Sensitivity of whole exome sequencing in detecting infantile- and late-onset Pompe disease

Mol Genet Metab. 2017 Dec;122(4):189-197. doi: 10.1016/j.ymgme.2017.10.008. Epub 2017 Oct 17.


Pompe disease is a metabolic myopathy with a wide spectrum of clinical presentation. The gold-standard diagnostic test is acid alpha-glucosidase assay on skin fibroblasts, muscle or blood. Identification of two GAA pathogenic variants in-trans is confirmatory. Optimal effectiveness of enzyme replacement therapy hinges on early diagnosis, which is challenging in late-onset form of the disease due to non-specific presentation. Next-generation sequencing-based panels effectively facilitate diagnosis, but the sensitivity of whole-exome sequencing (WES) in detecting pathogenic GAA variants remains unknown. We analyzed WES data from 93 patients with confirmed Pompe disease and GAA genotypes based on PCR/Sanger sequencing. After ensuring that the common intronic variant c.-32-13T>G is not filtered out, whole-exome sequencing identified both GAA pathogenic variants in 77/93 (83%) patients. However, one variant was missed in 14/93 (15%), and both variants were missed in 2/93 (2%). One complex indel leading to a severe phenotype was incorrectly called a nonsynonymous substitution c.-32-13T>C due to misalignment. These results demonstrate that WES may fail to diagnose Pompe disease. Clinicians need to be aware of limitations of WES, and consider tests specific to Pompe disease when WES does not provide a diagnosis in patients with proximal myopathy, progressive respiratory failure or other subtle symptoms.

Keywords: Acid-alpha-1,4-glucosidase deficiency; GAA; Glycogen storage disease type II; Limb girdle muscular dystrophy; Pompe disease; Whole-exome sequencing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diagnosis, Differential
  • Enzyme Replacement Therapy
  • Exome Sequencing / methods*
  • Genotype
  • Glycogen Storage Disease Type II / complications
  • Glycogen Storage Disease Type II / diagnosis*
  • Glycogen Storage Disease Type II / genetics*
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Late Onset Disorders / diagnosis*
  • Late Onset Disorders / genetics*
  • Mutation
  • Phenotype
  • Sensitivity and Specificity
  • alpha-Glucosidases / analysis
  • alpha-Glucosidases / blood
  • alpha-Glucosidases / genetics*


  • alpha-Glucosidases