Young-onset Parkinson disease: genes and variants

Genes linked to Young-onset Parkinson disease

• PRKN: E3 ubiquitin-protein ligase parkin

  Its parkin ubiquitin-ligase activity marks damaged mitochondrial proteins after PINK1 activation and helps eliminate dysfunctional mitochondria through mitophagy. Biallelic loss-of-function variants are a major cause of autosomal recessive juvenile or early-onset Parkinson disease.

  2 disease-causing and 2 uncertain variants in PRKN are linked to Young-onset Parkinson disease.

• LRRK2: Leucine-rich repeat serine/threonine-protein kinase 2

  Its kinase and GTPase activities regulate Rab proteins, vesicle trafficking, lysosomal function, and cellular stress responses. Gain-of-function variants, especially G2019S, are among the most common genetic causes of autosomal dominant Parkinson disease.

  1 disease-causing and 0 uncertain variants in LRRK2 are linked to Young-onset Parkinson disease.

• PARK7: Parkinson disease protein 7

  It supports mitochondrial quality control, redox homeostasis, and cellular responses to oxidative stress. Biallelic loss-of-function variants cause a rare autosomal recessive form of early-onset Parkinson disease.

  1 disease-causing and 0 uncertain variants in PARK7 are linked to Young-onset Parkinson disease.

• SYNJ1: Polyphosphatidylinositol phosphatase SYNJ1

  It remodels phosphoinositides during clathrin-mediated synaptic-vesicle recycling and helps nerve terminals rapidly regenerate release-ready vesicles. Biallelic pathogenic variants can cause early-onset parkinsonism or severe developmental and epileptic encephalopathy.

  1 disease-causing and 0 uncertain variants in SYNJ1 are linked to Young-onset Parkinson disease.

Known disease-causing variants in Young-onset Parkinson disease

Uncertain variants in Young-onset Parkinson disease that look disease-causing

Same protein, different disease

• Autosomal recessive juvenile Parkinson disease 2 is also caused by PRKN variants; they fall mostly in different places as the Young-onset Parkinson disease variants (15 disease-causing).
• Ovarian cancer is also caused by PRKN variants; they fall mostly in different places as the Young-onset Parkinson disease variants (5 disease-causing).
• Lung cancer is also caused by PRKN variants; they fall mostly in different places as the Young-onset Parkinson disease variants (4 disease-causing).
• Autosomal recessive early-onset Parkinson disease 6 is also caused by PARK7 variants; they fall mostly in different places as the Young-onset Parkinson disease variants (7 disease-causing).
• Autosomal dominant Parkinson disease 8 is also caused by LRRK2 variants; they fall mostly in different places as the Young-onset Parkinson disease variants (7 disease-causing).

Diseases related to Young-onset Parkinson disease

• Parkinson disease, also linked to LRRK2, PARK7 and PRKN
• Autosomal dominant Parkinson disease 8, also linked to LRRK2 and PRKN
• Ovarian cancer, also linked to PRKN
• Autosomal recessive juvenile Parkinson disease 2, also linked to PRKN
• Autosomal recessive early-onset Parkinson disease 6, also linked to PARK7
• Ovarian neoplasm, also linked to PRKN
• Lung cancer, also linked to PRKN
• Genetic developmental and epileptic encephalopathy, also linked to SYNJ1
• Early-onset Parkinson disease 20, also linked to SYNJ1

Frequently asked questions

Which genes are linked to Young-onset Parkinson disease?

In CATVariant, Young-onset Parkinson disease is linked to 4 analyzed proteins: PRKN (E3 ubiquitin-protein ligase parkin), LRRK2 (Leucine-rich repeat serine/threonine-protein kinase 2), PARK7 (Parkinson disease protein 7) and SYNJ1 (Polyphosphatidylinositol phosphatase SYNJ1).

How many genetic variants are linked to Young-onset Parkinson disease?

8 variants: 5 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 2 are of uncertain significance or have conflicting reports.

Which uncertain variants in Young-onset Parkinson disease look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example PRKN G430S. These are leads for expert review, not diagnoses.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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