GAA variants associated with reduced enzymatic activity but lack of Pompe-related symptoms, incidentally identified by exome sequencing

Anna Malekkou; Athina Theodosiou; Angelos Alexandrou; Ioannis Papaevripidou; Carolina Sismani; Edwin H Jacobs; George J G Ruijter; Violetta Anastasiadou; Sofia Ourani; Emilia Athanasiou; Anthi Drousiotou; Olga Grafakou; Petros P Petrou

doi:10.1016/j.ymgmr.2023.100997

GAA variants associated with reduced enzymatic activity but lack of Pompe-related symptoms, incidentally identified by exome sequencing

Mol Genet Metab Rep. 2023 Aug 7:36:100997. doi: 10.1016/j.ymgmr.2023.100997. eCollection 2023 Sep.

Affiliations

¹ Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, P. O. Box 23462, 1683 Nicosia, Cyprus.
² Cytogenetics and Genomics Department, The Cyprus Institute of Neurology and Genetics, P. O. Box 23462, 1683 Nicosia, Cyprus.
³ Center for Lysosomal and Metabolic Diseases, Department of Clinical Genetics, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands.
⁴ Clinical Genetics Department, Archbishop Makarios III Hospital, Korytsas 6, 2012 Nicosia, Cyprus.
⁵ Karaiskakio Foundation, P.O. Box 22680, 1523 Nicosia, Cyprus.
⁶ Inborn Errors of Metabolism Clinic, Department of Pediatrics, Archbishop Makarios III Hospital, Korytsas 6, 2012 Nicosia, Cyprus.

Abstract

Pompe disease is a rare metabolic myopathy caused by pathogenic variants affecting the activity of the lysosomal glycogen-degrading enzyme acid alpha-glucosidase (GAA). Impaired GAA function results in the accumulation of undegraded glycogen within lysosomes in multiple tissues but predominantly affects the skeletal, smooth and cardiac muscle. The degree of residual enzymatic activity appears to roughly correlate with the age of onset and the severity of the clinical symptoms. Here, we report four siblings in which the GAA variants NM_000152.5:c.2237G > C p.(Trp746Ser) and NM_000152.5:c.266G > A p.(Arg89His) were identified as an incidental finding of clinical exome sequencing. These variants are listed in the ClinVar and the Pompe disease GAA variant databases but are reported here for the first time in compound heterozygosity. All four siblings displayed normal urine tetrasaccharide levels and no clinical manifestations related to Pompe disease. Nevertheless, GAA enzymatic activity was within the range for late onset Pompe patients. Our report shows an association between a novel genotype and attenuated GAA enzymatic activity. The clinical significance can only be established by the regular monitoring of these individuals. The study highlights the major challenges for clinical care arising from incidental findings of next generation sequencing.

Keywords: Acid alpha glucosidase; Case report; Exome sequencing; Glycogen storage disorder; Pompe disease; Variants.

Publication types

Case Reports