Gaucher Disease

Gaucher disease (GD) is a lysosomal storage disease most often affecting individuals of Ashkenazi Jewish (AJ) descent. GD type 1 is the most common form with symptoms ranging from mild to severe. Symptoms include hepatosplenomegaly, anemia, thrombocytopenia, lung disease, and bone abnormalities. Symptoms of type 1 can appear anytime from childhood to adulthood. GD types 2 and 3 are neuronopathic forms differentiated mainly by disease progression and involve the central nervous system with life-threatening problems that typically appear in early infancy. Symptoms of types 2 and 3 also include eye abnormalities, seizures, and damage to the brain. Testing is used for prepregnancy carrier screening or for diagnostic testing in individuals suspected of having GD.

Disease Overview

Prevalence

• Approximately 1 in 57,000 to 1 in 75,000   in general population
• GD type 1 estimated at 1 in 855 in individuals of AJ descent 

Age of Onset

• Type 1: childhood/adulthood
• Type 2: typically before age 2, with death by age 2-4
• Type 3: typically in childhood, but survival into third or fourth decade

Symptoms

GD affects lysosomal storage and has extreme symptom variability, ranging from perinatal lethality to asymptomatic individuals.

• Type 1
  • Represents 95% of GD; characterized by non-neuronopathic symptoms including bone disease, hepatosplenomegaly, lung disease, and anemia 
• Type 2 (acute neuronopathic)
  • Primary central nervous system (CNS) involvement with rapidly progressive course
• Type 3 (subacute/chronic)
  • Primary CNS involvement with slowly progressive course

Genetics

Gene

GBA

Inheritance

Autosomal recessive

Penetrance

Variable

Test Methodology

• GBA sequencing: Long range PCR followed by bidirectional sequencing of all coding regions and intron-exon boundaries of the GBA gene
• GBA 8 Variants: Polymerase chain reaction (PCR) and fluorescence monitoring
  • Targeted variants: c.115+1G>A; c.84dupG, p.L29Afs; c.1226A>G, p.N409S; c.1263_1317del55; c.1297G>T, p.V433L; c.1342G>C, p.D448H; c.1448T>C, p.L483P; and c.1604G>A, p.R535H

Test Sensitivity and Specificity

Clinical Sensitivity

Sequencing: Approximately 99% 

Targeted variants: 90% in individuals of Ashkenazi Jewish descent; 55% in other ethnicities 

Analytic Sensitivity and Specificity

Approximately 99%

Limitations

• Diagnostic errors can occur due to rare sequence variations.
• Regulatory region variants, deep intronic variants, large deletions/duplications/insertions, gene conversion events and complex gene rearrangements may not be detected.