Molecular genetics of Pompe disease: A comprehensive overview

Ann Transl Med. 2019 Jul;7(13):278. doi: 10.21037/atm.2019.04.13.

PMID: 31392190

Paolo Peruzzo, Eleonora Pavan, Andrea Dardis

Highlights: To date, 582 mutations have been reported across the entire GAA gene which cause Pompe disease (PD). The data gathered in this review gives an overview of the molecular genetics of PD and can be used to help with diagnosis and genetic counselling of families who are affected by this disorder.

Abstract

Background: Pompe disease (PD) is an autosomal recessive lysosomal disorder caused by mutations in the GAA gene, which result in reduced activity of the acid alpha-glucosidase (GAA) enzyme. The accumulation of glycogen within the lysosomes is caused by this enzyme deficit. Clinically, the disease is divided into two categories: infantile type and childhood/adult type. The GAA gene has been identified on chromosome 17q25.2-q25.3, and up till now, 582 mutations have been reported across the entire gene (HGMD: http://www.hgmd.cf.ac.uk/ac/). All forms of mutations have been described; missense variants are the most common, followed by minor deletions. The majority of GAA mutations are private or only found in a few families. However, the c.-32-13T>G splice mutation, which is quite common in Caucasian patients affected by the childhood/adult type of the disease, with an allelic frequency ranging from 40% to 70%, is an exception.

Objective: This article examines the range of GAA mutations, their prevalence in different populations, and their classification based on their effect on GAA splicing, protein expression, and activity. In addition, the phenotype/genotype relationship is discussed whenever possible. The data gathered in this review gives an overview of the molecular genetics of PD and can be utilized to help with diagnosis and genetic counselling of families who are affected by this disorder.

Keywords: GAA mutations, Pompe disease, phenotype/genotype correlation