A De Novo Variant in Galactose-1-P Uridylyltransferase (GALT) Leading to Classic Galactosemia
Classic galactosemia (CG) is a potentially lethal genetic disease that results from profound impairment of galactose-1-P uridylyltransferase (GALT), the middle enzyme in the Leloir pathway of galactose metabolism. Patients with CG carry pathogenic loss-of-function mutations in both of their GALT alleles; the parents of patients are considered obligate carriers. We report here a first exception to that rule – a de novo GALT variant in a patient with classic galactosemia. The new variant, c.563A>C (p.Q188P), which introduces a missense substitution near the active site of the GALT enzyme, was found in the compound heterozygous state in a child with classic galactosemia, but not in either of her parents. Extensive genomic studies of DNA from the child and both parents confirmed the expected degrees of relationship in the trio as well as inheritance of a common c.563A>G (p.Q188R) GALT mutation from the mother. This result demonstrates that not all pathogenic GALT mutations are inherited and raises concern that GALT may have a higher new mutation rate than previously believed.
KeywordsDideoxy Sequencing Classic Galactosemia Leloir Pathway Compound Heterozygous State GALT Gene
We are especially grateful to the family who participated in this research study; without them none of this work would have been possible. We also thank the Emory Integrated Genomics Core who conducted the Affymetrix genotyping reported here. This work was supported in part by funds from NIH R01 DK059904 (PI: JLFK); DR was supported in part by funds from a training grant in Human Disease Genetics 1T32MH087977 (PI: ST Warren).
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