Comprehensive short and long read sequencing analysis for the Gaucher and Parkinson's disease-associated GBA gene

Commun Biol. 2022 Jul 6;5(1):670. doi: 10.1038/s42003-022-03610-7.

PMID: 35794204

Marco Toffoli, Xiao Chen, Fritz J Sedlazeck

Highlights: This study highlights the importance of accurate GBA analysis in Gaucher and Parkinson’s disease patients.

Abstract

Background: Carriers of GBA variants are more likely to develop Lewy body dementia (LBD) and Parkinson's disease (PD). Genetic analysis is made more difficult by the presence of the pseudogene GBAP1, which predisposes to structural variations.

Methods: Two approaches are offered in this study—Oxford Nanopore sequencing following PCR enrichment and Gauchian, a tool for short-read, whole-genome data analysis—to resolve recombinant alleles and other variants in GBA.

Results: For 42 samples with a variety of recombinants and GBAP1-related mutations, both approaches were consistent, and Gauchian performed better than the GATK Best Practices pipeline. Copy number variations (CNVs) spanning GBAP1 are rather common in Africans, according to analysis of over 10,000 individual sequences using the Gauchian method. In PD and LBD, CNV frequencies are comparable to those in controls. Gains and other mutations may coexist in patients, and a moderating influence cannot be ruled out. More GBA variants, particularly severe ones, are found in LBD than PD according to Gauchian.

Conclusion: These results underline how crucial proper GBA analysis is for these patients.

Keywords: Gaucher disease, Parkinson’s disease, Lewy body dementia