Genetic and functional studies reveal a novel noncoding variant in GALT associated with a false positive newborn screening result for galactosemia.

Abstract

BACKGROUND:

Classic galactosemia (CG) is a potentially lethal genetic disorder that results from profound loss of galactose-1-phosphate uridylyltransferase (GALT). CG is detected by newborn screening (NBS) in many countries; however, conclusive diagnosis can be complex due to broad and overlapping ranges of GALT activity. Molecular studies can also be complex due to allelic heterogeneity at the GALT locus.

METHODS:

We conducted both biochemical and molecular follow-up studies for an infant flagged by NBS for possible galactosemia. To clarify the diagnosis we also conducted biochemical and RNA studies of lymphoblasts prepared from the child and one parent.

RESULTS:

We identified a novel noncoding GALT variant, c.377+17C>T, that was homozygous in the child and heterozygous in both parents. The child and both parents also showed diminished GALT activity in red blood cells, and transformed lymphoblasts from the child and one parent further showed diminished GALT activity. However, qRT-PCR studies demonstrated apparently normal GALT mRNA levels in lymphoblasts, and Gal-1P values measured in the child following galactose exposure in infancy and at 1 year were normal.

CONCLUSIONS:

These results highlight the existence of rare but apparently benign variants in GALT and underscore the need for functional studies to distinguish pathogenic from benign variants.

• Authors: Ying Liu, Alpa Sidhu, Lora H Bean, Robert L Conway, Judith L Fridovich-Keil
• Journal: Clinica chimica acta; international journal of clinical chemistry (Clin Chim Acta) Vol. 446 Pg. 171-4 (Jun 15 2015) ISSN: 1873-3492 [Electronic] Netherlands
• PMID: 25920691 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Galactosephosphates
• galactose-1-phosphate
• UTP-Hexose-1-Phosphate Uridylyltransferase

Topics

• Adult
• Asymptomatic Diseases
• Cells, Cultured
• Consanguinity
• Female
• Galactosemias (blood, diagnosis, genetics)
• Galactosephosphates (metabolism)
• Gene Expression
• Genetic Loci
• Genetic Testing
• Herpesvirus 4, Human (growth & development)
• Heterozygote
• Homozygote
• Humans
• Infant, Newborn
• Lymphocytes (metabolism, virology)
• Male
• Mutation
• Neonatal Screening
• Transformation, Genetic
• UTP-Hexose-1-Phosphate Uridylyltransferase (deficiency, genetics)