GAA variants and phenotypes among 1,079 patients with Pompe disease: Data from the Pompe Registry

Hum Mutat. 2019 Nov;40(11):2146-2164. doi: 10.1002/humu.23878. Epub 2019 Aug 7.

PMID: 31342611

Arnold J. J. Reuser | Ans T. van der Ploeg | Yin‐Hsiu Chien | Juan Llerena, Jr. | Mary‐Alice Abbott | Paula R. Clemens | Virginia E. Kimonis | Nancy Leslie | Sonia S. Maruti | Bernd‐Jan Sanson | Roberto Araujo | Magali Periquet | Antonio Toscano | Priya S. Kishnani | on behalf of the Pompe Registry Sites

Summary: This study reports the number, nature, frequency, and geographic distribution of GAA sequence variants listed in the Pompe Registry. These data provide new information about the distribution of GAA variants globally and across the clinical spectrum, provide a first indication of the severity of novel variants, and assist in diagnostic practice and outcome prediction.

Abstract

Objective: Identification of variants in the acid α‐glucosidase (GAA) gene in Pompe disease provides important insights. This study reports the number, nature, frequency, and geographic distribution of GAA sequence variants listed in the Pompe Registry, a long‐term, multinational and observational program.

Methods: Variant data was examined and compared to publicly accessible GAA databases and resources. There were 2,075 GAA variants reported among 1,079 eligible patients (80 of which were novel). Variants were organized into groups that represented different phenotypes of Pompe disease. Symptom onset ≤12 months of age with cardiomyopathy was classified as Group A; symptom onset 12 months of age (includes patients with symptom onset ≤12 months of age without cardiomyopathy) was classified as Group B; and symptom onset >12 years of age was classified as Group C. Bioinformatics algorithms were used to predict the likely impact of novel variants. The pathogenicity of the variants was determined using ACMG guidelines. (The American College of Medical Genetics and Genomics guidelines).

Conclusion: Data reported from the Pompe Registry provide new information about the distribution of GAA variants globally and across the clinical spectrum, provide a first indication of the severity of novel variants, and assist in diagnostic practice and outcome prediction.