Extended Deletion in the GBA1 Gene, Masked by Apparent p.Asn409Ser Homozygous: Diagnostic Implications and the Need for an Integrated Genetic Approach
- 1Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), 90146 Palermo, Italy
- 2Department of Translational and Precision Medicine, “La Sapienza” University of Rome, 00161 Rome, Italy
Abstract
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.
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BibTeX
@article{anania2026extended,
title = {{Extended Deletion in the GBA1 Gene, Masked by Apparent p.Asn409Ser Homozygous: Diagnostic Implications and the Need for an Integrated Genetic Approach}},
author = {Monia Anania and Miriam Giacomarra and Giovanna Palumbo and Annalisa D’Errico and Emanuela Maria Marsana and Silvia Palladino and Giorgio Sforzini and Daniele Francofonte and Paolo Colomba and Giovanni Duro and Carmela Zizzo},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209123},
url = {https://www.mdpi.com/1422-0067/27/20/9123},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Extended Deletion in the GBA1 Gene, Masked by Apparent p.Asn409Ser Homozygous: Diagnostic Implications and the Need for an Integrated Genetic Approach
AU - Monia Anania
AU - Miriam Giacomarra
AU - Giovanna Palumbo
AU - Annalisa D’Errico
AU - Emanuela Maria Marsana
AU - Silvia Palladino
AU - Giorgio Sforzini
AU - Daniele Francofonte
AU - Paolo Colomba
AU - Giovanni Duro
AU - Carmela Zizzo
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209123
UR - https://www.mdpi.com/1422-0067/27/20/9123
AB - 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.
SN - 1422-0067
ER -