Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Janel Johnson; Ruth Chia; Danny Miller; Rachel Li; Ravindran Kumaran; Yevgeniya Abramzon; Nada Alahmady; Alan Renton; Simon Topp; J Raphael Gibbs; Mark Cookson; Marya Sabir; Clifton Dalgard; Claire Troakes; Ashley Jones; Aleksey Shatunov; Alfredo Iacoangeli; Ahmad Al Khleifat; Nicola Ticozzi; Vincenzo Silani; Cinzia Gellera; Ian Blair; Carol Dobson-Stone; John Kwok; Emily Bonkowski; Robin Palvadeau; Pentti Tienari; Karen Morrison; Pamela Shaw; Ammar Al-Chalabi; Robert Brown; Andrea Calvo; Gabriele Mora; Hind Al-Saif; Marc Gotkine; Fawn Leigh; Irene Chang; Seth Perlman; Ian Glass; Anna Scott; Christopher Shaw; a Nazli Basak; John Landers; Adriano Chiò; Thomas Crawford; Bradley Smith; Bryan Traynor; Claudia Fallini; Athina Soragia Gkazi; Emma Scotter; Kevin Kenna; Pamela Keagle; Cinzia Tiloca; Caroline Vance; Claudia Colombrita; Andrew King; Viviana Pensato; Barbara Castellotti; Frank Baas; Anneloor ten Asbroek; Diane Mckenna-Yasek; Russell Mclaughlin; Meraida Polak; Seneshaw Asress; Jesús Esteban-Pérez; Zorica Stevic; Sandra d'Alfonso; Letizia Mazzini; Giacomo Comi; Roberto del Bo; Mauro Ceroni; Stella Gagliardi; Giorgia Querin; Cinzia Bertolin; Wouter van Rheenen; Rosa Rademakers; Marka van Blitterswijk; Giuseppe Lauria; Stefano Duga; Stefania Corti; Cristina Cereda; Lucia Corrado; Gianni Sorarù; Kelly Williams; Garth Nicholson; Claire Leblond-Manry; Guy Rouleau; Orla Hardiman; Jan Veldink; Leonard van den Berg; Hardev Pall; Martin Turner; Kevin Talbot; Franco Taroni; Alberto García-Redondo; Zheyang Wu; Jonathan Glass; Antonia Ratti; Adelani Adeleye; Anthony Soltis; Camille Alba; Coralie Viollet; Dagmar Bacikova; Daniel Hupalo; Gauthaman Sukumar; Harvey Pollard; Matthew Wilkerson; Elisa Mcgrath Martinez; Sarah Ahmed; Sampath Arepalli; Robert Baloh; Robert Bowser; Christopher Brady; Alexis Brice; James Broach; Roy Campbell; William Camu; John Cooper-Knock; Jinhui Ding; Carsten Drepper; Vivian Drory; Travis Dunckley; John Eicher; Bryce England; Faraz Faghri; Eva Feldman; Mary Kay Floeter; Pietro Fratta; Joshua Geiger; Glenn Gerhard; Summer Gibson; John Hardy; Matthew Harms; Terry Heiman-Patterson; Dena Hernandez; Lilja Jansson; Janine Kirby; Neil Kowall; Hannu Laaksovirta; Natalie Landeck; Francesco Landi; Isabelle Le Ber; Serge Lumbroso; Daniel Macgowan; Nicholas Maragakis; Kevin Mouzat; Natalie Murphy; Liisa Myllykangas; Mike Nalls; Richard Orrell; Lyle Ostrow; Roger Pamphlett; Stuart Pickering-Brown; Erik Pioro; Olga Pletnikova; Hannah Pliner; Stefan Pulst; John Ravits; Alberto Rivera; Wim Robberecht; Ekaterina Rogaeva; Sara Rollinson; Jeffrey Rothstein; Sonja Scholz; Michael Sendtner; Katie Sidle; Zachary Simmons; Andrew Singleton; Nathan Smith; David Stone; Juan Troncoso; Miko Valori; Philip van Damme; Vivianna van Deerlin; Ludo van den Bosch; Lorne Zinman; Stefania Angelocola; Francesco Ausiello; Marco Barberis; Ilaria Bartolomei; Stefania Battistini; Enrica Bersano; Giulia Bisogni; Giuseppe Borghero; Maura Brunetti; Corrado Cabona; Fabrizio Canale; Antonio Canosa; Teresa Cantisani; Margherita Capasso; Claudia Caponnetto; Patrizio Cardinali; Paola Carrera; Federico Casale; Tiziana Colletti; Francesca Conforti; Amelia Conte; Elisa Conti; Massimo Corbo; Stefania Cuccu; Eleonora Dalla Bella; Eustachio d'Errico; Giovanni Demarco; Raffaele Dubbioso; Carlo Ferrarese; Pilar Ferraro; Massimo Filippi; Nicola Fini; Gianluca Floris; Giuseppe Fuda; Salvatore Gallone; Giulia Gianferrari; Fabio Giannini; Maurizio Grassano; Lucia Greco; Barbara Iazzolino; Alessandro Introna; Vincenzo La Bella; Serena Lattante; Rocco Liguori; Giancarlo Logroscino; Francesco Logullo; Christian Lunetta; Paola Mandich; Jessica Mandrioli; Umberto Manera; Fiore Manganelli; Giuseppe Marangi; Kalliopi Marinou; Maria Giovanna Marrosu; Ilaria Martinelli; Sonia Messina; Cristina Moglia; Lorena Mosca; Maria Murru; Paola Origone; Carla Passaniti; Cristina Petrelli; Antonio Petrucci; Susanna Pozzi; Maura Pugliatti; Angelo Quattrini; Claudia Ricci; Giulia Riolo; Nilo Riva; Massimo Russo; Mario Sabatelli; Paolina Salamone; Marco Salivetto; Fabrizio Salvi; Marialuisa Santarelli; Luca Sbaiz; Riccardo Sideri; Isabella Simone; Cecilia Simonini; Rossella Spataro; Raffaella Tanel; Gioacchino Tedeschi; Anna Ticca; Antonella Torriello; Stefania Tranquilli; Lucio Tremolizzo; Francesca Trojsi; Rosario Vasta; Veria Vacchiano; Giuseppe Vita; Paolo Volanti; Marcella Zollino; Elisabetta Zucchi; J. Raphael Gibbs; A. Nazli Basak; Sandra D’alfonso; Eustachio D’errico

