Test Code GALMP Galactosemia, GALT Gene, Variant Panel, Varies

Ordering Guidance

The recommended first-tier test is galactose-1-phosphate uridyltransferase (GALT) enzyme analysis; order GALT / Galactose-1-Phosphate Uridyltransferase, Blood.

This genetic variant panel is recommended for individuals with a GALT enzyme value less than 24.5 nmol/h/mg of hemoglobin.

Shipping Instructions

Specimen Required

Patient Preparation: A previous hematopoietic stem cell transplant from an allogenic donor will interfere with testing. For information about testing patients who have received a hematopoietic stem cell transplant, call 800-533-1710.

Submit only 1 of the following specimens:

Specimen Type: Whole blood

Container/Tube: Lavender top (EDTA) or yellow top (ACD)

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send whole blood specimen in original tube. Do not aliquot.

3. Whole blood collected postnatal from an umbilical cord is also acceptable. See Additional Information

Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 4 days/Frozen 4 days

Additional Information:

1. Specimens are preferred to be received within 4 days of collection. Extraction will be attempted for specimens received after 4 days, and DNA yield will be evaluated to determine if testing may proceed.

2. To ensure minimum volume and concentration of DNA are met, the requested volume must be submitted. Testing may be canceled if DNA requirements are inadequate.

3. For postnatal umbilical cord whole blood specimens, maternal cell contamination studies are recommended to ensure test results reflect that of the patient tested. A maternal blood specimen is required to complete maternal cell contamination studies. Order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on both the cord blood and maternal blood specimens under separate order numbers.

Specimen Type: Extracted DNA

Container/Tube:

Preferred: Screw Cap Micro Tube, 2 mL with skirted conical base

Acceptable: Matrix tube, 1 mL

Collection Instructions:

1. The preferred volume is at least 100 mcL at a concentration of 75 ng/mcL.

2. Include concentration and volume on tube.

Specimen Stability Information: Frozen (preferred) 1 year/Ambient/Refrigerated

Additional Information: DNA must be extracted in a CLIA-certified laboratory or equivalent and must be extracted from a specimen type listed as acceptable for this test (including applicable anticoagulants). Our laboratory has experience with Chemagic, Puregene, Autopure, MagnaPure, and EZ1 extraction platforms and cannot guarantee that all extraction methods are compatible with this test. If testing fails, one repeat will be attempted, and if unsuccessful, the test will be reported as failed and a charge will be applied. If applicable, specific gene regions that were unable to be interrogated due to DNA quality will be noted in the report.

Forms

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. Molecular Genetics: Biochemical Disorders Patient Information (T527)

Secondary ID

606343

Useful For

Second-tier test for confirming a diagnosis of galactosemia as indicated by enzymatic testing or newborn screening

Carrier testing family members of an affected individual of known genotype (has variants included in the panel)

Resolution of Duarte variant and Los Angeles (LA) variant genotypes

Highlights

A targeted genotyping array is utilized to detect 24 genetic targets associated with galactosemia for the purpose of diagnostic testing or carrier screening.

Disease States

Galactosemia

Testing Algorithm

For cord blood specimens that have an accompanying maternal blood specimen, maternal cell contamination studies will be performed at an additional charge.

For more information see Galactosemia Testing Algorithm

Special Instructions

Method Name

Targeted Genotyping Array followed by Multiplex Ligation-Dependent Probe Amplification (MLPA), Polymerase Chain Reaction (PCR), Relative Quantitative PCR (qPCR), or Sanger Sequencing, as needed

Reporting Name

Galactosemia Mutation Panel

Specimen Type

Varies

Specimen Minimum Volume

See Specimen Required

Specimen Stability Information

Specimen Type	Temperature	Time
Varies	Varies

Reject Due To

All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.

