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

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

Arnold J J Reuser  1 , Ans T van der Ploeg  2 , Yin-Hsiu Chien  3 , Juan Llerena Jr  4 , Mary-Alice Abbott  5 , Paula R Clemens  6 , Virginia E Kimonis  7 , Nancy Leslie  8 , Sonia S Maruti  9 , Bernd-Jan Sanson  9 , Roberto Araujo  9 , Magali Periquet  10 , Antonio Toscano  11 , Priya S Kishnani  12 , On Behalf Of The Pompe Registry Sites
Affiliations

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

Arnold J J Reuser et al. Hum Mutat. 2019 Nov.

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.

Keywords: GAA genotypes; GAA variants; Pompe disease; Pompe Registry; acid α-glucosidase.

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Conflict of interest statement

The Pompe Registry is sponsored by Sanofi Genzyme, Cambridge, MA.

Arnold J.J. Reuser (AJJR) has no conflicts of interest to declare.

Ans T. van der Ploeg (AvdP) has received consulting fees from Sanofi Genzyme and has provided consulting services, participated in advisory boards meetings and received grants for premarketing studies and research from industries via agreements between Erasmus MC and the industry.

Yin‐Hsiu Chien (Y‐HC) has received research support, consulting fees, reimbursement for attending symposium and other expenses, and fees for non‐CME/CE Services from Sanofi Genzyme.

Juan Llerena, Jr., (JL) is a member of the Pompe Registry International Advisory Board and has received reimbursement for participation as a speaker at lectures and symposia participation from Sanofi Genzyme.

Mary‐Alice Abbott (M‐AA) has received reimbursement for expenses related to attending Pompe Registry meetings from Sanofi Genzyme and compensation for attendance at meetings of the Scientific Advisory Board NA Pompe Registry from Sanofi Genzyme.

Paula R. Clemens (PRC) has received research funding from Sanofi, the NIH, MDA, NS Pharma, and Amicus Therapeutics; reimbursement for attending symposium and other expenses from Sanofi, MDA, NS Pharma, and Amicus Therapeutics; and consulting fees from UCB Biopharma, Spark Therapeutics, and Pfizer.

Virginia E. Kimonis (VEK) has received research support from Sanofi Genzyme for the Pompe Exercise project and participates in the Pompe Registry which is funded by Sanofi Genzyme.

Nancy Leslie (NL) has received honoraria for participation in the Pompe Registry Advisory Board from Sanofi Genzyme.

Roberto Araujo (RA) and Magali Periquet (MP) are employees of Sanofi Genzyme. RA and MP also own shares of Sanofi Genzyme.

Sonia S. Maruti was an employee of Sanofi Genzyme at the time of this analysis. Her current affiliation is Boehringer Ingelheim.

Bernd‐Jan Sanson (BJS) was an employee of Sanofi Genzyme at the time of this analysis. His current affiliation is Kiadis Pharma, Amsterdam, The Netherlands.

Antonio Toscano (AT) has received reimbursement for participation either as a speaker for lectures and symposia or as a Pompe Registry board member from Sanofi Genzyme.

Priya S. Kishnani (PSK) has received consulting fees, honoraria, and/or research funding from Sanofi Genzyme, Amicus Therapeutics, Baebies, Shire Pharmaceuticals, Alexion and the Lysosomal Disease Network, and is a member of the Pompe and Gaucher Disease Registry

Figures

Figure 1
Figure 1
Location of novel variants in the GAA gene. (a) GAA gene with novel variants reported in the Pompe Registry. Variant listings are color coded to identify corresponding domain in the GAA protein (panel c). Variants listed in black text are either intronic or have no apparent protein‐level change. (b) GAA mRNA. (c) GAA protein
See this image and copyright information in PMC

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