Is Gauchian genotyping ofGBA1variants reliable?

Abstract

AbstractBiallelic mutations inGBA1result in Gaucher disease (GD), the inherited deficiency of glucocerebrosidase. Variants inGBA1are also a common genetic risk factor for Parkinson disease (PD). Currently, some PD centers screen for mutantGBA1alleles to stratify patients who may ultimately benefit fromGBA1-targeted therapeutics. However, accurately detecting variants, especially recombinant alleles resulting from a crossover betweenGBA1and its pseudogene, is challenging, impacting studies of both GD andGBA1-associated parkinsonism. Recently, the software tool Gauchian was introduced to identifyGBA1variants from whole genome sequencing. We evaluated Gauchian in 90 Sanger-sequenced patients with GD and fiveGBA1heterozygotes. While Gauchian genotyped most patients correctly, it missed some rare orde novomutations due to its limited internal database and over-reliance on intergenic structural variants. This resulted in misreported homozygosity, incomplete genotypes, and undetected recombination events, limiting Gauchian’s utility in variant screening and precluding its use in diagnostics.