GALT Gene, Full Gene Analysis
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Classic galactosemia is an autosomal recessive disorder of galactose metabolism caused by mutations in the galactose-1-phosphate uridyltransferase (GALT) gene. The complete or near complete deficiency of the GALT enzyme is life threatening. If left untreated, complications include liver failure, sepsis, mental retardation, and death. Galactosemia is treated by a galactose-free diet, which allows for rapid recovery from the acute symptoms and a generally good prognosis. Despite adequate treatment from an early age, children with galactosemia remain at increased risk for developmental delays, speech problems, and abnormalities of motor function. Females with galactosemia are at increased risk for premature ovarian failure. The prevalence of classic galactosemia is approximately 1 in 30,000.
Duarte variant galactosemia (compound heterozygosity for the Duarte variant, N314D, and a classic mutation) is generally associated with higher levels of GALT activity (5%-20%) than classic galactosemia (<5%); however, this may be indistinguishable by newborn screening assays. Typically, individuals with Duarte variant galactosemia have a milder phenotype, but are often treated with a low galactose diet during infancy. The LA variant, consisting of N314D and a second change, L218L, is associated with higher levels of GALT activity than the Duarte variant alone.
Newborn screening, which identifies potentially affected individuals by measuring total galactose (galactose and galactose-1-phosphate) and/or determining the activity of the GALT enzyme, varies from state to state. The diagnosis of galactosemia is established by follow-up quantitative measurement of GALT activity. If enzyme activity levels are indicative of carrier or affected status, molecular testing for common GALT mutations may be performed. If 1 or both disease-causing mutations are not detected by targeted mutation analysis and biochemical testing has confirmed the diagnosis of galactosemia, sequencing of the GALT gene is available to identify private mutation(s).
The GALT gene maps to 9p13. More than 180 mutations have been identified in the GALT gene. Several disease-causing mutations are common in patients with classic galactosemia (G/G genotype). The most frequently observed is the Q188R mutation. This mutation accounts for 60% to 70% of classic galactosemia alleles. The S135L mutation is the most frequently observed mutation in African Americans and accounts for approximately 50% of the mutant alleles in this population. The K285N mutation is common in those of eastern European descent and accounts for 25% to 40% of the alleles in this population. The L195P mutation is observed in 5% to 7% of classic galactosemia. The Duarte variant (N314D) is found in 5% of the general United States population.
The above mutations, plus the LA variant, are included in GCT / Galactosemia Reflex, Blood, which is the preferred test for the diagnosis of galactosemia or for follow-up to positive newborn screening results. These mutations are also included in GAL6 / Galactosemia Gene Analysis (6-Mutation Panel). Full sequencing of the GALT gene can be useful for the identification of mutations when 1 or no mutations are found with these tests in an individual with demonstrated GALT activity deficiency. Full sequencing of the GALT gene identifies over 95% of the sequence variants in the coding region and splice junctions. See Galactosemia Testing Algorithm in Special Instructions for additional information. Refer to Galactosemia: Current Testing Strategy and Aids for Test Selection, Mayo Medical Laboratories Communique 2005 May;30(5) for more information regarding diagnostic strategy.
Identifying mutations in individuals who test negative for the common mutations and who have a biochemical diagnosis of galactosemia or galactose-1-phosphate uridyltransferase activity levels indicative of carrier status
All detected alterations will be evaluated according to the American College of Medical Genetics and Genomics (AMCG) recommendations. Variants will be classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
A small percentage of individuals who are carriers or have a diagnosis of galactosemia may have a mutation that is not identified by the methods described above (eg, large genomic deletions, promoter mutations). The absence of a mutation(s), therefore, does not eliminate the possibility of positive carrier status or the diagnosis of galactosemia. For carrier testing, it is important to first document the presence of a galactose-1-phosphate uridyltransferase (GALT) gene mutation in an affected family member.
In some cases, DNA alterations of undetermined significance may be identified.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical and biochemical findings, additional testing should be considered.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.
This test is not recommended for carrier screening or diagnosis in individuals with a positive newborn screen; see GCT / Galactosemia Reflex, Blood.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Elsas LJ 2nd, Lai K: The molecular biology of galactosemia. Genet Med 1998 Nov-Dec;1(1):40-48
2. Novelli G, Reichardt JK: Molecular basis of disorders of human galactose metabolism: past, present, and future. Mol Genet Metab 2000 Sep-Oct;71(1-2):62-65
3. Bosch AM, Ijlst L, Oostheim W, et al: Identification of novel mutations in classical galactosemia. Hum Mutat 2005 May;25(5):502
4. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10(4):294-300