PINK1

Inheritance Pattern: AR

Disease ID:MONDO:0011613

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0005180

Submitter: ClinGen

PINK1 was first reported in relation to autosomal-recessive Parkinson´s disease in 2004 (Valente et al. 2004, PMID: 15087508). Parkinson´s disease is a progressive degenerative disorder of the central nervous system characterized by loss of dopamine-producing neurons in the substantia nigra. Signs and symptoms include tremor, which is most pronounced during rest, muscle rigidity, slowing of voluntary movements (bradykinesia), and a tendency to fall back (postural instability). Many pathogenic variants in the biallelic state have been reported in PINK1 in about 200 patients by different authors/groups from different ethnicities (Kasten et al. 2018, PMID: 29644727, www.mdsgene.org). The mutational spectrum is broad, including nonsense, frameshift, splice site, missense changes, and also structural variants (e.g. exon deletions). Fifteen families from five publications are included in this curation, covering patients with biallelic missense or truncating variants. The additional evidence from the literature was not included in this curation because the maximum score for genetic evidence (12 pts.) has been reached. The disease follows a recessive mode of inheritance with seemingly full, age-dependent penetrance. Notably, there is an ongoing debate on the potential role of heterozygous variants as genetic risk factors for Parkinson´s disease (Klein et al. 2007, PMID: 17582365; Hu et al. 2022, PMID: 36305379). The gene-disease association is also supported by recurrent experimental evidence, including animal models and in-vitro functional assays. The mechanism of pathogenicity appears to be a loss-of-function (LOF) indicated by the many truncating variants and further supported by knock-out fly models (Park et al. 2006, PMID: 16672980; Wang et al. 2006, PMID: 16938835). There is a well-defined functional interaction with another autosomal-recessive Parkinson´s disease-linked gene, i.e. PRKN encoding Parkin. While Parkin functions as an E3-ubiquiting ligase for mitochondrial proteins, PINK1 serves as a sensor for disrupted mitochondria (Narendra et al. 2010, PMID: 20126261; Rakovic et al. 2010, PMID: 20508036). It has further repeatedly been shown that several of the PINK1 missense variants impair proper mitophagy (e.g. Kawajiri et al. 2010, PMID: 20153330; Ando et al. 2017, PMID: 28438176). In summary, biallelic, pathogenic variants in PINK1 are definitively causing autosomal-recessive Parkinson´s disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

Inheritance Pattern: AR

Disease ID:MONDO:0011613

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0011613

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0011613

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0017279

Submitter: Orphanet