SYNJ1-Related Disorders via the SYNJ1 Gene

Parkinson disease affects more than 1% of 55-year-olds and more than 3% of those older than 75 years. SYNJ1-related Parkinson disease (Parkinson disease 20) is a relatively rare, young adult onset (around twenties) disorder. The major symptoms include progressive Parkinsonism, bradykinesia, rigidity, tremor, shuffling gait, and postural instability. Different from other types of Parkinson disease, patients may present other features such as seizures, dystonia, cognitive impairment, and abnormal eye movements in early childhood. Brain MRI reveals cerebral cortical atrophy. Patients have a favorable response to L-DOPA, but can also have secondary dyskinesias (Krebs et al. 2013. PubMed ID: 23804563; Quadri et al. 2013. PubMed ID: 23804577; Cao et al. 2017. PubMed ID: 28231468; Olgiati et al. 2014. PubMed ID: 24816432; Rauschendorf et al. 2017. PubMed ID: 27869329).

In addition, pathogenic variants in SYNJ1 are also causative for early infantile epileptic encephalopathy 53. Major symptoms include intractable epilepsy, progressive neurological decline and intellectual disability. Other features include hypotonia, dystonia, central visual impairment, and progressive feeding problems (Hardies et al. 2016. PubMed ID: 27435091).

Both SYNJ1-related disorders share overlapping features such as seizures. As Parkinson disease and epilepsy can be caused by defect in a number of genes with variable and overlapping presentations, they can be difficult to diagnose by clinical manifestation, EEG and image study only. An accurate molecular diagnosis is critical for treatment, prognosis, prediction of recurrence risk, as well as future family planning.

SYNJ1-related Parkinson disease (Parkinson disease 20) and SYNJ1-related early infantile epileptic encephalopathy 53 are inherited in autosomal recessive manner. They are caused by pathogenic variants in SYNJ1, which encodes Synaptojanin-1, a major presynaptic polyphosphoinositide phosphatase. Synaptojanin-1 plays an important role in the phosphoinositide metabolism in synaptic vesicle recycling. SYNJ1-related disorders are a minor cause for Parkinson disease and early infantile epileptic encephalopathy (Krebs et al. 2013. PubMed ID: 23804563).

Synapsins play a role in synaptic neurotransmission, neuronal development, synaptogenesis, maintenance of mature synapses, and plasticity. Pathogenic variants in SYNJ1 include nonsense, missense, splicing, and small frameshift deletion/duplication variants. No large deletions/duplications in the SYNJ1 locus have been reported (Human Gene Mutation Database). No de novo variants have been documented in this gene. The vast majority of pathogenic variants are missense. The most documented variant in SYNJ1, p.Arg258Gln, is located in the Synaptojanin N-terminal region with allele frequency of 0.002% in the non-Finnish European population (gnomAD database). A mouse model carrying a pathogenic variant showed a link between synaptic endocytic dysfunction and Parkinson’s disease (Krebs et al. 2013. PubMed ID: 23804563; Olgiati et al. 2014. PubMed ID: 24816432; Cao et al. 2017. PubMed ID: 28231468). SYNJ1 has been cited as a nonessential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

Clinical sensitivity of SYNJ1 in a large cohort of patients with SYNJ1-related disorders is unavailable in the literature. Most of the studies are rare case reports.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the SYNJ1 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to 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).

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels.