Dataset Information

Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia.

ABSTRACT:

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.

SUBMITTER: Morsy H

PROVIDER: S-EPMC10620943 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia.

Morsy Heba H Benkirane Mehdi M Cali Elisa E Rocca Clarissa C Zhelcheska Kristina K Cipriani Valentina V Galanaki Evangelia E Maroofian Reza R Efthymiou Stephanie S Murphy David D O'Driscoll Mary M Suri Mohnish M Banka Siddharth S Clayton-Smith Jill J Wright Thomas T Redman Melody M Bassetti Jennifer A JA Nizon Mathilde M Cogne Benjamin B Jamra Rami Abu RA Bartolomaeus Tobias T Heruth Marion M Krey Ilona I Gburek-Augustat Janina J Wieczorek Dagmar D Gattermann Felix F Mcentagart Meriel M Goldenberg Alice A Guyant-Marechal Lucie L Garcia-Moreno Hector H Giunti Paola P Chabrol Brigitte B Bacrot Severine S Buissonnière Roger R Magry Virginie V Gowda Vykuntaraju K VK Srinivasan Varunvenkat M VM Melegh Béla B Szabó András A Sümegi Katalin K Cossée Mireille M Ziff Monica M Butterfield Russell R Hunt David D Bird-Lieberman Georgina G Hanna Michael M Koenig Michel M Stankewich Michael M Vandrovcova Jana J Houlden Henry H

Genetics in medicine : official journal of the American College of Medical Genetics 20221104 1

<h4>Purpose</h4>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.<h4>Methods</h4>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 fi ...[more]

PMID: 36331550

Similar Datasets

Project description:ImportanceThe family of genes implicated in hereditary spastic paraplegias (HSPs) is quickly expanding, mostly owing to the widespread availability of next-generation DNA sequencing methods. Nevertheless, a genetic diagnosis remains unavailable for many patients.ObjectiveTo identify the genetic cause for a novel form of pure autosomal dominant HSP.Design, setting, and participantsWe examined and followed up with a family presenting to a tertiary referral center for evaluation of HSP for a decade until August 2014. Whole-exome sequencing was performed in 4 patients from the same family and was integrated with linkage analysis. Sanger sequencing was used to confirm the presence of the candidate variant in the remaining affected and unaffected members of the family and screen the additional patients with HSP. Five affected and 6 unaffected participants from a 3-generation family with pure adult-onset autosomal dominant HSP of unknown genetic origin were included. Additionally, 163 unrelated participants with pure HSP of unknown genetic cause were screened.Main outcome and measureMutation in the neuronal isoform of carnitine palmitoyl-transferase (CPT1C) gene.ResultsWe identified the nucleotide substitution c.109C>T in exon 3 of CPT1C, which determined the base substitution of an evolutionarily conserved Cys residue for an Arg in the gene product. This variant strictly cosegregated with the disease phenotype and was absent in online single-nucleotide polymorphism databases and in 712 additional exomes of control participants. We showed that CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons and interacts with atlastin-1, an endoplasmic reticulum protein encoded by the ATL1 gene known to be mutated in pure HSPs. The mutation, as indicated by nuclear magnetic resonance spectroscopy studies, alters the protein conformation and reduces the mean (SD) number (213.0 [46.99] vs 81.9 [14.2]; P < .01) and size (0.29 [0.01] vs 0.26 [0.01]; P < .05) of lipid droplets on overexpression in cells. We also observed a reduction of mean (SD) lipid droplets in primary cortical neurons isolated from Cpt1c-/- mice as compared with wild-type mice (1.0 [0.12] vs 0.44 [0.05]; P < .001), suggesting a dominant negative mechanism for the mutation.Conclusions and relevanceThis study expands the genetics of autosomal dominant HSP and is the first, to our knowledge, to link mutation in CPT1C with a human disease. The association of the CPT1C mutation with changes in lipid droplet biogenesis supports a role for altered lipid-mediated signal transduction in HSP pathogenesis.

Dataset Information

Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia.

Purpose

Methods

Results

Conclusion

Publications

Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia.

Similar Datasets

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