Understanding Parkinson disease in Spain: Genetic and clinical insights

Abstract

Background and purpose: Parkinson disease (PD) is a complex and heterogeneous neurodegenerative disorder with a broad spectrum of clinical manifestations, determined by a complex interplay of environmental and genetic factors. This study aimed to investigate genetic variants associated with PD and assess their impact on the disease phenotype through genotype-phenotype correlations.

Methods: We employed a targeted resequencing panel to analyze 27 genes linked to PD in a cohort of 1185 PD patients from southern Spain. Variants were categorized based on the American College of Medical Genetics and Genomics pathogenicity criteria. Demographic and clinical data were also collected.

Results: Among the patients analyzed, 13.5% carried potential disease-causing pathogenic or likely pathogenic variants in 12 different genes, indicating significant genetic heterogeneity. The most frequently affected genes were LRRK2, PRKN, and GBA1 (accounting for 72.1% of positive cases). Sex-specific differences were observed, with a higher proportion of female patients carrying LRRK2 variants. Differences in age at onset and clinical features were also observed among the different mutated genes. Notably, variants in genes associated with atypical parkinsonism presented distinct clinical presentations, highlighting the importance of genetic factors in the differential diagnosis.

Conclusions: Our study provides valuable information on the genetic landscape of PD and its clinical manifestations. The observed genotype-phenotype correlations, along with sex-specific differences, emphasize the complexity of PD pathogenesis, underlining the importance of personalized approaches to PD diagnosis and treatment. Further investigations into genetic interactions and population-specific effects are warranted to enhance our understanding of PD etiology and improve patient care.

Keywords: Parkinson disease; clinical insights; genetic insights; targeted sequencing.

FIGURE 1

The frequency of causative genes in patients initially diagnosed with Parkinson disease (PD). (a) Overall diagnostic yield. (b) Distribution of disease‐causative genes in 160 probands. (c) Features of the analyzed PD cohort. EOPD, early onset PD (age at onset ≤ 50 years); LOPD, late onset PD (age at onset > 50 years); NGD, patients with a negative genetic diagnosis; PGD, patients with a positive genetic diagnosis; UGD, patients with an unknown genetic diagnosis.

FIGURE 2

Boxplots of age at onset under specific genes. Dots represent the age at onset in each patient carrying putative causative variants in each gene. Horizontal lines represent the median onset. M, mild; NGD, Parkinson disease (PD) patients with a negative genetic diagnosis; PGD, PD patients with a positive genetic diagnosis; RF, risk factor; S, severe; T, total cohort with pathogenic or likely pathogenic variants in GBA1 and those with risk variants in GBA1; UGD, PD patients with an unknown genetic diagnosis.

FIGURE 3

Bar graphs showing family history of Parkinson disease (PD) and gender distribution across specific genes. NGD, PD patients with a negative genetic diagnosis; PGD, PD patients with a positive genetic diagnosis; UGD, PD patients with an unknown genetic diagnosis.