUSION: This is the first comprehensive genetic epidemiological study of patients with HSP in Hungary. Next generation sequencing improved the yield of genetic diagnostics in this disease group even when the phenotype was atypical. However, considering the frequency of the HSP-causing gene defects, SPG4, the most common form of the disease, should be tested first to be cost effective in this economic region.
Authors: Chi-Lun Chang; Aubrey V Weigel; Maria S Ioannou; H Amalia Pasolli; C Shan Xu; David R Peale; Gleb Shtengel; Melanie Freeman; Harald F Hess; Craig Blackstone; Jennifer Lippincott-Schwartz Journal: J Cell Biol Date: 2019-06-21 Impact factor: 10.539
Authors: Colby R Sandate; Agnieszka Szyk; Elena A Zehr; Gabriel C Lander; Antonina Roll-Mecak Journal: Nat Struct Mol Biol Date: 2019-07-08 Impact factor: 15.369
Authors: Matias Wagner; Daniel P S Osborn; Ina Gehweiler; Maike Nagel; Ulrike Ulmer; Somayeh Bakhtiari; Rim Amouri; Reza Boostani; Faycal Hentati; Maryam M Hockley; Benedikt Hölbling; Thomas Schwarzmayr; Ehsan Ghayoor Karimiani; Christoph Kernstock; Reza Maroofian; Wolfgang Müller-Felber; Ege Ozkan; Sergio Padilla-Lopez; Selina Reich; Jennifer Reichbauer; Hossein Darvish; Neda Shahmohammadibeni; Abbas Tafakhori; Katharina Vill; Stephan Zuchner; Michael C Kruer; Juliane Winkelmann; Yalda Jamshidi; Rebecca Schüle Journal: Nat Commun Date: 2019-10-21 Impact factor: 14.919