Abstract
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.
Competing interests: None declared
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Acknowledgments
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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Communicated by: John H Walter, MD FRCPCH
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Genomic studies confirm a de novo variant in human galactose-1-P uridylyltransferase (GALT) leading to classic galactosemia.
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Thanh-Thanh (Claire) V. Tran declares that she has no conflict of interest.
Ying Liu declares that she has no conflict of interest.
Michael Zwick declares that he has no conflict of interest.
Dhanya Ramachandran declares that she has no conflict of interest.
David Cutler declares that he has no conflict of interest.
Xiaoping Huang declares that she has no conflict of interest.
Gerard Berry declares that he has no conflict of interest.
Judith Fridovich-Keil declares that she has no conflict of interest.
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“All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5).”
All data from specific individuals reported here were collected following appropriate informed consent/assent and with approval by the Emory University Institutional Review Board (IRB# 00024933, PI: JL Fridovich-Keil).
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“This article does not contain any studies with animal subjects performed by any of the authors.”
Contributions of Each Author
Thanh-Thanh (Claire) V. Tran confirmed the GALT genotype of the child, performed GALT genotyping for both parents, and also helped to edit the manuscript.
Ying Liu helped to oversee Ms. Tran’s work, designed the GALT sequencing primers, and also helped to edit the manuscript.
Michael Zwick oversaw the Affymetrix 6.0 genotyping of the three DNA samples that confirmed both parent–child relationships and also helped to edit the manuscript.
Dhanya Ramachandran performed genotype calling and statistical analyses on Affymetrix SNP 6.0 data and also helped to edit the manuscript.
David Cutler assisted with the interpretation of the Affymetrix genotyping data and also helped to edit the manuscript.
Xiaoping Huang and Gerard Berry originally identified the Q188P variant in the child and also helped to write and edit the manuscript.
Judith Fridovich-Keil initiated the project, coordinated the efforts of the other authors, and wrote most of the manuscript.
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Tran, TT.(.V. et al. (2014). A De Novo Variant in Galactose-1-P Uridylyltransferase (GALT) Leading to Classic Galactosemia. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 19. JIMD Reports, vol 19. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_349
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DOI: https://doi.org/10.1007/8904_2014_349
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