Genetics of Pompe Disease

Pompe disease is a rare autosomal recessive genetic disease caused by the inheritance of pathogenic recessive mutations in both copies of the GAA gene.

Genetic Inheritance
of Pompe Disease

The GAA gene is about 18.3 kb long and contains 20 exons (coding regions), interspersed by non-coding introns (Figure 1).  It is located toward the distal portion of the long arm of chromosome 17 (17q25.2-q25.3).  The cDNA is more than 3.6 kb long with 2859 nucleotides of coding sequence.

For a detailed examination of the GAA gene, refer to the Backgrounder on Genetics.

Figure 1

A schematic representation of the GAA genomic location and the relative genomic position of various mutations.

Figure 1. Schematic representation of GAA genomic location (top) and relative genomic position of various mutations (bottom). GAA maps to ch17q25.3 and contains 20 exons (19 coding). The GAA gene encodes a transcript containing 952 amino acids.

To date, more than 500 mutations have been identified, although not all are pathogenic in nature. Of these, more than 300 are pathogenic mutations. The Pompe Center at Erasmus MC catalogs mutations identified worldwide. Mutations include missense mutations (50% of all reported mutations), nonsense variants, splice-site variants, small and large deletions, and small insertions. Mutations such as nonsense, splice-site, and frameshifting deletions/insertions affect mRNA stability. Some mutation types occur with a higher frequency in Pompe patients than others, mainly because the GAA gene structure lends itself to transcription errors due to areas of base pair repeats.

For a detailed examination of the GAA pathogenic genotypes, refer to the Backgrounder on Genetics.

There are known pseudodeficiency mutations that result in reduced enzyme activity when measured using a laboratory assay (artificial substrate). These pseudodeficiency mutations do not result in Pompe disease because the enzyme can process natural (endogenous) substrate normally.

As a general rule, GAA enzyme activity correlates with the age of onset and rate of progression:

  • Pathogenic GAA variants that result in very low or no enzyme activity result in infantile-onset Pompe disease (IOPD). Mutations that introduce mRNA instability such as nonsense variants are more commonly seen in IOPD.
  • Cross-reactive immunological material (CRIM) status refers to the presence of (CRIM+) or absence (CRIM-) of endogenous GAA protein with or without enzymatic activity.
  • Typically, infants who have inherited a pair of null variants tend to be CRIM negative.
  • Pathogenic GAA variants that express some enzyme activity result in late-onset Pompe disease (LOPD), with age of onset and rate of progression proportional to the level of enzyme activity.
  • Missense and splice-site variants result in either complete or partial absence of GAA enzyme activity and are seen in both IOPD and LOPD patients.

Epidemiology (Incidence and Prevalence)

The estimated overall incidence of Pompe disease is 1 in 40,000, the estimated prevalence is between 5,000 and 10,000 patients worldwide. Some pathogenic variants are seen more commonly in certain populations.

Table 1.Percentage of patients with selected GAA pathogenic variants

GAA Pathogenic Variant

  • % of Affected Individuals

c.336-13T>G

36%-90% of individuals with late-onset glycogen storage disease II

p.Glu176ArgfsTer45

34% of Dutch population

9% of US population

p.Gly828_Asn882del

25% of Dutch & Canadian infants

5% of US population

p.Asp645Glu

≤ 80% of Taiwanese & Chinese Infants

p.Arg854Ter

≤ 60% of individuals of African descent with a common phenotype

For examples of genotype–phenotype correlation, with specific pathogenic variants and information on the most common pathogenic variants, download the Backgrounder on Genetics.

For information about incidence and prevalence of Pompe disease across different geographical regions, refer to Pompe Disease and Family Genetics.