Acid β-glucosidase (GBA1) gene mutational spectrum and clinical phenotypes in patients with gaucher disease: seven novel mutations in a multicenter retrospective cohort study from upper Egypt.

Background: This study aimed to identify GBA1 variants in Egyptian Gaucher disease (GD) patients residing in a region with high consanguinity and to correlate these genotypes with their clinical phenotypes.

Methodology: This descriptive study included 68 Egyptian patients diagnosed with GD. Diagnosis relied upon reduced β-glucocerebrosidase activity measured by tandem mass spectrometry from dried blood spots and confirmed by GBA1 single-gene sequencing. Clinical and laboratory information were gathered from patient records, and neurological evaluations were conducted by a neurologist.

Results: Thirty patients (44.1%) were classified as type 1 GD, three (4.4%) as type 2 GD, and 35 patients (51.5%) as type 3 GD. Variant analysis of the 136 alleles identified 19 different variants. The most prevalent mutant allele was c.1448T > C p.(Leu483Pro) (50.7%). Seven novel variants were documented: five homozygous missense variants, including c.263 C > T p.(Met88Thr), c.1331 A > G p.(Asp444Gly), c.1409 C > T p.(Ser470Phe), c.907 C > G p.(Leu303Val), c.1574G > A p.(Gly525Asp), two heterozygous missense variants: c.380 C > G p.(Ala127Gly) and c.453 + 2T > C. All carriers of these novel variants were phenotypically classified as type 1 GD. Genotype-phenotype correlations confirmed that the c.1226 A > G p.(Asn409Ser) variant was confined to type 1 GD, whereas c.1448T > C p.(Leu483Pro) was associated with types 2 and 3 GD.

Conclusion: Variant analysis of 136 alleles identified 19 GBA1 variants, including seven novel variants. These findings enhance genotype-phenotype correlations, provide genetic counseling, and enable customized molecular analyses for families at risk.