Inès Mademan, Florian Harmuth, Ilaria Giordano, Dagmar Timmann, Stefania Magri, Tine Deconinck, Jens Claaßen, Daniel Jokisch, Gencer Genc, Daniela Di Bella, Silvia Romito, Rebecca Schüle, Stephan Züchner, Franco Taroni, Thomas Klockgether, Ludger Schöls, Peter De Jonghe, Peter Bauer, EOA Consortium, Jonathan Baets, Matthis Synofzik
Brain - Journal of Neurology, volume 139, issue 5, pages 1378-1393
We recently reported in Brain a large multi-centre study suggesting that truncating SYNE1 mutations are a recurrent cause of recessive ataxia also outside Quebec (23/434 = 5.3% of patients with unexplained early-onset ataxia) (Synofzik et al., 2016). Moreover, this study indicated that SYNE1 ataxia might commonly present with complex multisystemic phenotypes rather than pure cerebellar ataxia, including in particular motor neuron and brainstem dysfunction (Synofzik et al., 2016). However, confirmation of both the frequency estimate and the complex phenotypic spectrum is still lacking, raising the question whether these findings indeed represent systematic results rather than just exceptional or coincidental associations.
Here, we now report the mutational and phenotypic findings on SYNE1 from a second, independent ataxia series of 116 patients. These findings not only confirm the high frequency of SYNE1 ataxia and extend both the mutational spectrum (seven novel index patients, 12 novel SYNE1 mutations) and the multisystemic phenotypic spectrum, including amyotrophic lateral sclerosis (ALS)-like motor neuron features, they also indicate that muscle immunohistochemistry might provide a valuable diagnostic biomarker for clarifying the pathogenic contribution of SYNE1 missense variants. This observation may have consequences for clinical SYNE1 diagnostics, as diagnostic tests are urgently needed for clarifying the role of the ubiquitous SYNE1 missense variants with unknown clinical significance (VUS), which are frequently found in neurological and non-neurological patients and controls (Synofzik et al., 2016).
Index subjects (n = 116) with unexplained degenerative ataxia compatible with autosomal recessive inheritance (no ataxia in the parental generation) and negative for trinucleotide repeat expansions causing Friedreich’s ataxia (FRDA) were compiled from three sources: the Early Onset Ataxia Consortium (n = 88), the ataxia centre Antwerp, Belgium (n = 9), and the ataxia centre Milano, Italy (n = 19). All subjects originated from European, Middle East or Mediterranean countries. This series was sequenced after and independent from the cohort of the previous SYNE1 study (Synofzik et al., 2016). None of the subjects had been part of the previous screening cohort. Subjects were screened for SYNE1 mutations by one of the following three next-generation sequencing methods: (i) a high coverage HaloPlex gene panel kit (Agilent) including >120 known ataxia genes (n = 88); (ii) targeted exon-capture sequencing strategy (Illumina Nextera Rapid Capture Custom kit) including 107 known ataxia genes (n = 19); or (iii) whole-exome sequencing using the SureSelect Human All Exon 50 Mb kit (Agilent) (n = 9) (for technical details, filter settings, and criteria for inclusion of SYNE1 missense variants, see the online Supplementary material). All index patients carrying two pathogenic SYNE1 alleles and their affected siblings received a systematic clinical assessment, as described in detail in the previous study (Synofzik et al., 2016) (Table 1).