Newborn screening for Pompe disease in Japan: report and literature review of mutations in the GAA gene in Japanese and Asian patients

• Published in: Journal of human genetics 2019-08, Vol.64 (8), p.741-755
• Main Authors: Momosaki, Ken, Kido, Jun, Yoshida, Shinichiro, Sugawara, Keishin, Miyamoto, Tatsuki, Inoue, Takahito, Okumiya, Toshika, Matsumoto, Shirou, Endo, Fumio, Hirose, Shinichi, Nakamura, Kimitoshi
• Format: Article
• Language: English
• Subjects: Acids; Age of Onset; Alleles; alpha-Glucosidases - genetics; alpha-Glucosidases - metabolism; Amino Acid Substitution; Asian Continental Ancestry Group - genetics; Chromatography; Disease; DNA Mutational Analysis; Enzyme Activation; Enzymes; Fibroblasts; Gene Frequency; Genetic Association Studies; Genetic counseling; Genetic Predisposition to Disease; Genetic Testing; Genotype; Glycogen Storage Disease Type II - diagnosis; Glycogen Storage Disease Type II - epidemiology; Glycogen Storage Disease Type II - genetics; High-Throughput Nucleotide Sequencing; Humans; Infant, Newborn; Japan - epidemiology; Literature reviews; Mass spectrometry; Medical screening; Mutation; Neonatal Screening; Neonates; Pediatrics; Point mutation; Population; Population Surveillance; Scientific imaging; Workflow; α-Glucosidase
• ISSN: 1434-5161; 1435-232X
• DOI: 10.1038/s10038-019-0603-7

A newborn screening program for Pompe disease using dried blood spots (DBSs) was initiated in Japan. Here, we summarized this screening program and described the results of the GAA gene analysis. From April 2013 to November 2016, 103,204 newborns were screened; 71 had low acid alpha-glucosidase (AαGlu) activity. GAA sequencing showed that 32 (45.1%) and 37 (52.1%) of these newborns were homozygous and heterozygous for pseudodeficiency alleles c.[1726G>A; 2965G>A], respectively. Moreover, 24 of 32 newborns with homozygous c.[1726G>A; 2965G>A] alleles had no mutations, and the other eight had one mutation each. Thirty-five of 37 newborns with heterozygous c.[1726G>A; 2965G>A] alleles had one mutation, and the other two had two mutations each. Only one newborn who had two mutations did not harbor c.[1726G>A; 2965G>A] alleles. Thus, it was difficult to distinguish newborns with c.[1726G>A; 2965G>A] alleles from newborns with pre-symptomatic Pompe disease using AαGlu assays in DBSs or fibroblasts; GAA gene sequencing was necessary. Seventy-one newborns had 50 variants, including 21 mutations or predictably pathogenic variants, and 29 polymorphisms or predictably non-pathogenic variants. Four of 21 mutations or predictably pathogenic variants and four of 29 polymorphisms or predictably non-pathogenic variants were novel. No infantile-onset Pompe disease was detected, and three newborns were diagnosed with potential late-onset Pompe disease. In the literature, 156 variants have been reported for 296 patients from 277 families in 41 articles from Japan, Korea, Taiwan, and China. Our results provide insights into GAA gene mutation profiles and the relationship between GAA and Pompe disease in Asian populations.