Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Johnson JO

PROVIDER: S-EPMC8406220 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Johnson Janel O JO Chia Ruth R Miller Danny E DE Li Rachel R Kumaran Ravindran R Abramzon Yevgeniya Y Alahmady Nada N Renton Alan E AE Topp Simon D SD Gibbs J Raphael JR Cookson Mark R MR Sabir Marya S MS Dalgard Clifton L CL Troakes Claire C Jones Ashley R AR Shatunov Aleksey A Iacoangeli Alfredo A Al Khleifat Ahmad A Ticozzi Nicola N Silani Vincenzo V Gellera Cinzia C Blair Ian P IP Dobson-Stone Carol C Kwok John B JB Bonkowski Emily S ES Palvadeau Robin R Tienari Pentti J PJ Morrison Karen E KE Shaw Pamela J PJ Al-Chalabi Ammar A Brown Robert H RH Calvo Andrea A Mora Gabriele G Al-Saif Hind H Gotkine Marc M Leigh Fawn F Chang Irene J IJ Perlman Seth J SJ Glass Ian I Scott Anna I AI Shaw Christopher E CE Basak A Nazli AN Landers John E JE Chiò Adriano A Crawford Thomas O TO Smith Bradley N BN Traynor Bryan J BJ Smith Bradley N BN Ticozzi Nicola N Fallini Claudia C Gkazi Athina Soragia AS Topp Simon D SD Scotter Emma L EL Kenna Kevin P KP Keagle Pamela P Tiloca Cinzia C Vance Caroline C Troakes Claire C Colombrita Claudia C King Andrew A Pensato Viviana V Castellotti Barbara B Baas Frank F Ten Asbroek Anneloor L M A ALMA McKenna-Yasek Diane D McLaughlin Russell L RL Polak Meraida M Asress Seneshaw S Esteban-Pérez Jesús J Stevic Zorica Z D'Alfonso Sandra S Mazzini Letizia L Comi Giacomo P GP Del Bo Roberto R Ceroni Mauro M Gagliardi Stella S Querin Giorgia G Bertolin Cinzia C van Rheenen Wouter W Rademakers Rosa R van Blitterswijk Marka M Lauria Giuseppe G Duga Stefano S Corti Stefania S Cereda Cristina C Corrado Lucia L Sorarù Gianni G Williams Kelly L KL Nicholson Garth A GA Blair Ian P IP Leblond-Manry Claire C Rouleau Guy A GA Hardiman Orla O Morrison Karen E KE Veldink Jan H JH van den Berg Leonard H LH Al-Chalabi Ammar A Pall Hardev H Shaw Pamela J PJ Turner Martin R MR Talbot Kevin K Taroni Franco F García-Redondo Alberto A Wu Zheyang Z Glass Jonathan D JD Gellera Cinzia C Ratti Antonia A Brown Robert H RH Silani Vincenzo V Shaw Christopher E CE Landers John E JE Dalgard Clifton L CL Adeleye Adelani A Soltis Anthony R AR Alba Camille C Viollet Coralie C Bacikova Dagmar D Hupalo Daniel N DN Sukumar Gauthaman G Pollard Harvey B HB Wilkerson Matthew D MD Martinez Elisa McGrath EM Abramzon Yevgeniya Y Ahmed Sarah S Arepalli Sampath S Baloh Robert H RH Bowser Robert R Brady Christopher B CB Brice Alexis A Broach James J Campbell Roy H RH Camu William W Chia Ruth R Cooper-Knock John J Ding Jinhui J Drepper Carsten C Drory Vivian E VE Dunckley Travis L TL Eicher John D JD England Bryce K BK Faghri Faraz F Feldman Eva E Floeter Mary Kay MK Fratta Pietro P Geiger Joshua T JT Gerhard Glenn G Gibbs J Raphael JR Gibson Summer B SB Glass Jonathan D JD Hardy John J Harms Matthew B MB Heiman-Patterson Terry D TD Hernandez Dena G DG Jansson Lilja L Kirby Janine J Kowall Neil W NW Laaksovirta Hannu H Landeck Natalie N Landi Francesco F Le Ber Isabelle I Lumbroso Serge S MacGowan Daniel J L DJL Maragakis Nicholas J NJ Mora Gabriele G Mouzat Kevin K Murphy Natalie A NA Myllykangas Liisa L Nalls Mike A MA Orrell Richard W RW Ostrow Lyle W LW Pamphlett Roger R Pickering-Brown Stuart S Pioro Erik P EP Pletnikova Olga O Pliner Hannah A HA Pulst Stefan M SM Ravits John M JM Renton Alan E AE Rivera Alberto A Robberecht Wim W Rogaeva Ekaterina E Rollinson Sara S Rothstein Jeffrey D JD Scholz Sonja W SW Sendtner Michael M Shaw Pamela J PJ Sidle Katie C KC Simmons Zachary Z Singleton Andrew B AB Smith Nathan N Stone David J DJ Tienari Pentti J PJ Troncoso Juan C JC Valori Miko M Van Damme Philip P Van Deerlin Vivianna M VM Van Den Bosch Ludo L Zinman Lorne L Landers John E JE Chiò Adriano A Traynor Bryan J BJ Angelocola Stefania M SM Ausiello Francesco P FP Barberis Marco M Bartolomei Ilaria I Battistini Stefania S Bersano Enrica E Bisogni Giulia G Borghero Giuseppe G Brunetti Maura M Cabona Corrado C Calvo Andrea A Canale Fabrizio F Canosa Antonio A Cantisani Teresa A TA Capasso Margherita M Caponnetto Claudia C Cardinali Patrizio P Carrera Paola P Casale Federico F Chiò Adriano A Colletti Tiziana T Conforti Francesca L FL Conte Amelia A Conti Elisa E Corbo Massimo M Cuccu Stefania S Dalla Bella Eleonora E D'Errico Eustachio E DeMarco Giovanni G Dubbioso Raffaele R Ferrarese Carlo C Ferraro Pilar M PM Filippi Massimo M Fini Nicola N Floris Gianluca G Fuda Giuseppe G Gallone Salvatore S Gianferrari Giulia G Giannini Fabio F Grassano Maurizio M Greco Lucia L Iazzolino Barbara B Introna Alessandro A La Bella Vincenzo V Lattante Serena S Lauria Giuseppe G Liguori Rocco R Logroscino Giancarlo G Logullo Francesco O FO Lunetta Christian C Mandich Paola P Mandrioli Jessica J Manera Umberto U Manganelli Fiore F Marangi Giuseppe G Marinou Kalliopi K Marrosu Maria Giovanna MG Martinelli Ilaria I Messina Sonia S Moglia Cristina C Mora Gabriele G Mosca Lorena L Murru Maria R MR Origone Paola P Passaniti Carla C Petrelli Cristina C Petrucci Antonio A Pozzi Susanna S Pugliatti Maura M Quattrini Angelo A Ricci Claudia C Riolo Giulia G Riva Nilo N Russo Massimo M Sabatelli Mario M Salamone Paolina P Salivetto Marco M Salvi Fabrizio F Santarelli Marialuisa M Sbaiz Luca L Sideri Riccardo R Simone Isabella I Simonini Cecilia C Spataro Rossella R Tanel Raffaella R Tedeschi Gioacchino G Ticca Anna A Torriello Antonella A Tranquilli Stefania S Tremolizzo Lucio L Trojsi Francesca F Vasta Rosario R Vacchiano Veria V Vita Giuseppe G Volanti Paolo P Zollino Marcella M Zucchi Elisabetta E

