Clinical Classification of Variants in the Valosin-Containing Protein Gene Associated With Multisystem Proteinopathy
Schiava, Marianela (TNewcastle University and Newcastle Hospitals NHS Foundation Trusts (Regne Unit))
Ikenaga, Chiseko (Johns Hopkins University School of Medicine (Estats Units d'Amèrica))
Töpf, Ana (Newcastle University and Newcastle Hospitals NHS Foundation Trusts (Regne Unit))
Caballero-Ávila, Marta (Institut d'Investigació Biomèdica Sant Pau)
Chou, Tsuifen (California Institute of Technology (Estats Units d'Amèrica))
Li, Shan (California Institute of Technology (Estats Units d'Amèrica))
Wang, Feng (California Institute of Technology (Estats Units d'Amèrica))
Daw, Jil A. W. (Washington University School of Medicine (Estats Units d'Amèrica))
Stojkovic, Tanya (Hôpital Pitié-Salpêtière (París, França))
Villar-Quiles, Rocío Nur (APHP Hôpital Pitié-Salpêtrière (França))
Nishino, Ichizo (Nagoya University Graduate School of Medicine (Japó))
Inoue, Michio (Nagoya University Graduate School of Medicine (Japó))
Nishimori, Yukako (Nagoya University Graduate School of Medicine (Japó))
Saito, Yoshihiko (Nagoya University Graduate School of Medicine (Japó))
Katsuno, Masahisa (National Hospital Organization Suzuka Hospital (Japó))
Noda, Seiya (National Hospital Organization Suzuka Hospital (Japó))
Ito, Chihiro (Aichi Medical University School of Medicine (Japó))
Otsuka, Mieko (International University of Health and Welfare Hospital (Japó))
Nahir, Sruthi (Sree Chitra Tirunal Institute for Medical Sciences and Technology (Índia))
Manousakis, Georgios (University of Minnesota (Estats Units d'Amèrica))
Walk, David (University of Minnesota (Estats Units d'Amèrica))
Quinn, Colin (University of Pennsylvania (Estats Units d'Amèrica))
Alfano, Lindsay N. (The Ohio State University College of Medicine (Estats Units d'Amèrica))
Sahenk, Zarife (The Ohio State University College of Medicine (Estats Units d'Amèrica))
Tasca, Giorgio (Fondazione Policlinico Universitario A Gemelli (Itàlia))
Monforte, Mauro (Fondazione Policlinico Universitario A Gemelli (Itàlia))
Sabatelli, Mario (Fondazione policlinico universitario A. Gemelli (Itàlia))
Bisogni, Giulia (Fondazione policlinico universitario A. Gemelli (Itàlia))
Oldfors, Anders (University of Gothenburg (Suècia))
Rydeliu, Anna (Lund University (Suècia))
Pal, Ebdre (University of Pécs (Hongria))
Paradas, Carmen (Instituto de Salud Carlos III)
Vélez-Gómez, Beatriz (Instituto de Salud Carlos III)
De Bleecker, Jan (Neurology Department and Neuromuscular Reference Centre (Bèlgica))
Farugia, Maria Elena (Queen Elizabeth University Hospital (Regne Unit))
Longman, Cheryl A. L. (Queen Elizabeth University Hospital (Regne Unit))
Harms, Matthew B. (Columbia University Irving Medical Centre (Estats Units d'Amèrica))
Ralston, Stuart (University of Edinburgh (Escòcia))
Zanoteli, Edmar (Universidade de São Paulo)
Macedo Serafim da Silva, Andre (Universidade de São Paulo)
Sotoca Fernández, Javier (Hospital Universitari Vall d'Hebron)
Juntas Morales, Raúl (Hospital Universitari Vall d'Hebron)
Bevilacqua, JA. (Universidad de Chile)
Balart, Mireya (Clínica Dávila (Xile))
Talbot, Stuart (Newcastle University (Regne Unit))
Straub, Volker (Newcastle University and Newcastle Hospitals NHS Foundation Trusts (Regne Unit))
Guglieri, Michela (Newcastle University and Newcastle Hospitals NHS Foundation Trusts (Regne Unit))
Marini-Bettolo, Chiara (Newcastle University and Newcastle Hospitals NHS Foundation Trusts (Regne Unit))
Diaz-Manera, Jordi (Washington University School of Medicine (Estats Units d'Amèrica))
Weihl, Conrad C. (Washington University School of Medicine (Estats Units d'Amèrica))
Universitat Autònoma de Barcelona

Data:	2023
Resum:	Pathogenic variants in the valosin-containing protein (VCP) gene cause a phenotypically heterogeneous disorder that includes myopathy, motor neuron disease, Paget disease of the bone, frontotemporal dementia, and parkinsonism termed multisystem proteinopathy. This hallmark pleiotropy makes the classification of novel VCP variants challenging. This retrospective study describes and assesses the effect of 19 novel or nonpreviously clinically characterized VCP variants identified in 28 patients (26 unrelated families) in the retrospective VCP International Multicenter Study. A 6-item clinical score was developed to evaluate the phenotypic level of evidence to support the pathogenicity of the novel variants. Each item is allocated a value, a score ranging from 0. 5 to 5. 5 points. A receiver-operating characteristic curve was used to identify a cutoff value of 3 to consider a variant as high likelihood disease associated. The scoring system results were confronted with results of in vitro ATPase activity assays and with in silico analysis. All variants were missense, except for one small deletion-insertion, 18 led to amino acid changes within the N and D1 domains, and 13 increased the enzymatic activity. The clinical score coincided with the functional studies in 17 of 19 variants and with the in silico analysis in 12 of 19. For 12 variants, the 3 predictive tools agreed, and for 7 variants, the predictive tools disagreed. The pooled data supported the pathogenicity of 13 of 19 novel VCP variants identified in the study. This study provides data to support pathogenicity of 14 of 19 novel VCP variants and provides guidance for clinicians in the evaluation of novel variants in the VCP gene.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Neurology: Genetics, Vol. 9 Núm. 5 (15 2023) , p. e200093, ISSN 2376-7839

DOI: 10.1212/NXG.0000000000200093
PMID: 37588275

12 p, 417.1 KB

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