doi:10.1001/jamaneurol.2021.2598

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Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Journal article

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Peer reviewed

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Janel Johnson, Ruth Chia, Danny Miller, Rachel Li, Ravindran Kumaran, Yevgeniya Abramzon, Nada Alahmady, Alan Renton, Simon Topp, J Raphael Gibbs, …

JAMA neurology, Vol.78(10)

01/10/2021

DOI: https://doi.org/10.1001/jamaneurol.2021.2598

PMCID: PMC8406220

PMID: 34459874

Abstract

Adolescent

Adult

Mutation

Serine C-Palmitoyltransferase

Whole Exome Sequencing

Young Adult

Amyotrophic Lateral Sclerosis

Child

Child, Preschool

Female

Genetic Predisposition to Disease

Humans

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, setting, and participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main outcomes and measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

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Title: Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis
Creators - without role: Janel Johnson - National Institutes of Health
Ruth Chia - National Institutes of Health
Danny Miller - Seattle Children's Hospital
Rachel Li - Children's Hospital of Richmond at VCU
Ravindran Kumaran - National Institutes of Health
Yevgeniya Abramzon - National Institutes of Health
Nada Alahmady - Imam Abdulrahman Bin Faisal University
Alan Renton - National Institutes of Health
Simon Topp - King's College London
J Raphael Gibbs - National Institutes of Health
Mark Cookson - University College London
Marya Sabir - National Institutes of Health
Clifton Dalgard - Uniformed Services University of the Health Sciences
Claire Troakes - King's College London
Ashley Jones - King's College London
Aleksey Shatunov - King's College London
Alfredo Iacoangeli - King's College London
Ahmad Al Khleifat - King's College London
Nicola Ticozzi - IRCCS Istituto Auxologico Italiano
Vincenzo Silani - IRCCS Istituto Auxologico Italiano
Cinzia Gellera - Fondazione IRCCS Istituto Neurologico Carlo Besta
Ian Blair - Macquarie University
Carol Dobson-Stone - University of Sydney
John Kwok - University of Sydney
Emily Bonkowski - Seattle Children's Hospital
Robin Palvadeau - Koç University
Pentti Tienari - University of Helsinki
Karen Morrison - Queen's University Belfast
Pamela Shaw - University of Sheffield
Ammar Al-Chalabi - King's College London
Robert Brown - University of Massachusetts Chan Medical School
Andrea Calvo - Azienda Ospedaliera Citta' della Salute e della Scienza di Torino
Gabriele Mora - Istituti Clinici Scientifici Maugeri
Hind Al-Saif - Children's Hospital of Richmond at VCU
Marc Gotkine - Hebrew University of Jerusalem
Fawn Leigh - Seattle Children's Hospital
Irene Chang - University of Washington Medical Center
Seth Perlman - University of Washington
Ian Glass - University of Washington Medical Center
Anna Scott - Seattle Children's Hospital
Christopher Shaw - UK Dementia Research Institute
a Nazli Basak - Koç University
John Landers - University of Massachusetts Chan Medical School
Adriano Chiò - University of Turin
Thomas Crawford - Johns Hopkins University
Bradley Smith - King's College London
Bryan Traynor - National Institute on Aging
Claudia Fallini - University of Massachusetts Chan Medical School
Athina Soragia Gkazi - King's College London
Emma Scotter - University of Auckland
Kevin Kenna - University of Massachusetts Chan Medical School
