Compound heterozygous and digenic inheritance in early-onset Parkinson’s disease: a systematic review

Abstract

Compound heterozygous (CH) genotypes represent an established biallelic autosomal-recessive mechanism in early-onset Parkinson’s disease (EOPD), whereas digenic inheritance (DI) has been proposed for variant combinations across two genes but is more difficult to establish. We systematically evaluated the genetic architecture and clinical features of CH cases and cases reported as DI in the published literature. This PRISMA-compliant systematic review included studies reporting CH or DI EOPD through September 2026. Two reviewers independently screened studies, extracted data, and curated variant- and case-level information. Variants were harmonized using current Human Genome Variation Society nomenclature and classified by gene, variant type, ancestry, and inheritance model. We included 106 studies comprising 304 CH and 16 DI cases. CH was dominated by PRKN , with structural variants present in 85% (205/241) of PRKN cases, predominantly exon-level deletions. PINK1 was the second most frequently implicated CH gene, whereas other CH subtypes were rare and genetically heterogeneous. Cases reported as DI involved seven genes, most commonly LRRK2 – PRKN and PINK1 – PRKN , although most variant combinations were unique. Across the CH and reported-DI groups, patients presented with a core Parkinsonian syndrome but showed substantial variability in age at onset, motor severity, and non-motor manifestations. PRKN -associated CH cases generally had earlier onset and favorable levodopa responsiveness, whereas PLA2G6 - and VPS13C -associated cases more often exhibited cognitive impairment, psychiatric features, or structural neuroimaging abnormalities. No reproducible genotype-specific phenotype emerged. Compound heterozygous represents a conventional biallelic recessive mechanism in EOPD and was largely driven by PRKN structural variation. In contrast, cases reported as DI were rare and heterogeneous, and the available evidence generally did not establish causal digenic inheritance. These findings support comprehensive detection of structural and sequence variants while highlighting the need for segregation, functional, and replication evidence to distinguish causal DI from modifier effects or coincidental variant co-occurrence.