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A founder noncoding GALT variant interfering with splicing causes galactosemia
Author(s) -
Latchman Kumarie,
Brown Jeanette,
Sineni Claire J.,
RaginDames Lorrien,
Guo Shengru,
Huang Jingyu,
Thorson Willa,
Hacker Stephanie,
Barbouth Deborah,
Tekin Mustafa,
Bademci Guney
Publication year - 2020
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1002/jimd.12293
Subject(s) - galactosemia , genetics , rna splicing , sanger sequencing , biology , human genetics , genetic testing , exome sequencing , haplotype , newborn screening , allele , mutation , gene , rna , biochemistry , galactose
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.