Extended Deletion in the GBA1 Gene, Masked by Apparent p.Asn409Ser Homozygous: Diagnostic Implications and the Need for an Integrated Genetic Approach

This case report describes a 22-year-old woman with a phenotype compatible with Gaucher disease, characterized by hepatomegaly, splenomegaly, and thrombocytopenia. β-glucocerebrosidase activity was lower than reference values, making further genetic testing necessary. Sanger sequencing of the GBA1 gene revealed the presence of the pathogenic variant p.N409S in apparent homozygosity. Plasma glucosylsphingosine (Lyso-Gb1) testing provided further biochemical support for the diagnosis. Family screening, by Sanger sequencing, showed that the father is a heterozygous carrier of the p.N409S variant, while the mother and brother do not have any variants in the GBA1 gene. The absence of the maternal variant suggested the possible presence, in the proband, of a second structural alteration that could not be detected by traditional Sanger sequencing. As a result, an analysis was performed using Multiplex Ligation–dependent Probe Amplification (MLPA), which documented a large heterozygous deletion involving exon 6 in both the proband and her mother, allowing us to define a mutational pattern consisting of p.Asn409Ser in trans with an exon deletion. This case report demonstrates the importance of an integrated diagnostic approach in the analysis of genetic diseases, in which clinical evaluation, biochemical tests and molecular techniques complement each other. The combination of family studies and methods complementary to Sanger sequencing, such as analyses for the detection of structural rearrangements, is essential for accurate genotypic characterization. This approach is essential not only for the correct interpretation of the genetic pattern, but also for providing appropriate genetic counselling and defining optimal clinical management of the patient.