The most common structural variant expected at the GBA1 locus may be detected by a simple amplification method: Implications for screening Parkinson’s disease variants

Abstract

Introduction

Recombinant alleles are responsible for a large part of Gaucher disease (GD) causing alterations. This is because GBA1, the gene involved in GD, has a 96 % homologous pseudogene, GBAP1, at a 1.6kb distance. GBA1 gene variants are also the most common molecular alteration among Parkinson’s Disease (PD) patients, even in heterozygosity. The most common GD causing recombinant allele is RecNciI (which comprises three single nucleotide variants: p.L483P, p.A495P and p.Val499=). Every time this GBA1 recombinant allele is formed by an unequal crossing over event, another allele is formed with a copy number gain, i.e., a triplicate copy where GBA1 and GBAP1 are preserved, and a third intermediate copy is formed with its sequence starting at GBAP1 and then reverting to GBA1 after the recombination point (called here TRIP-SV).

Methods

Two cohorts were screened for the mid part of the TRIP-SV in PD patients using a specific amplification method. One cohort was formed by 65 early onset PD patients and the other with 100 idiopathic PD patients.

Results

In each cohort one patient carrying the TRIP-SV was detected. Sanger sequencing confirmed the expected sequence of the TRIP-SV.

Conclusion

Our findings indicate that it is mandatory that groups analyzing the GBA1 gene searching for molecular causation of PD investigate the presence of this SV encompassing the GBA1/GBAP1 region, which pathogenicity deserves further studies.