How is Gaucher disease inherited?

Gaucher disease is an autosomal recessive disorder secondary to mutations in the gene that encodes glucocerebrosidase, GBA1. This gene comprises 11 exons and is located on chromosome 1q21.1,2

An autosomal gene is located on a numbered chromosome and typically affects males and females in a similar manner. There are two copies of every autosomal gene, and genetic carriers of an autosomal recessive disorder generally do not show any symptoms, because having one mutated gene is not enough to cause the disease. In those with two copies of the mutated gene, one copy is passed from the father and the other from the mother. For autosomal recessive disorders, if both parents are heterozygous genetic carriers of the disease, there is a 1 in 4 chance that the child will inherit both copies of the recessive mutated gene and develop the disease (Figure 1).3

Figure 1.
Autosomal recessive inheritance when both parents are unaffected genetic carriers for Gaucher disease3

What are the genotype–phenotype characteristics of Gaucher disease?

More than 300 gene mutations for GBA1 have been identified (The Human Gene Mutation Database []), the majority of which are due to single nucleotide substitutions. Nucleotide insertions, deletions or other complex alleles account for the remainder.4 Legacy and current nomenclature of common GBA1 mutations is presented in Table 1.

Table 1.
Examples of legacy and current nomenclature of GBA1 mutations. Reproduced and adapted with permission from Ortiz-Cabrera NV et al. Mol Genet Metab Rep 2016; 9: 79-85.5


Burden_L2_Genetic_Table 1(3).png


Data from the Gaucher Outcome Survey

The Gaucher Outcome Survey is an international Gaucher disease registry (sponsored by Shire, now part of Takeda) established in 2010 for patients with a confirmed diagnosis of Gaucher disease, regardless of disease type or treatment status. As of February 2017, 1209 patients were enrolled in 31 active sites across 11 countries. The majority of patients enrolled had Gaucher disease Type 1 (91.5% [1106/1209]), four (0.3%) patients had Gaucher disease Type 2, and 37 (3.1%) had Gaucher disease Type 3 (data missing for 62 [5.1%] patients). Most patients were of Ashkenazi Jewish ethnicity (55.8% [675/1209]) and were primarily located in Israel (73.8%) or the United States (25.5%).6

Of 847 patients with genotype data, N370S/N370S (c.1226A>G; p.Asp409Ser) was the single most prevalent genotype (44.2%); however, the distribution of Gaucher disease genotypes varied between countries (Figure 2).6

Figure 2.
Prevalence of GBA1 genotypes among patients in the Gaucher Outcome Survey with evaluable data. Reproduced with permission from Zimran A et al. Am J Hematol 2018; 93: 205-212.6

Genotype–phenotype correlations

The N370S (c.1226A>G; p.Asp409Ser) mutation is associated with Gaucher disease Type 1, the non-neuronopathic form of the disease.7 The presence of this mutation even on a single allele ensures residual enzyme activity of glucocerebrosidase for proper catabolism in neurons, which prevents the neurological symptoms of the disease.8 Patients who are homozygous for the L444P (c.1448T>C; p.Leu483Pro) mutation are more likely to develop Gaucher disease Type 3 and the associated neurological symptoms.7,8

C-ANPROM/INT//7566; Date of preparation: September 2020