Submission Details

The relationship between GALT and galactosemia, an autosomal recessive disorder of galactose metabolism, was evaluated using the ClinGen Clinical Validity Framework as of April 22, 2022. GALT encodes for galactose-1-phosphate uridylyltransferase, the second enzyme in the galactose metabolic pathway, also known as the Leloir pathway. Galactosemia can be classified into three categories based on the residual GALT activity. Patients with classic galactosemia patients have absent or barely detectable erythrocyte and hepatic GALT activity. These patients present with life-threatening complications including feeding problems, failure to thrive, hepatocellular damage, bleeding, and E coli sepsis unless a lactose-restricted diet is implemented in the first ten days of life. Even on a lactose-restricted diet, affected children are at increased risk for developmental delays, speech problems, and cataracts, and almost all females with classic galactosemia manifest hypergonadatropic hypogonadism or premature ovarian insufficiency. Clinical variant galactosemia is associated with residual GALT activity in erythrocytes and liver (<15%) but also presents with life-threatening complications requiring lactose restriction. Biochemical variant galactosemia (also known as Duarte galactosemia) is typically clinically asymptomatic and there is discussion regarding whether lactose restriction in the first year of life is warranted (Fridovich-Keil, et al, 2020, PMID: 25473725). This gene-disease relationship is supported by genetic and experimental evidence. Biallelic variants in GALT were first reported in individuals with galactosemia in 1991 (Reichardt and Woo, PMID: 2011574). Over 300 GALT variants causing galactosemia have been reported in humans, with a predominance of missense variants (Coelho et al, 2017, PMID: 28281081). This curation included 25 variants from 15 probands from 7 publications (Reichardt and Woo, 1991, PMID: 2011574; Reichardt et al, 1991, PMID: 1897530; Ashino et al, 1995, PMID: 7550229; Sommer et al, 1995, PMID: 8598637; Hirokawa et al, 1999, PMID: 10573007; Estrada et al, 2013, PMID: 24045215; Ramadža et al, 2018, PMID: 29252199). Several pathogenic variants are reported as common in various populations (Coelho et al, 2017, PMID 28281081; Berry, 2021, PMID: 20301691). Of note, one GALT pathogenic variant in trans with the GALT Duarte (D2; c.[940A>G;-119_116delGTCA]) variant or with the D2 allele in homozygosity, is associated with Duarte galactosemia ((Fridovich-Keil, et al, 2020, PMID: 25473725). More genetic evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Experimental evidence supporting this gene-disease relationship includes the biochemical function of the gene product which is consistent with the phenotype in patients (Friedman et al, 1971, PMID: 167035; Timson et al, 2016, PMID: 26143117; Coelho et al, 2017, PMID: 28281081), studies on mutant yeast expressing various human GALT variants (Riehman et al, 2001, PMID: 11152465), biochemical studies on expression of the clinical and biochemical phenotype of a GALT null mouse (Tang et al, 2014, PMID: 24549051), and the impact of gene therapy on a the biochemical and clinical features of a rat model (Daenzer et al, 2022, PMID: 34964137). Additional experimental evidence is available in the literature but the maximum score for experimental evidence (6 points) has been reached. In summary, GALT is definitively associated with autosomal recessive galactosemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.