Two Different PRKN Compound Heterozygous Variants Combinations in the Same Family

Bi-allelic PRKN variants are involved in 34% to 45% of familial recessive early-onset Parkinson ’ s diseases, 1,2

dopaminergic depletion (Fig. 1B). At 37, she displayed a persistent bilateral predominantly left-sided ARS with typical rest tremors and dystonic posture with clawed toes. Her disease progressed slowly without significant axial signs nor cognitive status or impulse control disorder.
We report four relatives displaying PARK-Parkin related to two combinations of PRKN pathogenic variants.
To our knowledge, our report is the first to describe two sets of PRKN pathogenic variants CNV/CNV and CNV/SNV in the same family. This report highlights that different molecular mechanisms can induce one disease, even in the same family. It encourages geneticists to consider a recessive pathology even when dominant inheritance is suggested and supports the importance of combining CNV and SNV analysis.
The hypothesis that heterozygous PRKN variants are risk factors of classical PD was definitively ruled out recently. 8 Then our report strongly supports the re-assessment strategy of possible additional gene mutations in patients with single PRKN variant and familial PD.
Bi-allelic PRKN variants are involved in PARK-Parkin and a vast mutational spectrum has already been described. However, no correlation between the severity and/or precocity of clinical involvement and the nature of the variants in PRKN has been established. Nevertheless, incomplete penetrance or variable expression has already been reported, 9,10 for example, in a family with five PRKN compound heterozygous relatives including one asymptomatic member. 9 Phenotype could also be modulated by variants in other key genes belonging to the parkin pathway. 9,10 Such compensatory mechanism has already been suggested considering an additional PINK1 variant enhancing PRKN mutations. 3 The daughter developed PARK-Parkin around 10 years before other relatives in the present family. Although PINK1 was included in the targeted genes panel with no anomaly detected, all genes among the parkin pathway have not been explored, and additional variant in a non-tested gene cannot be ruled out. This difference in age at onset could also be explained by the C-terminal position of the splice variant inducing abnormal protein production, compared to the absence of protein induced by the N-terminal deletions. 4 For example, the most severe phenotype in Erer's cohort was reported with heterozygous exon 11 nonsense variant associated with a non-pathogenic variant in intron 4. 1 Protein expression assays such as Western Blot could be interesting to support this hypothesis. In any case, other similar cases are requested to confirm this hypothesis.