Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia
Heba Morsy
(1)
,
Mehdi Benkirane
(2, 3)
,
Elisa Cali
(1)
,
Clarissa Rocca
(1)
,
Kristina Zhelcheska
(1)
,
Valentina Cipriani
(4)
,
Evangelia Galanaki
(1)
,
Reza Maroofian
(1)
,
Stephanie Efthymiou
(1)
,
David Murphy
(1)
,
Mary O’Driscoll
(5)
,
Mohnish Suri
(6)
,
Siddharth Manish Banka
(7)
,
Jill Clayton-Smith
(7)
,
Thomas Wright
(8)
,
Melody Redman
(9, 10)
,
Jennifer Bassetti
(11)
,
Mathilde Nizon
(12)
,
Benjamin Cogné
(12)
,
Rami Abu Jamra
(13)
,
Tobias Bartolomaeus
(13)
,
Marion Heruth
(13)
,
Ilona Krey
(13)
,
Janina Gburek-Augustat
(13)
,
Dagmar Wieczorek
(14)
,
Felix Gattermann
(14)
,
Meriel Mcentagart
(15)
,
Alice Goldenberg
(16)
,
Lucie Guyant-Maréchal
(17)
,
Hector Garcia-Moreno
(18, 1)
,
Paola Giunti
(18, 1)
,
Brigitte Chabrol
(17)
,
Severine Bacrot
(19)
,
Roger Buissonnière
(19)
,
Virginie Magry
(20)
,
Vykuntaraju Gowda
(21)
,
Varunvenkat Srinivasan M.
(21)
,
Béla Melegh
(22)
,
András Szabó
(22)
,
Katalin Sümegi
(22)
,
Mireille Cossée
(2)
,
Monica Ziff
(23)
,
Russell Butterfield
(24)
,
David Hunt
(25)
,
Georgina Bird-Lieberman
(26)
,
Michael Hanna
(1)
,
Michel Koenig
(2)
,
Michael Stankewich
(27)
,
Jana Vandrovcova
(1)
,
Henry Houlden
(1)
1
UCL Queen Square Institute of Neurology
2 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
3 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
4 William Harvey Research Institute, Barts and the London Medical School
5 Birmingham Women’s and Children’s Hospitals NHS Foundation Trust
6 Nottingham Clinical Genetics Service
7 MCGM - Manchester Centre for Genomic Medicine [Manchester, UK]
8 MFT - Manchester University NHS Foundation Trust
9 Chapel Allerton Hospital
10 Leeds Teaching Hospitals NHS Trust
11 Weill Cornell Medicine [Cornell University]
12 ITX-lab - ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291
13 University Hospital Leipzig = Universitätsklinikum Leipzig
14 University Hospital Düsseldorf
15 St George’s University Hospitals
16 Service de Génétique [CHU Rouen]
17 Service de pédiatrie et neurologie pédiatrique
18 UCLH - University College London Hospitals NHS Foundation Trust [London, UK]
19 CHV - Centre Hospitalier de Versailles André Mignot
20 Unité de génétique médicale et oncogénétique [CHU Amiens Picardie]
21 Auteur indépendant
22 UP MS - University of Pécs Medical School
23 GOSHC - Great Ormond Street Hospital for Children NHS Foundation Trust [London, UK]
24 School of Medicine [University of Utah, Salt Lake City]
25 PAH - Princess Anne Hospital [Southampton, UK]
26 University Hospital Southampton NHS Foundation Trust
27 Department of Pathology [Yale]
2 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
3 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
4 William Harvey Research Institute, Barts and the London Medical School
5 Birmingham Women’s and Children’s Hospitals NHS Foundation Trust
6 Nottingham Clinical Genetics Service
7 MCGM - Manchester Centre for Genomic Medicine [Manchester, UK]
8 MFT - Manchester University NHS Foundation Trust
9 Chapel Allerton Hospital
10 Leeds Teaching Hospitals NHS Trust
11 Weill Cornell Medicine [Cornell University]
12 ITX-lab - ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291
13 University Hospital Leipzig = Universitätsklinikum Leipzig
14 University Hospital Düsseldorf
15 St George’s University Hospitals
16 Service de Génétique [CHU Rouen]
17 Service de pédiatrie et neurologie pédiatrique
18 UCLH - University College London Hospitals NHS Foundation Trust [London, UK]
19 CHV - Centre Hospitalier de Versailles André Mignot
20 Unité de génétique médicale et oncogénétique [CHU Amiens Picardie]
21 Auteur indépendant
22 UP MS - University of Pécs Medical School
23 GOSHC - Great Ormond Street Hospital for Children NHS Foundation Trust [London, UK]
24 School of Medicine [University of Utah, Salt Lake City]
25 PAH - Princess Anne Hospital [Southampton, UK]
26 University Hospital Southampton NHS Foundation Trust
27 Department of Pathology [Yale]
Heba Morsy
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- ORCID : 0000-0002-9047-0959
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Mehdi Benkirane
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- ORCID : 0000-0001-6445-6347
David Murphy
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- PersonId : 756686
- ORCID : 0000-0002-3771-3800
Siddharth Manish Banka
- Fonction : Auteur
- PersonId : 892314
Jill Clayton-Smith
- Fonction : Auteur
- PersonId : 972683
Mathilde Nizon
- Fonction : Auteur
- PersonId : 781224
- ORCID : 0000-0003-2170-4210
Benjamin Cogné
- Fonction : Auteur
- PersonId : 776524
- ORCID : 0000-0002-5503-6292
Alice Goldenberg
- Fonction : Auteur
- PersonId : 1176981
- ORCID : 0000-0002-5864-9182
Brigitte Chabrol
- Fonction : Auteur
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- IdHAL : brigitte-chabrol
Mireille Cossée
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- PersonId : 758937
- ORCID : 0000-0002-5931-7454
Michel Koenig
- Fonction : Auteur
- PersonId : 739633
- IdHAL : michel-koenig
- ORCID : 0000-0002-2430-7328
- IdRef : 073737607
Henry Houlden
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- PersonId : 956118
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Résumé
Purpose: Nonerythrocytic 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.
Methods: We 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.
Results: Statistically 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.
Conclusion: We 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.
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