Identification of a Novel <i>GBA</i> Deletion Spanning 20,627bp Associated with Gaucher Disease: A Case Report

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by variants in the <i>GBA</i> gene. This study reports a novel pathogenic large deletion in the <i>GBA</i> gene identified in a 70-day-old male infant presenting with cholestasis and hepatosplenomegaly, leading to a diagnosis of GD. Comprehensive genetic analysis using whole-exome sequencing (WES) revealed compound heterozygous variants, a maternally inherited c.1448T>C (p.Leu483Pro) missense variant and a paternally derived large deletion encompassing both the <i>GBAP1</i> pseudogene and the functional <i>GBA</i> gene. The paternal origin of the deletion was confirmed by quantitative PCR (qPCR), and long-range PCR with subsequent sequencing precisely mapped the breakpoints, characterizing the deletion as 20,627 bp in length. A critical diagnostic finding was that standard Sanger sequencing initially failed to detect this deletion, misleadingly suggesting the infant was homozygous for the missense variant. This case highlights a significant limitation of Sanger sequencing, which can misinterpret large heterozygous deletions as false homozygosity due to allele dropout. Consequently, this report underscores the necessity of employing comprehensive genomic methods like WES as a first-line diagnostic test for lysosomal storage disorders such as GD, ensuring accurate detection of complex variants including large structural variants.