Autosomal dominant Parkinson disease 8: genes and variants

Genes linked to Autosomal dominant Parkinson disease 8

• 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.

  7 disease-causing and 451 uncertain variants in LRRK2 are linked to Autosomal dominant Parkinson disease 8.

• SNCA: Alpha-synuclein

  Alpha-synuclein is a neuronal protein that supports synaptic-vesicle trafficking, priming, and neurotransmitter release. Misfolded or aggregated alpha-synuclein is a defining feature of Parkinson disease and Lewy-body disorders.

  3 disease-causing and 1 uncertain variants in SNCA are linked to Autosomal dominant Parkinson disease 8.

• 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.

  1 disease-causing and 0 uncertain variants in PRKN are linked to Autosomal dominant Parkinson disease 8.

Where Autosomal dominant Parkinson disease 8 variants cluster

• LRRK2 Roc (positions 1328–1511): 4 of 7 disease-causing changes, 7.8× more than its size predicts.

Known disease-causing variants in Autosomal dominant Parkinson disease 8

Which prediction tools work for Autosomal dominant Parkinson disease 8

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 73 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 64 out of 100

Same protein, different disease

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

Diseases related to Autosomal dominant Parkinson disease 8

• Parkinson disease, also linked to LRRK2, PRKN and SNCA
• Young-onset Parkinson disease, also linked to LRRK2 and PRKN
• Ovarian cancer, also linked to PRKN
• Autosomal recessive juvenile Parkinson disease 2, also linked to PRKN
• Ovarian neoplasm, also linked to PRKN
• Lung cancer, also linked to PRKN
• Lewy body dementia, also linked to SNCA

Frequently asked questions

Which genes are linked to Autosomal dominant Parkinson disease 8?

In CATVariant, Autosomal dominant Parkinson disease 8 is linked to 3 analyzed proteins: LRRK2 (Leucine-rich repeat serine/threonine-protein kinase 2), SNCA (Alpha-synuclein) and PRKN (E3 ubiquitin-protein ligase parkin).

How many genetic variants are linked to Autosomal dominant Parkinson disease 8?

524 variants: 11 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 452 are of uncertain significance or have conflicting reports.

Which uncertain variants in Autosomal dominant Parkinson disease 8 look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Autosomal dominant Parkinson disease 8?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.64, based on 9 disease-causing and 69 harmless variants).

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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