title: AP5Z1/SPG48 frequency in autosomal recessive and sporadic spastic paraplegia.
abstract: Hereditary spastic paraplegias (HSP) constitute a rare and highly heterogeneous group of neurodegenerative disorders, defined clinically by progressive lower limb spasticity and pyramidal weakness. Autosomal recessive HSP as well as sporadic cases present a significant diagnostic challenge. Mutations in AP5Z1, a gene playing a role in intracellular membrane trafficking, have been recently reported to be associated with spastic paraplegia type 48 (SPG48). Our objective was to determine the relative frequency and clinical relevance of AP5Z1 mutations in a large cohort of 127 HSP patients. We applied a targeted next-generation sequencing approach to analyze all coding exons of the AP5Z1 gene. With the output of high-quality reads and a mean coverage of 51-fold, we demonstrated a robust detection of variants. One 43-year-old female with sporadic complicated paraplegia showed two heterozygous nonsynonymous variants of unknown significance (VUS3; p.[R292W];[(T756I)]). Thus, AP5Z1 gene mutations are rare, at least in Europeans. Due to its low frequency, systematic genetic testing for AP5Z1 mutations is not recommended until larger studies are performed to add further evidence. Our findings demonstrate that amplicon-based deep sequencing is technically feasible and allows a compact molecular characterization of multiple HSP patients with high accuracy.
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen Tübingen, Germany ; Institute of Human Genetics, University Medical Center Freiburg Freiburg, Germany.
authors.forename: Nina A
authors.initials: NA
authors.lastname: Schlipf
authors.affiliation: Clinical Neurogenetics, Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen Tübingen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.affiliation: Department of Neurology, University of Mainz Mainz, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Klimpe
authors.affiliation: Clinical Neurogenetics, Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen Tübingen, Germany ; German Center for Neurodegenerative Diseases (DZNE) Tübingen, Germany.
authors.forename: Kathrin N
authors.initials: KN
authors.lastname: Karle
authors.affiliation: Clinical Neurogenetics, Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen Tübingen, Germany ; German Center for Neurodegenerative Diseases (DZNE) Tübingen, Germany.
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
authors.affiliation: Clinical Neurogenetics, Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen Tübingen, Germany ; German Center for Neurodegenerative Diseases (DZNE) Tübingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Wolf
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen Tübingen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.affiliation: Clinical Neurogenetics, Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen Tübingen, Germany ; German Center for Neurodegenerative Diseases (DZNE) Tübingen, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
keywords: AP5Z1; SPG48; hereditary spastic paraplegia; targeted next-generation sequencing