Pamela Keagle - University of Massachusetts Chan Medical School
Cinzia Tiloca - IRCCS Istituto Auxologico Italiano
Caroline Vance - King's College London
Claudia Colombrita - IRCCS Istituto Auxologico Italiano
Andrew King - King's College London
Viviana Pensato - Fondazione IRCCS Istituto Neurologico Carlo Besta
Barbara Castellotti - Fondazione IRCCS Istituto Neurologico Carlo Besta
Frank Baas - Leiden University Medical Center
Anneloor ten Asbroek
Diane Mckenna-Yasek - University of Massachusetts Chan Medical School
Russell Mclaughlin - Trinity College Dublin
Meraida Polak - Emory University
Seneshaw Asress
Jesús Esteban-Pérez - Centro de Investigación Biomédica en Red
Zorica Stevic - University of Belgrade
Sandra d'Alfonso
Letizia Mazzini - Azienda Ospedaliero Universitaria Maggiore della Carita
Giacomo Comi - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Roberto del Bo - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Mauro Ceroni - University of Pavia
Stella Gagliardi - Center for Genomic Science
Giorgia Querin - University of Padua
Cinzia Bertolin - University of Padua
Wouter van Rheenen - University Medical Center Utrecht
Rosa Rademakers - Jacksonville College
Marka van Blitterswijk - Mayo Clinic in Florida
Giuseppe Lauria - Fondazione IRCCS Istituto Neurologico Carlo Besta
Stefano Duga - Humanitas University
Stefania Corti - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Cristina Cereda - Center for Genomic Science
Lucia Corrado - Università degli Studi del Piemonte Orientale “Amedeo Avogadro”
Gianni Sorarù - University of Padua
Kelly Williams - Macquarie University
Garth Nicholson - Macquarie University
Claire Leblond-Manry - Institut Pasteur
Guy Rouleau - McGill University
Orla Hardiman - Trinity College Dublin
Jan Veldink - University Medical Center Utrecht
Leonard van den Berg - University Medical Center Utrecht
Hardev Pall - University of Birmingham
Martin Turner - University of Oxford
Kevin Talbot - University of Oxford
Franco Taroni - Fondazione IRCCS Istituto Neurologico Carlo Besta
Alberto García-Redondo - Centro de Investigación Biomédica en Red
Zheyang Wu - Worcester Polytechnic Institute
Jonathan Glass - Emory University
Antonia Ratti - IRCCS Istituto Auxologico Italiano
Adelani Adeleye - Henry M. Jackson Foundation
Anthony Soltis - Henry M. Jackson Foundation
Camille Alba - Uniformed Services University of the Health Sciences
Coralie Viollet - Henry M. Jackson Foundation
Dagmar Bacikova - Henry M. Jackson Foundation
Daniel Hupalo - Uniformed Services University of the Health Sciences
Gauthaman Sukumar - Uniformed Services University of the Health Sciences
Harvey Pollard - Uniformed Services University of the Health Sciences
Matthew Wilkerson - Henry M. Jackson Foundation
Elisa Mcgrath Martinez - Henry M. Jackson Foundation
Sarah Ahmed - National Institute of Neurological Disorders and Stroke
Sampath Arepalli - National Institute on Aging
Robert Baloh - Cedars-Sinai Medical Center
Robert Bowser - Barrow Neurological Institute
Christopher Brady - VA Boston Healthcare System
Alexis Brice - Institut du Cerveau
James Broach - Penn State Milton S. Hershey Medical Center
Roy Campbell - University of Illinois Urbana-Champaign
William Camu - Université de Montpellier
John Cooper-Knock
Jinhui Ding - National Institute on Aging
Carsten Drepper - University of Würzburg
Vivian Drory - Tel Aviv Sourasky Medical Center
Travis Dunckley - Arizona State University
John Eicher - United States Military Academy
Bryce England - National Institute of Mental Health
