Duplication within 14q32.13 implicates a chimeric CLMN::SYNE3 RNA transcript in cerebellar ataxia

The spinocerebellar ataxias (SCAs) are a clinically heterogenous group of neurodegenerative disorders that affect movement, vision, speech and balance. Here, we reassign the linkage of SCA30 to 14q32.13 based on a cumulative LOD score >12. Within this interval we identified a 331 kb duplication, absent in population controls and not observed in >800 unrelated individuals with genetically unresolved cerebellar ataxia. RNA-Seq analysis of patient-derived lymphoblastoid cell lines revealed a splice-mediated chimeric transcript resulting from the duplication event. This transcript joined exon 1 of CLMN to exon 2 of SYNE3. In silico translation predicted that this chimeric transcript would produce a short N-terminal peptide corresponding to exon 1 of CLMN and the usually untranslated region of exon 2 of SYNE3 fused to the complete and in-frame SYNE3 protein. Transient overexpression of SYNE3 or the CLMN::SYNE3 fusion protein, in both HeLa cells and mouse primary cortical neurons, resulted in equivalent cellular outcomes including altered nuclear morphology and chromosomal DNA fragmentation. SYNE3 forms part of the linker of nucleoskeleton and cytoskeleton complex and is not usually expressed in cerebellar Purkyn[e] neurons while, CLMN has a Purkyn[e] specific expression pattern within the brain. Our data suggests that ectopic expression of SYNE3 in cerebellar Purkyn[e] neurons, mediated by the CLMN promoter, leads to cerebellar atrophy and causes spinocerebellar ataxia in the SCA30 family. This is an example of Mendelian disease arising from a novel, chimeric transcript with a likely dominant negative effect. Chimeric transcripts are commonly associated with cancers, but they are not often associated with monogenic disorders. Detection of chimeric transcripts as part of structural variant analysis could increase the genetic diagnostic yield of Mendelian disorders.