Juvenile Onset or Early Adult Onset Parkinson Disease via the DNAJC6 Gene

Parkinson disease is primarily a disorder of the elderly. It affects more than 1% of 55-year-olds and more than 3% of those older than 75 years. However, juvenile onset and early adult onset forms also occur, and these forms more often have monogenic causes (Cook Shukla et al. 2019. PubMed ID: 20301402).

DNAJC6-related Parkinson disease 19 is relatively rare. This disease is divided into two forms. One type is juvenile onset with rapidly progressive (onset age around 7-11), whereas the other is early adult onset with slowly progress Parkinson disease (onset age around 30-40). The major symptoms include progressive Parkinsonism, bradykinesia, rigidity, tremor, shuffling gait, and postural instability. In some cases, patients may present other neurological symptoms such as seizures or intellectual disability. Brain MRI reveals cerebral cortical atrophy. Patients have a variable response to L-DOPA from poor effect, mild effect to good effect (Edvardson et al. 2012. PubMed ID: 22563501; Körolu et al. 2013. PubMed ID: 23211418; Olgiati et al. 2016. PubMed ID: 26528954; Puschmann. 2017. PubMed ID: 28733970).

As juvenile onset or early adult onset Parkinson disease can be caused by defect in a number of genes with variable and overlapping presentations, diagnosis by clinical manifestation and image study only can be difficult. An accurate molecular diagnosis is critical for optimal treatment, prognosis, prediction of recurrence risk, as well as future family plans.

DNAJC6-related Parkinson disease (Parkinson disease 19) is inherited in autosomal recessive manner. DNAJC6 encodes HSP40 auxilin, a neuronal protein involved om clathrin-mediated endocytosis and regulating molecular chaperone activity. Auxilin is expressed in neurons, especially in nerve terminals. A null mouse model of DNAJC6 shows a defect in clathrin mediated endocytosis. DNAJC6 related disorders are a rare cause of Parkinson disease (Edvardson et al. 2012. PubMed ID: 22563501; Köroğlu et al. 2013. PubMed ID: 23211418; Olgiati et al. 2016. PubMed ID: 26528954).

Pathogenic variants in DNAJC6 include nonsense, missense, splicing, and a small frameshift deletion. A large deletion in the DNAJC6 locus has also been reported (Human Gene Mutation Database). Apparently, truncating variants in DNAJC6 are causative for juvenile onset Parkinson disease, whereas missense variants typically result in early adult onset Parkinson disease. No de novo variants have been documented in this gene. Documented causative variants are family specific. DNAJC6 has been cited as a conditionally essential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info). DNAJC6 is relatively intolerant to loss-of-function variants (Genome Aggregation Database).

Clinical sensitivity of DNAJC6 in a large cohort of patients with DNAJC6-related disorders relevant phenotypes is unavailable in the literature because most of the studies are case reports. However, variants in this gene are a rare cause of Parkinson disease.

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 DNAJC6 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).

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).