Faraz Faghri - University of Illinois Urbana-Champaign
Eva Feldman - University of Michigan–Ann Arbor
Mary Kay Floeter - National Institute of Neurological Disorders and Stroke
Pietro Fratta - Sobell House
Joshua Geiger - National Institute of Neurological Disorders and Stroke
Glenn Gerhard - Penn State Milton S. Hershey Medical Center
Summer Gibson - University of Utah
John Hardy - University College London
Matthew Harms - Columbia University
Terry Heiman-Patterson - Drexel University
Dena Hernandez - National Institute on Aging
Lilja Jansson - University of Helsinki
Janine Kirby - University of Sheffield
Neil Kowall - VA Boston Healthcare System
Hannu Laaksovirta - University of Helsinki
Natalie Landeck - National Institute on Aging
Francesco Landi - Università Cattolica del Sacro Cuore
Isabelle Le Ber - Institut du Cerveau
Serge Lumbroso - Université de Nîmes
Daniel Macgowan - Mount Sinai Beth Israel
Nicholas Maragakis - Johns Hopkins University
Kevin Mouzat - Université de Nîmes
Natalie Murphy - National Institute on Aging
Liisa Myllykangas - Folkhälsans Forskningscentrum
Mike Nalls - National Institute on Aging
Richard Orrell - University College London
Lyle Ostrow - Johns Hopkins University
Roger Pamphlett - University of Sydney
Stuart Pickering-Brown - University of Manchester
Erik Pioro - Cleveland Clinic
Olga Pletnikova - Johns Hopkins University
Hannah Pliner - National Institute on Aging
Stefan Pulst - University of Utah
John Ravits - University of California, San Diego
Alberto Rivera - National Institute on Aging
Wim Robberecht - KU Leuven
Ekaterina Rogaeva - University of Toronto
Sara Rollinson - University of Manchester
Jeffrey Rothstein - Johns Hopkins University
Sonja Scholz - National Institute of Neurological Disorders and Stroke
Michael Sendtner - University of Würzburg
Katie Sidle - University College London
Zachary Simmons - Penn State Milton S. Hershey Medical Center
Andrew Singleton - National Institute on Aging
Nathan Smith
David Stone - United States Military Academy
Juan Troncoso - Johns Hopkins University
Miko Valori - University of Helsinki
Philip van Damme - VIB-KU Leuven Center for Brain & Disease Research
Vivianna van Deerlin - University of Pennsylvania
Ludo van den Bosch - KU Leuven
Lorne Zinman - University of Toronto
Stefania Angelocola
Francesco Ausiello - Neuroscience Institute
Marco Barberis - Azienda Ospedaliera Citta' della Salute e della Scienza di Torino
Ilaria Bartolomei - Istituti di Ricovero e Cura a Carattere Scientifico
Stefania Battistini - University of Siena
Enrica Bersano - Fondazione IRCCS Istituto Neurologico Carlo Besta
Giulia Bisogni - Centro Clinico Nemo
Giuseppe Borghero - University of Cagliari
Maura Brunetti - University of Turin
Corrado Cabona - Ospedale Policlinico San Martino
Fabrizio Canale - University of Campania "Luigi Vanvitelli"
Antonio Canosa - University of Turin
Teresa Cantisani - Azienda Ospedaliera di Perugia
Margherita Capasso - Ospedale SS. Annunziata
Claudia Caponnetto - Ospedale Policlinico San Martino
Patrizio Cardinali
Paola Carrera - Istituti di Ricovero e Cura a Carattere Scientifico
Federico Casale - University of Turin
Tiziana Colletti - University of Palermo
Francesca Conforti - University of Calabria
Amelia Conte - Centro Clinico Nemo
Elisa Conti - Azienda Ospedaliera San Gerardo
Massimo Corbo
Stefania Cuccu - University of Cagliari
Eleonora Dalla Bella
Eustachio d'Errico
Giovanni Demarco
Raffaele Dubbioso - University of Naples Federico II
Carlo Ferrarese - Azienda Ospedaliera San Gerardo
Pilar Ferraro - Ospedale Policlinico San Martino
Massimo Filippi - Vita-Salute San Raffaele University
Nicola Fini - Azienda Unita' Sanitaria Locale Di Modena
Gianluca Floris - University of Cagliari
Giuseppe Fuda - University of Turin
Salvatore Gallone - University of Turin
Giulia Gianferrari - Azienda Unita' Sanitaria Locale Di Modena
Fabio Giannini - University of Siena
Maurizio Grassano - University of Turin
Lucia Greco - Centro Clinico Nemo
Barbara Iazzolino
Alessandro Introna - University of Bari Aldo Moro
Vincenzo La Bella - University of Palermo
Serena Lattante - Istituti di Ricovero e Cura a Carattere Scientifico
Rocco Liguori - University of Bologna
Giancarlo Logroscino - University of Bari Aldo Moro
Francesco Logullo - University of Macerata
Christian Lunetta - Centro Clinico Nemo
Paola Mandich - Ospedale Policlinico San Martino
Jessica Mandrioli - Azienda Unita' Sanitaria Locale Di Modena
Umberto Manera - University of Turin
Fiore Manganelli - University of Naples Federico II
Giuseppe Marangi - Agostino Gemelli University Polyclinic
Kalliopi Marinou - Istituti Clinici Scientifici Maugeri
Maria Giovanna Marrosu - University of Cagliari
Ilaria Martinelli - Azienda Unita' Sanitaria Locale Di Modena
Sonia Messina - University of Messina
Cristina Moglia - Azienda Ospedaliera Citta' della Salute e della Scienza di Torino
Lorena Mosca
Maria Murru - University of Cagliari
Paola Origone - Ospedale Policlinico San Martino
Carla Passaniti - University of Campania "Luigi Vanvitelli"
Cristina Petrelli - University of Macerata
Antonio Petrucci - IRCCS San Camillo Hospital
Susanna Pozzi - Centro Clinico Nemo
Maura Pugliatti - University of Ferrara
Angelo Quattrini - Vita-Salute San Raffaele University
Claudia Ricci - University of Turin
Giulia Riolo - University of Siena
Nilo Riva - Vita-Salute San Raffaele University
Massimo Russo - University of Messina
Mario Sabatelli - Università Cattolica del Sacro Cuore
Paolina Salamone - University of Turin
Marco Salivetto - Centro Clinico Nemo
Fabrizio Salvi - Istituti di Ricovero e Cura a Carattere Scientifico
Marialuisa Santarelli - Ospedale San Filippo Neri
Luca Sbaiz - Azienda Ospedaliera Citta' della Salute e della Scienza di Torino
Riccardo Sideri - Istituti Clinici Scientifici Maugeri
Isabella Simone - University of Bari Aldo Moro
Cecilia Simonini - Azienda Unita' Sanitaria Locale Di Modena
Rossella Spataro - University of Palermo
Raffaella Tanel - Ospedale Santa Chiara
Gioacchino Tedeschi - University of Campania "Luigi Vanvitelli"
Anna Ticca - Azienda Ospedaliera S.Maria
Antonella Torriello - Ospedali Riuniti San Giovanni di Dio e Ruggi d'Aragona
Stefania Tranquilli - University of Cagliari
Lucio Tremolizzo - Azienda Ospedaliera San Gerardo
Francesca Trojsi - University of Campania "Luigi Vanvitelli"
Rosario Vasta - University of Turin
Veria Vacchiano
Giuseppe Vita - University of Messina
Paolo Volanti - Istituti Clinici Scientifici Maugeri
Marcella Zollino - Università Cattolica del Sacro Cuore
Elisabetta Zucchi - Azienda Unita' Sanitaria Locale Di Modena
J. Raphael Gibbs - National Institutes of Health
A. Nazli Basak - Koç University
Sandra D’alfonso - Università degli Studi del Piemonte Orientale “Amedeo Avogadro”
Eustachio D’errico - University of Bari Aldo Moro
Publication Details: JAMA neurology, Vol.78(10)
Identifiers: 9945468309311
Academic Unit: Institut des Neurosciences de Montpellier - INM
Language: English
Resource Type: Journal article
Local Fields: hal-03638943