A Case Report of SYNE1 Deficiency-Mimicking Mitochondrial Disease and the Value of Pangenomic Investigations

Abstract

Mitochondrial disorders are characterized by a huge clinical, biochemical, and genetic heterogeneity, which poses significant diagnostic challenges. Several studies report that more than 50% of patients with suspected mitochondrial disease could have a non-mitochondrial disorder. Thus, only the identification of the causative pathogenic variant can confirm the diagnosis. Herein, we describe the diagnostic journey of a family suspected of having a mitochondrial disorder who were referred to our Genetics Department. The proband presented with the association of cerebellar ataxia, COX-negative fibers on muscle histology, and mtDNA deletions. Whole exome sequencing (WES), supplemented by a high-resolution array, comparative genomic hybridization (array-CGH), allowed us to identify two pathogenic variants in the non-mitochondrial SYNE1 gene. The proband and her affected sister were found to be compound heterozygous for a known nonsense variant (c.13258C>T, p.(Arg4420Ter)), and a large intragenic deletion that was predicted to result in a loss of function. To our knowledge, this is the first report of a large intragenic deletion of SYNE1 in patients with cerebellar ataxia (ARCA1). This report highlights the interest in a pangenomic approach to identify the genetic basis in heterogeneous neuromuscular patients with the possible cause of mitochondrial disease. Moreover, even rare copy number variations should be considered in patients with a phenotype suggestive of SYNE1 deficiency.

Keywords: SYNE1; WES; array-CGH; mitochondrial disorder.

Figure 1

(A) Pedigree of the family and segregation analysis of the SYNE1 variant NM_182961.4:c.13258C>T and the deletion NC_000006.11:g.152538134_152535265del. The filled bottom left quarter represents cerebellar ataxia symptom, the filled bottom right quarter represents axonal sensitive neuropathy, and the striped top quarter represents pyramidal syndrome. (B) View from Cytogenomic software (v.4.0.3.12) of SYNE1 with a focus on the two deleted oligonucleotides (red dots). (C) Schematic view of the deletion encompassing the exon 122 and part of intron 121 and intron 122. (D) Representative Sanger sequencing electrophoregrams illustrating the breakpoint between intron 121 and intron 122. The 23 bp homology sequence is shown in the red square.