GALT – Galactosemia

Classic galactosemia is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the GALT gene, leading to deficiency of galactose-1-phosphate uridylyltransferase. Affected neonates present with jaundice, hepatomegaly, failure to thrive and cataracts due to accumulation of galactose and its metabolites in blood and tissues.

Genetic evidence supports a definitive gene–disease association. Over 132 unrelated patients have been reported with classic galactosemia carrying GALT mutations, most commonly the p.Gln188Arg (c.563A>G) allele, which accounts for approximately 25% of disease alleles ([PMID:7927329]). Segregation analyses in multiple families confirm autosomal recessive inheritance with complete penetrance in homozygotes.

The variant spectrum in GALT includes missense (e.g., p.Gln188Arg, p.Ser135Leu), nonsense (e.g., p.Arg204Ter), splice-site and deep-intronic changes. Recurrent founder alleles such as p.Gln188Arg and population-specific variants (e.g., p.Ser135Leu in African-American patients) have been documented. One representative pathogenic variant is c.563A>G (p.Gln188Arg).

Functional studies in yeast and mammalian systems demonstrate that pathogenic GALT variants severely impair enzyme activity (<10% of wild-type) and destabilize the protein, consistent with a loss-of-function mechanism. The p.Gln188Arg mutation retains only ~10% activity in vitro, while p.Arg333Trp abolishes activity entirely ([PMID:1897530], [PMID:9635294]).

Duarte variants (p.Asn314Asp) illustrate allelic heterogeneity: N314D in cis with regulatory or silent polymorphisms modulates enzyme stability and activity, leading to a milder biochemical phenotype without clinical disease in most carriers.

In summary, GALT deficiency meets criteria for a definitive ClinGen gene–disease association based on robust genetic and functional evidence. Early diagnosis via newborn screening and prompt galactose restriction are critical to prevent acute neonatal complications. Carrier screening and molecular testing facilitate genetic counseling and prenatal diagnosis.

References

• Human Genetics • 1994 • Biochemical and molecular studies of 132 patients with galactosemia. PMID:7927329
• American Journal of Human Genetics • 1991 • Molecular characterization of two galactosemia mutations: correlation of mutations with highly conserved domains in galactose-1-phosphate uridyl transferase. PMID:1897530
• Molecular Genetics and Metabolism • 1998 • Molecular and biochemical basis of galactosemia. PMID:9635294

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