Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia
Heba Morsy, Mehdi Benkirane, Elisa Calì, Clarissa Rocca, Kristina Zhelcheska, Valentina Cipriani, Evangelia Galanaki, Reza Maroofian, Stéphanie Efthymiou, David Murphy, Mary O’Driscoll, Mohnish Suri, Siddharth Banka, Jill Clayton‐Smith, Thomas Wright, Melody Redman, Jennifer A. Bassetti, Mathilde Nizon, Benjamin Cogné, Rami Abu Jamra, Tobias Bartolomaeus, Marion Heruth, Ilona Krey, Janina Gburek‐Augustat, Dagmar Wieczorek, Felix Gattermann, Meriel McEntagart, Alice Goldenberg, Lucie Guyant‐Maréchal, Héctor García‐Moreno, Paola Giunti, B. Chabrol, Séverine Bacrot, Roger Buissonnière, Virginie Magry, Vykuntaraju K. Gowda, Varunvenkat M. Srinivasan, Béla Melegh, András Szabó, Katalin Sümegi, Mireille Cossée, Monica Ziff, Russell J. Butterfield, David Hunt, Georgina Bird-Lieberman, Michael G. Hanna, Michel Koenig, Michael C. Stankewich, Jana Vandrovcová, Henry Houlden, John C. Ambrose, Paramasivam Arumugam, Emma L. Baple, Marta Bleda, F. Boardman-Pretty, J. M. Boissiere, C. R. Boustred, Helen Brittain, Mark J. Caulfield, G. C. Chan, C. E. H. Craig, Louise C. Daugherty, Anna de Burca, A. Devereau, Greg Elgar, Rebecca E. Foulger, Tom Fowler, Pedro Furió‐Tarí, J.M. Hackett, Dina Halai, Angela Hamblin, Shirley Henderson, John E. Holman, Tim Hubbard, Kristina Ibáñez, Richard V. Jackson, J. Louise Jones, Dalia Kasperavičiūtė, Melis Kayikci, L. Lahnstein, Katy L. Lawson, S. E. A. Leigh, Ivone Leong, Fabrice Lopez, F. Maleady-Crowe, James Mason, Ellen M. McDonagh, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Christopher A. Odhams, Christine Patch, D. Perez-Gil, Dimitris Polychronopoulos, J. Pullinger, T. Rahim, Augusto Rendon, Pablo Riesgo-Ferreiro, T. Rogers
Abstract
PurposeNonerythrocytic αII-spectrin (SPTAN1) variants have been previously associated with intellectual disability and epilepsy. We conducted this study to delineate the phenotypic spectrum of SPTAN1 variants.MethodsWe carried out SPTAN1 gene enrichment analysis in the rare disease component of the 100,000 Genomes Project and screened 100,000 Genomes Project, DECIPHER database, and GeneMatcher to identify individuals with SPTAN1 variants. Functional studies were performed on fibroblasts from 2 patients.ResultsStatistically significant enrichment of rare (minor allele frequency < 1 × 10–5) probably damaging SPTAN1 variants was identified in families with hereditary ataxia (HA) or hereditary spastic paraplegia (HSP) (12/1142 cases vs 52/23,847 controls, p = 2.8 × 10–5). We identified 31 individuals carrying SPTAN1 heterozygous variants or deletions. A total of 10 patients presented with pure or complex HSP/HA. The remaining 21 patients had developmental delay and seizures. Irregular αII-spectrin aggregation was noted in fibroblasts derived from 2 patients with p.(Arg19Trp) and p.(Glu2207del) variants.ConclusionWe found that SPTAN1 is a genetic cause of neurodevelopmental disorder, which we classified into 3 distinct subgroups. The first comprises developmental epileptic encephalopathy. The second group exhibits milder phenotypes of developmental delay with or without seizures. The final group accounts for patients with pure or complex HSP/HA.