Objective: We aim to identify new gene variants associated with familial and early-onset Parkinson’s disease (PD), through genetic comparison of affected and unaffected family members. A secondary aim is to establish a network of PD patients with an identified genetic cause, who are eligible to participate in future research and clinical trials.

Background: Known genetic mutations account for only ~1% of PD cases. Those with an early age at onset or a family history of PD are more likely to have a strong genetic contribution, however even among these patients the majority do not carry an identified mutation.

Method: We are recruiting PD patients with either an age at onset ≤ 45 years, a family history of PD, or an identified PD mutation (index case), and their affected and unaffected relatives. Blood or saliva samples are collected for DNA extraction, and clinical data are collected via standardised assessments and questionnaires. A range of genotyping methods are employed including allele specific assays, single nucleotide variant chips and whole exome/genome sequencing.

Results: We have screened 926 samples (from PD patients and their relatives) with at least one method: 156 samples have been screened with the LRRK2 KASPR assay for G2019S, 916 samples have been screened with the NeuroChip SNP array, 679 samples have been screened with MLPA, 46 samples have been whole exome sequenced, and 135 samples have been whole genome sequenced through the 100,000 Genomes Project. 12.8% of the 732 families screened carry a PD-associated variant. 4.1% carry a pathogenic LRRK2 mutation, 4.8% carry a heterozygous variant in GBA, 1.6% carry bi-allelic mutations in PRKN/PINK1, and 2.3% carry single heterozygous mutations in PRKN/PINK1.  95.6% of recruited patients have consented to be contacted about future research opportunities.

Conclusion: No known mutations have been identified for ~90% of the patients with early onset or familial PD screened so far. It is likely there are additional rare pathogenic and risk conferring variants to discover through planned linkage and segregation analyses. A cohort of patients interested in participating in future studies has been established.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsons-families-project-analysis-of-a-large-cohort-of-patients-with-early-onset-and-familial-parkinsons-disease/