Spinocerebellar Ataxia, Autosomal Recessive-8 via the SYNE1 Gene Exons 2-146

Autosomal recessive cerebellar ataxia 1 (ARCA1), also known as autosomal recessive spinocerebellar ataxia 8 (SCAR8) is a phenotypically homogeneous disorder with onset from the late teens to the fifth decade of life. Patients present with cerebellar ataxia or dysarthria and slowly progress to significant manifestations of both (Gros-Louis et al. 2007). Additional clinical signs include dysmetria, abnormal tendon reflexes in the lower extremities, and mild oculomotor involvement (Dupré et al. 2007). MRI studies show diffuse atrophy limited to the cerebellum (Dupré et al. 2011). Emery-Dreifuss muscular dystrophy (EDMD) is characterized clinically by joint contractures beginning in early childhood, slowly progressive muscle weakness and wasting, and cardiac involvement. A phenotype consisting of congenital muscular dystrophy (CMD) with adducted thumbs, mild mental retardation, and cerebellar hypoplasia has been reported in two sibs from a consanguineous family (Voit et al. 2002). SYNE1 variants were identified in these patients, and their muscle lacked SYNE1 protein at the nuclear envelope (Voit et al. 2007). One pedigree with arthrogryposis multiplex congenita due to a homozygous SYNE1 splicing variant has been reported (Attali et al. 2009).

Cerebellar ataxia due to SYNE1 variants is inherited as an autosomal recessive disorder in families in the Beauce region of southeastern Quebec and, for this reason, it is also known as recessive ataxia of Beauce (Noreau A et al. 2013). EDMD due to SYNE1 variants appears to be inherited in a dominant pattern as a result of disrupted binding of nesperin-1 to lamin and emerin (Zhang et al. 2007). CMD with adducted thumbs and mental retardation is inherited as an autosomal recessive disorder, as is the one case of SYNE1-related arthrogryposis.

SYNE1 variants are the only known cause of autosomal recessive spinocerebellar ataxia 8. Clinical sensitivity should be high for patients with symptoms consistent with a pure cerebellar ataxia who are of French Canadian heritage. Because allelic heterogeneity exists for this homogeneous population, it is reasonable to expect this gene to be causative in other populations as well. Among 190 probands with EDMD and without lamin or emerin variants, three were found to have heterozygous SYNE1 variants (Zhang et al. 2007). Too few cases of CMD caused by SYNE1 variants have been reported to estimate clinical sensitivity.

This test provides full coverage of all coding exons of the SYNE1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).