Objective: To screen for PRKN mutations at the population scale.

Background: PRKN mutations are the most common recessive cause of Parkinson’s disease (PD) and are a promising target for gene replacement therapies. Identification of biallelic PRKN carriers at the population scale, however, remains a challenge, as half of mutations are copy number variants (CNVs) and many single nucleotide variants (SNVs) are of unknown significance.

Method: Genotyping microarray (NeuroX or Neuro Consortium Array) data were evaluated as a screening tool for PRKN biallelic patients in a cohort of 732 PD patients. All patients also received whole genome sequencing (WGS), which served as the gold standard for evaluating microarray accuracy. Finally, an algorithm was developed to identify PRKN CNVs from microarray data and applied to participants in the UK Biobank.

Results: All PRKN CNVs (14/14) and roughly a third of pathogenic SNPs (6/19) in our cohort were identified by microarray. Microarray detected at least one mutation in 7/8 biallelic PRKN patients and 8/17 monoallelic PRKN patients. This yielded a negative predictive value of 99.8% and a positive predictive value (PPV) of 46.7% for identifying biallelic PRKN patients (sensitivity = 87.5% and specificity = 98.9%). Including cutoff values for age at onset (AAO), ≤40, and olfaction, UPSIT ≥ 20, increased the PPV to 75%. In cases where pathogenicity of a variant was uncertain, assaying skin fibroblasts reliably distinguished monoallelic (N=3) from biallelic (N=8) PRKN carriers and resolved a novel intronic variant identified by WGS as loss of function. Finally, an algorithm for calling PRKN CNVs from microarray data was developed and applied to approximately half a million participants in the UK Biobank, detecting 2,597 CNVs. Additionally, 3,975 alleles had a p.T240M or p.R275W pathogenic mutation. Altogether, 1.34% of participants carried a pathogenic mutation. Those with one detected PRKN mutation were as likely as those without a mutation to have PD (OR = 1.38, p-value = 0.063) or a parent with PD (OR = 1.05, p-value = 0.41).

Conclusion: PRKN mutation screening by microarray is feasible at a population scale and is further improved by inclusion of clinical data, such as AAO and UPSIT. Additionally, in the largest cohort of PRKN carriers tested, having a PRKN heterozygous mutation did not increase the risk of PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/comprehensive-analysis-of-prkn-in-a-large-parkinsons-disease-cohort-identifies-causative-mutations-and-validates-population-scale-screening-by-microarray/