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

Abstract

Identification of variants in the acid α‐glucosidase (GAA) gene in Pompe disease provides valuable insights and systematic overviews are needed. We report on the number, nature, frequency, and geographic distribution of GAA sequence variants listed in the Pompe Registry, a long‐term, observational program and the largest global repository of Pompe disease data. Variant information was reviewed and compared with publicly available GAA databases/resources. Among 1,079 eligible patients, 2,075 GAA variants (80 unique novel) were reported. Variants were listed by groups representing Pompe disease phenotypes. Patients were classified as Group A: Symptom onset ≤ 12 months of age with cardiomyopathy; Group B: Symptom onset ≤ 12 years of age (includes patients with symptom onset ≤ 12 months of age without cardiomyopathy); or Group C: Symptom onset > 12 years of age. Likely impact of novel variants was predicted using bioinformatics algorithms. Variants were classified by pathogenicity using ACMG guidelines. Data reported from the Pompe Registry provide new information about the distribution of GAA variants globally and across the clinical spectrum, add to the number and diversity of GAA variants registered in public databases through published data sharing, provide a first indication of the severity of novel variants, and assist in diagnostic practice and outcome prediction.

Newborn Screening for Pompe Disease in Illinois: Experience with 684,290 Infants

“…In the meantime, a method of systemic data collection to enable long-term assessment of outcomes and best practices is critically needed. Although there is an industry-sponsored registry for patients with confirmed Pompe disease [18], it is not ideal for the inclusion of asymptomatic patients, particularly those with genotypes that do not permit a definitive diagnosis ("possible" Pompe patients) and is not accessible by all treating physicians. A similar need exists for other disorders, including other lysosomal disorders, recently added to newborn screening since many are associated with phenotypes that may not become evident until much later in childhood or even in adult life.…”

Second Tier Molecular Genetic Testing in Newborn Screening for Pompe Disease: Landscape and Challenges

“…To date, over 500 pathogenic (P) or likely pathogenic (LP) variants and numerous benign variants and variants of unknown significance (VUS) in the GAA gene have been reported (ClinVar, 2017; Erasmus MC University Medical Center, 2017; Aggregation Databases (ExAC, gnomAD), 2017; Leiden Open Variation Database (LOVD), 2018; The Human Genome Mutation Database (HGMD), 2017). A review of GAA variants suggests that missense variants are the most frequent molecular genetic cause of PD (~50%), followed by small deletions [8,15]. Variant hotspots are also known, such as the c.-32-13T>G splice site single nucleotide variant and the exon 18 deletion (c.2481+102_2646+31del).…”

“…Variant hotspots are also known, such as the c.-32-13T>G splice site single nucleotide variant and the exon 18 deletion (c.2481+102_2646+31del). These and other ethnic variants are well described [8,15], but require detection by DNA sequencing methods that can identify both single nucleotide variations (SNVs), as well as copy number variations (CNVs, also known as deletion/duplication events), and these are discussed later.…”

“…These topics have been well covered by other reviews [8,15], and therefore only discussed in the context of second tier testing algorithm for PD NBS (Figure 2). In PD, the genotype is generally fully penetrant; IOPD phenotypes especially demonstrate limited heterogeneity.…”

“…Recent reports on IOPD continue to shed light on some of the unique challenges care providers face in diagnosing and managing this genetic disease [2,7]. While delays in PD symptom onset and diagnosis are less common in IOPD (under 3-4 months) compared to LOPD, based on the Pompe Registry data [8], the IOPD cases with cross-reactive immunological material (CRIM), negative statuses almost invariably develop high antibody titers to enzyme replacement therapy (ERT). As high antibody titers to ERT reduce the effectiveness of ERT treatment, CRIM-negative patients require immunomodulation therapy prior to initiation of ERT.…”