Exploring the genetic spectrum of parkinsonism in Brazil

Parkinsonism is a motor syndrome traditionally considered sporadic, but genetic factors are increasingly recognized. While next-generation sequencing (NGS) has identified pathogenic variants in Parkinson's disease (PD) and related disorders, data from admixed populations like Brazilians remain limited. This study aimed to evaluate the utility of whole-exome sequencing (WES) in identifying pathogenic variants in Brazilian patients with early-onset parkinsonism or a family history of the condition.

Patients from the Federal University of Paraná's movement disorders clinic were recruited between December 2019 and July 2023. Inclusion criteria included parkinsonism, symptom onset before 45 years, and/or family history. WES was performed, with variant pathogenicity assessed using ACMG criteria. Clinical data included MDS-UPDRS-III and MoCA scores.

Of 52 patients evaluated, 44 met PD criteria (pathogenic variants in 20.45%), while 8 had syndromic parkinsonism (pathogenic variants in 50%). The most commonly implicated genes were GBA and LYST, followed by LRRK2, PRKN, and NPC1. A novel C19Orf12 variant (c.362T > G, p.Leu121Arg) was identified in juvenile parkinsonism. Additionally, a LYST variant (c.9320G > A, p.Arg3107His), associated with Chédiak-Higashi syndrome but without classic hematological features, was reported.

WES proved valuable in detecting rare pathogenic variants in Brazilian patients, uncovering atypical phenotypes and expanding the spectrum of genetic findings. These results highlight the need for broader genetic studies in admixed populations to refine diagnostics and better characterize such unique cohorts.