Early-onset Parkinson's disease in a patient with a rare homozygous pathogenic GBA1 variant and no Gaucher disease symptoms

Parkinson's disease (PD) is a multifaceted neurodegenerative disorder with both non-motor and motor symptoms. Variants in the glucosylceramidase beta 1 (GBA1) gene are the strongest genetic risk factor for PD, while homozygous or compound heterozygous variants in this gene classically cause Gaucher disease (GD). This study presents an early-onset PD patient with a homozygous GBA1 deletion. Whole-exome sequencing (WES) was performed, and the identified variant was validated via Sanger sequencing. The variant was classified according to ACMG guidelines and ClinGen updates. The patient, a Brazilian female of mixed ethnicity, exhibited the full spectrum of classical motor and non-motor PD symptoms without evident hallmarks of GD. The identified homozygous GBA1 variant (NM_000157.4:c.222_224del; p.T75del; rs761621516) has a very low global allele frequency (0.00003284) and is associated with reduced enzymatic activity. This variant exhibits a founder effect among individuals of African descent. This case highlights an intricate genotype-phenotype landscape for GBA1 variants, underscoring the role of homozygous GBA1 variants in PD pathogenesis.