The prevalence of GALM mutations that cause galactosemia: A database of functionally evaluated variants

Galactosemia is a metabolic disorder that affects the appropriate metabolism of β-D-galactose. Deficiencies in three of the enzymes of the Leloir pathway, namely, GALT, GALK1, or GALE, are characterized as type I, II, and III galactosemia, respectively. Recently, we reported a novel type of galactosemia (type IV galactosemia) due to biallelic GALM mutations. Genetic diagnosis is indispensable for diagnosing GALM deficiency because no biochemical diagnosis method has been established. Given that apparently pathogenic variants in GALM are found in public variant databases, we presumed the presence of pathogenic variants that have not been reported. In this study, we explore 67 GALM variants that are prevalent in the ExAC database, including 57 missense variants, 7 stop-gain variants, 2 frameshift variants, and 1 splice-site variant. We performed an in vitro expression assay and an enzyme activity assay. Among the 66 variants except for 1 splice-site variant, 29 produced no or faint protein expression and were judged as pathogenic variants. Furthermore, the remaining 37 variants were evaluated by enzyme activity assay. Two showed mildly reduced enzyme activity and were classified as benign. Based on our study, the estimated incidence of GALM deficiency is 1:228,411 in all populations, 1:10,388 in the African population, and 1:80,747 in the Japanese population. Our GALM mutation database is useful for the genetic diagnosis of GALM deficiency.