JAMA neurology 20211001 10

<h4>Importance</h4>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.<h4>Objective</h4>To identify the genetic variants associated with juvenile ALS.<h4>Design, setting, and participants</h4>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 ...[more]

PMID: 34459874

Similar Datasets

Project description:Background and objectivesAmyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron degeneration, with juvenile ALS (jALS) defined as disease with age at onset (AAO) before 25 years. We aimed to identify the genetic basis of 2 unrelated patients with jALS with very rapid deterioration and early age intellectual disability (ID) and to assess association of genetic findings with both phenotypes in a large cohort of patients with ALS and controls, and in the literature.MethodsExome sequencing was performed in 2 unrelated probands and their parents. Trio analyses included de novo, rare homozygosity, and compound heterozygosity analyses. A TaqMan genotyping assay was used to genotype ALS cohorts. A systematic literature review was conducted and additional information from authors obtained to assess prevalence of fused in sarcoma (FUS)-ALS associated with ID.ResultsA de novo mutation FUS-P525L was identified in both patients. Additional variations were identified in other genes related to intellectual disabilities. Among 8 additional unrelated juvenile patients, one carried the same FUS mutation and had a similar medical history of mild ID and fulminant ALS, whereas the others did not carry any FUS coding mutations and had no reported learning or intellectual disabilities (p = 0.0083). In addition, 486 patients with ALS with AAO ≥25 years were negative for this mutation. An extensive literature review showed that among all patients with FUS-related ALS with full phenotype reports, 10.3% exhibited additional learning/intellectual disabilities.DiscussionFUS-P525L mutation was identified in 3 among 10 patients with jALS (30%) in our clinical cohort, all with a very aggressive disease course and ID. Together with literature reports, these results support a novel association between mutations in FUS and early life ID. Additional variations identified in genes related to ID and brain development in our patients (GPT2, DNAH10, and SCUBE2) may suggest a complex oligogenic inheritance for this phenotype. We propose that this mutation should be screened in patients with ALS with very early AAO, aggressive disease course, and sporadic occurrence, especially when ALS is accompanied by ID.

Dataset Information

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

Importance

Objective

Design, setting, and participants

Main outcomes and measures

Results

Conclusions and relevance

Publications

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

Similar Datasets

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