A founder noncoding GALT variant interfering with splicing causes galactosemia

Kumarie Latchman, Jeanette Brown, Claire J. Sineni, Lorrien Ragin-Dames, Shengru Guo, Jingyu Huang, Willa Thorson, Stephanie Hacker, Deborah S Barbouth, Mustafa Tekin, Guney Bademci

Research output: Contribution to journalArticle

Abstract

Galactosemia is a rare, treatable hereditary disorder of carbohydrate metabolism. We investigated the etiology of decreased GALT enzyme activity in a cohort of newborns referred by the Florida Newborn Screening Program with no detectable GALT variants in diagnostic molecular tests. Six affected individuals from four families with Guatemalan heritage were included. GALT enzyme activity ranged from 20% to 34% of normal. Clinical findings were unremarkable except for speech delay in two children. Via genome sequencing followed by Sanger confirmation we showed that all affected individuals were homozygous for a deep intronic GALT variant, c.1059+390A>G, which segregated as an autosomal recessive trait in all families. The intronic variant disrupts splicing and leads to a premature termination and is associated with a single haplotype flanking GALT, suggesting a founder effect. In conclusion, we present a deep intronic GALT variant leading to a biochemical variant form of galactosemia. This variant remains undiagnosed until it is specifically targeted in molecular testing.

Original languageEnglish (US)
JournalJournal of Inherited Metabolic Disease
DOIs
StateAccepted/In press - 2020

Keywords

  • galactosemia
  • GALT
  • genome sequencing
  • Maya
  • newborn screening
  • pseudoexon

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Latchman, K., Brown, J., Sineni, C. J., Ragin-Dames, L., Guo, S., Huang, J., Thorson, W., Hacker, S., Barbouth, D. S., Tekin, M., & Bademci, G. (Accepted/In press). A founder noncoding GALT variant interfering with splicing causes galactosemia. Journal of Inherited Metabolic Disease. https://doi.org/10.1002/jimd.12293