Homozygous GBA1 p.T82I variant in type 1 Gaucher disease: clinical and biochemical characterization

Gaucher disease (GD) is the most common lysosomal storage disorder caused by biallelic pathogenic variants in GBA1, resulting in deficient β-glucocerebrosidase activity. Clinical characterization of rare GBA1 variants is crucial for understanding disease heterogeneity. We report an extremely rare GBA1 variant previously catalogued at the sequence level in HGMD and UniProtKB, and recently listed in ClinVar without a clinical significance assertion, but lacking phenotypic data.

A 23-year-old male presented with fatigue, chills, shivering, and diffuse bone pain. Physical examination revealed hepatosplenomegaly, and laboratory tests showed moderate thrombocytopenia. Leukocyte β-glucocerebrosidase activity was markedly reduced (0.90 nmol/mg/h), and plasma Lyso-Gb1 was highly elevated (431.3 ng/mL; reference <14.0 ng/mL). DXA (Dual-energy X-ray Absorptiometry) demonstrated osteopenia (lumbar spine Z-score: -2.3). Genetic analysis identified a homozygous GBA1 NM_000157.4:c.245C>T (p.Thr82Ile; rs1141811) variant. Family screening showed heterozygosity in both parents and one sibling.

This report provides the first comprehensive clinical characterization of the rare GBA1 p.Thr82Ile variant, expanding the phenotypic spectrum of Type 1 GD.