Clinical Information

Galactosemia is an autosomal recessive disorder that results from a deficiency of any 1 of the 4 enzymes catalyzing the conversion of galactose to glucose: galactose-1-phosphate uridyltransferase (GALT), galactokinase (GALK), uridine diphosphate galactose-4-epimerase (GALE), and galactose mutarotase (GALM). GALT deficiency is the most common cause of galactosemia and is often referred to as classic galactosemia. Classic galactosemia is caused by pathogenic variants in the GALT gene. The complete or near-complete deficiency of GALT enzyme is life threatening if left untreated. Complications in the neonatal period include failure to thrive, liver failure, sepsis, and death.(1)

Galactosemia is treated by a galactose-restricted diet, which allows for rapid recovery from the acute symptoms and a generally good prognosis.(2) Despite adequate treatment from an early age, individuals with galactosemia remain at increased risk for developmental delays, speech problems, and abnormalities of motor function. Female individuals with galactosemia are at increased risk for premature ovarian failure. Based upon reports by newborn screening programs, the frequency of classic galactosemia in the United States is approximately 1 in 30,000, although literature reports range from 1 in 10,000 to 1 in 60,000 live births.

Duarte-variant galactosemia (compound heterozygosity for the c.-119_-116del/c.940A>G (p.N314D) variants in addition to a classic variant) is generally associated with higher levels of enzyme activity (5%-20%) than classic galactosemia (<5%); however, this may be indistinguishable by newborn screening assays.(3) Previously, it was unknown whether children with Duarte-variant galactosemia were at an increased risk for adverse developmental outcomes due to milk exposure and were often treated with a low galactose diet during infancy. More recently, the outcomes data suggest a lack of evidence for developmental complications due to milk exposure, therefore treatment recommendations remain controversial.(2,4) The Duarte variant, c.-119_-116del/c.940A>G (p.N314D), is found in 5% of the general United States population. The Los Angeles variant, which consists of p.N314D and a second variant, p.L218L, is associated with higher levels of GALT enzyme activity than the Duarte-variant allele.

Newborn screening for galactosemia is performed in all 50 US states, though the method by which potentially affected individuals are detected varies from state to state and may include the measurement of total galactose (galactose and galactose-1-phosphate) or determining the activity of the GALT enzyme. The diagnosis of galactosemia is established by follow-up quantitative measurement of GALT enzyme activity. If enzyme levels are indicative of carrier or affected status, molecular testing for common GALT variants may be performed. If one or both disease-causing variants are not detected by targeted variant analysis and biochemical testing has confirmed the diagnosis of galactosemia, sequencing of the GALT gene (GALZ / Galactosemia, GALT Gene, Full Gene Analysis, Varies) is available to identify additional variants.

For more information see Galactosemia Testing Algorithm.

Table. Targeted Variants

Associated phenotype

Gene (transcript)

Variants

Galactosemia

GALT (NM_000155)

c.-119_-116del*, c.136_140del, c.221T>C*, c.253-2A>G*, c.292G>A*, c.404C>T*, c.413C>T*, c.425T>A*, c.443G>A*, c.505C>A, c.512T>C*, c.563A>G*, c.584T>C*, c.607G>A*, c.626A>G*, c.855G>T*, c.940A>G*, c.958G>A*, c.997C>G*, c.997C>T*, c.1018G>T, c.1030C>A*, c.1138T>C*

Deletion analysis of exon 1-11

*Previously detected in a known positive sample

Reference Values

An interpretive report will be provided.

Interpretation

The interpretive report includes an overview of the findings as well as the associated clinical significance.

Results should be interpreted in the context of biochemical results.

If results of the galactose-1-phosphate uridyltransferase enzyme analysis and this test are discordant, then consider GALZ / Galactosemia, GALT Gene, Full Gene Analysis, Varies.

Method Description

The targeted genotyping assay utilizing the ThermoFisher GeneTitan platform is used to detect 24 targets in the GALT gene. Confirmatory testing of homozygous results is performed as reflex tests when appropriate. For details regarding the targeted disease-causing variants identified by this test, see the Targeted Variants table in Clinical Information.

Multiplex ligation-dependent probe amplification, polymerase chain reaction (PCR), relative quantitative PCR, and Sanger sequencing are used to confirm variants detected by array when appropriate.(Unpublished Mayo method)

Day(s) Performed