Genetic and functional studies reveal a novel noncoding variant in GALT associated with a false positive newborn screening result for galactosemia.
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.
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Ying
Y
Liu
Children's Hospital of Michigan Metabolic Clinic, Wayne State University, Detroit, MI 48201, USA.
Alpa
A
Sidhu
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Lora H
LH
Bean
Children's Hospital of Michigan Metabolic Clinic, Wayne State University, Detroit, MI 48201, USA.
Robert L
RL
Conway
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: jfridov@emory.edu.
Judith L
JL
Fridovich-Keil
D000328:Adult; D058070:Asymptomatic Diseases; D002478:Cells, Cultured; D003241:Consanguinity; D005260:Female; D005693:Galactosemias / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D005695:Galactosephosphates / Q000378:metabolism; D015870:Gene Expression; D056426:Genetic Loci; D005820:Genetic Testing; D004854:Herpesvirus 4, Human / Q000254:growth & development; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008214:Lymphocytes / Q000378:metabolism / Q000821:virology; D008297:Male; D009154:Mutation; D015997:Neonatal Screening; D014170:Transformation, Genetic; D005694:UTP-Hexose-1-Phosphate Uridylyltransferase / Q000172:deficiency / Q000235:genetics*
D005695:Galactosephosphates; C029973:galactose-1-phosphate; D005694:UTP-Hexose-1-Phosphate Uridylyltransferase
Functional studies; Galactosemia; Newborn screening; Non-coding variant; qRT-PCR