A Novel Exon Duplication in the SACS Gene in Charlevoix-Saguenay Ataxia and a Summary of Polish Cases

Jakub P Fichna,1,* Ewelina Elert-Dobkowska,2,* Wiktoria Radziwonik-Fraczyk,2 Karolina Ziora-Jakutowicz,2 Michalina Maria Wężyk,1 Mariusz Berdyński,1 Jacek Zaremba,2 Cezary Żekanowski,1 Małgorzata Bednarska-Makaruk2 1Department of Neurogenetics and Functional Genomics, Mossakowski Medical Research Institute - Polish Academy of Sciences, Warsaw, Poland; 2Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland*These authors contributed equally to this workCorrespondence: Jakub P Fichna, Department of Neurogenetics and Functional Genomics, Mossakowski Medical Research Institute - Polish Academy of Sciences, Pawinskiego 5 Street, Warszawa, 02-106, Poland, Tel +48 22 608 6485, Fax +48 22 668 5532, Email [email protected]: Mutations in the SACS gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a clinically and genetically heterogeneous neurodegenerative disorder. ARSACS typically manifests as slowly progressive ataxia with spasticity and sensorimotor neuropathy. Nevertheless, an array of additional features may also be observed, including hearing impairment, epileptic seizures, and even the absence of spasticity. Reports of SACS mutations in Polish patients are rare. Here we report a compound heterozygous pathogenic variants in the SACS gene, a novel duplication of exon 6, and a frameshift deletion c.12923_12927del 12921_12925del p.(Lys4308SerfsTer21) in a Polish patient presenting with progressive ataxia, spasticity, and peripheral neuropathy. This is the first case with a rearrangement of a complete single exon of the SACS gene. We also review six previously described Polish individuals with SACS variants, noting that all presented with cerebellar ataxic gait and cerebellar atrophy on brain MRI scans. Across these cases, nine rare pathogenic SACS variants were identified. This study adds to the ARSACS-associated mutation spectrum, provides further insights into genotype-phenotype correlations, and highlights the importance of testing for structural variants.Keywords: ataxia, neurodegeneration, diagnostics, next generation sequencing, CNV, expression