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Molecular genetics of Gaucher disease

The 7.6 kb GBA gene encoding acid β-glucosidase is located on chromosome 1.1 Over 330 GBA gene mutations causing Gaucher disease have been identified.2  They are most commonly missense mutations, but nonsense mutations, small insertions or deletions, splice junction mutations, and complex mutations (alleles with two or more mutations) have also been found.1 The six most prevalent mutations account for around 90% of disease-causing alleles among Ashkenazi Jewish patients with Gaucher disease type 1 and 50% to 75% of disease-causing alleles among non-Ashkenazi patients.1 However, because there are many sporadic or ‘private’ mutations that cause Gaucher disease, albeit in the minority of patients, DNA analysis does not always confirm diagnosis.1,3

Disease-causing GBA gene mutations may affect the catalytic function, intracellular stability and/or subcellular trafficking of acid β-glucosidase.4 Individuals with Gaucher disease usually have some level of acid β-glucosidase activity, although two null alleles (alleles that do not produce any enzyme) have been found.3

Inheritance of Gaucher disease

The GBA gene is inherited in an autosomal recessive fashion and therefore affects both males and females.3 An individual must carry two mutant alleles, one from each parent, for the disease to manifest. Individuals who harbour one mutant allele and one non-disease-causing allele are unaffected carriers of the disease. The risk of two carriers having a child with Gaucher disease is 1 in 4 with each pregnancy. All children born to an affected individual are obligate carriers.

Autosomal recessive inheritance of Gaucher disease

Genetic determinants of Gaucher disease phenotype

Mutations of the GBA gene give rise to a continuum of phenotypes which for clinical utility are designated Gaucher disease type 1, type 2 or type 3.5 There are generally no strict correlations between GBA gene mutation and Gaucher disease phenotype. An exception is the N370S allele, which is predictive of type 1 disease as it has never been associated with Gaucher disease type 2 or type 3 either in the heteroallelic or homoallelic state.4 In addition, homozygosity for the D409H allele causes a distinctive variant phenotype of Gaucher disease type 3 (classified type 3c) that is characterised by cardiac complications (see more in Clinical Presentation).6

In many cases it is not possible to identify Gaucher disease subtype or accurately predict disease severity or rate of progression based on genotype. However, some generalisations can be made, which may be helpful in the counselling and management of patients.5 These are highlighted in the table below.

Genotype-phenotype correlations in Gaucher disease

Genotype Phenotype

Predictive of non-neuronopathic disease4
Milder disease compared with N370S compound heterozygotes5

N370S compound heterozygote Predictive of non-neuronopathic disease4
N370S/84GG Earlier onset compared with other type 1 genotypes7
L444P/L444P Strongly but not exclusively associated with neuronopathic disease (type 2/type 3)8
D409H/D409H Uniquely associated with mild visceral manifestations but aortic and cardiac valvular calcifications, proximal coronary artery disease, hydrocephalus, and skeletal abnormalities8
Two complex alleles or L444P/complex allele Associated with Gaucher disease type 24

Identification of Gaucher disease genotype provides only limited prognostic information as there is generally a highly heterogeneous expression of the disease among individuals with the same GBA gene mutation. For example, even though homozygosity for the N370S allele is associated with milder disease than heterozygosity for the N370S allele, the severity and pattern of organ involvement is heterogeneous among N370S homozygotes. Some N370S homozygotes can have severe manifestations comparable to that observed in N370S compound heterozygotes.9


  1. 1.Hruska KS, LaMarca ME, Scott CR, Sidransky E. (2008) Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat 29(5): 567-583.
  2. 2.Motta I, Filocamo M, Poggiali E, et al. (2015) A multicentre observational study for early diagnosis of Gaucher disease in patients with Splenomegaly and/or Thrombocytopenia. Eur J Haematol 96(4): 352-359.
  3. 3.Grabowski, G. A., Petsko GA, Kolodny EH. Gaucher Disease. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, et al., editors. The Online Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 2014.
  4. 4.Grabowski GA. (2008) Phenotype, diagnosis, and treatment of Gaucher's disease. Lancet 372(9645): 1263-1271.
  5. 5.Baris HN, Cohen IJ, Mistry PK. (2014) Gaucher disease: the metabolic defect, pathophysiology, phenotypes and natural history. Pediatr Endocrinol Rev 12 Suppl 1: 72-81.
  1. 6.Grabowski GA, Kolodny EH, Weinreb NJ, et al. Gaucher Disease: Phenotypic and Genetic Variation. . In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, et al., editors. New York, NY: McGraw-Hill; 2014.
  2. 7.Grabowski GA, Zimran A, Ida H. (2015) Gaucher disease types 1 and 3: Phenotypic characterization of large populations from the ICGG Gaucher Registry. Am J Hematol 90 Suppl 1: S12-18.
  3. 8.Mistry PK, Belmatoug N, vom Dahl S, Giugliani R. (2015) Understanding the natural history of Gaucher disease. Am J Hematol 90 Suppl 1: S6-11.
  4. 9.Fairley C, Zimran A, Phillips M, et al. (2008) Phenotypic heterogeneity of N370S homozygotes with type I Gaucher disease: an analysis of 798 patients from the ICGG Gaucher Registry. J Inherit Metab Dis 31(6): 738-744.