Genetic heterozygosity and pseudodeficiency in the Pompe disease newborn screening pilot program

Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of lysosomal acid α-glucosidase (GAA) activity. This is the first LSD in which newborn screening has been shown to improve clinical outcomes. Newborn screening also identified multiple rare gene variants in this population. Among 132,538 newborns screened, 107 babies (1 in 1239) who had low dried blood spot GAA activity were genotyped. Sixty-nine (64.5%) babies had a total of 54 mutations and 35 novel predictably pathogenic mutations; 36 babies (33.6%) who had no mutation were homozygous for the c.[1726A; 2065A] pseudodeficiency allele. Because 81% of the chromosomes (14% in the controls) were in haplotype ∗03, we found a link between the pseudodeficiency allele and other mutated alleles. The newborns with Pompe disease detected by screening had lymphocyte GAA activities 0.45 to 1.65 nmol/mg/h (normal 66.7 ± 33.8), while only 2 of the 100 false-positive cases had GAA activity less than 2.00 nmol/mg/h (or 3% of the normal mean). Therefore, newborn screening for Pompe disease could be successfully conducted by including genotyping and lymphocyte GAA assay, even in a population with mutation heterozygosity and pseudodeficiency.