Invitae Galactosemia Panel


Test description

The Invitae Galactosemia Panel analyzes the GALE, GALK1, and GALT genes, which encode enzymes responsible for galactose metabolism. This test is useful for the diagnosis of patients whose clinical symptoms, abnormal newborn screening results, or biochemical findings indicate galactosemia.

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Primary panel (3 genes)


GALT: Analysis includes the 5 kb deletion NM_000155.3:c.[-1039_753del; 820+50_*789delinsGAATAGACCCCA] as well as the Duarte variant NM_000155.3: c.-119_-116delGTCA.

Galactose-1-phosphate uridylyltransferase (GALT) deficiency (classic galactosemia, clinical variant galactosemia, Duarte variant galactosemia), galactoepimerase (GALE) deficiency, galactokinase (GALK) deficiency

Galactosemia is a group of autosomal-recessive-inherited metabolic disorders that are caused by a deficiency in one of three enzymes involved in the catabolism of the simple sugar galactose. Patients with galactosemia experience toxic elevations of galactose and other galactose metabolites in the blood when they are exposed to milk and other lactose products. Many infants affected with galactosemia are detected through state newborn-screening programs.

GALT deficiency
Galactose-1-phosphate uridylyltransferase (GALT) deficiency is the most common enzyme deficiency in galactosemia, including classic galactosemia, clinical variant galactosemia, and Duarte variant galactosemia.

In classic galactosemia and clinical variant galactosemia, GALT enzymatic activity is absent or very low. Affected infants appear normal at birth, but once they ingest lactose, they quickly develop life-threatening symptoms, including feeding problems with vomiting and diarrhea, liver damage leading to jaundice, kidney disease, congenital bilateral cataracts, E. coli sepsis, seizures, bleeding diathesis, and failure to thrive. Even with adequate treatment from an early age, children with classic galactosemia remain at increased risk for developmental delays, speech problems, and abnormalities of motor function. Almost all females with classic galactosemia manifest premature ovarian insufficiency. Patients with variant galactosemia who are well-managed typically do not develop the long-term complications that are associated with classic galactosemia.

Duarte variant galactosemia is a common and milder form of GALT deficiency. Individuals with Duarte variant galactosemia is associated with compound heterozygosity for the Duarte mutation, N314D, and a classic mutation. Most patients are asymptomatic, although some have been reported with speech and language difficulties. Treatment for Duarte variant galactosemia remains controversial.

Patients with little or no residual GALT enzyme activity typically have the severe neonatal presentation while patients with higher residual enzyme activity have the less-severe forms. Early diagnosis and elimination of dietary galactose reduce mortality in patients with classic GALT deficiency, but even patients with optimal treatment can still suffer from ovarian insufficiency, mental retardation, speech dyspraxia, ataxia, and learning disabilities.

GALE deficiency
Galactoepimerase (GALE) deficiency is defined by a spectrum of enzyme deficiencies involving different tissues. Clinical presentations vary from asymptomatic to severe. Patients with severe GALE deficiency accumulate cytotoxic galactose 1-phosphate in the cells and may manifest symptoms resembling classic galactosemia. The severe form of GALE deficiency is extremely rare.

GALK deficiency
Patients with galactokinase (GALK) deficiency have biochemical findings of galactosemia (increased plasma galactose levels, urinary galactitol excretion), though galactose-1-phosphate levels are not elevated. Patients with GALK deficiency do not develop the life-threatening complications observed in classic galactosemia. Clinically, they are only at high risk of developing cataracts.

For patients with a clinical and biochemical diagnosis of galactosemia, the detection rate of pathogenic variants in one of these three genes is nearly 100%.

Gene % of galactosemia cases attributed
GALE rare
GALK1 23%–-37%
GALT 63%–77%

GALT, GALE, and GALK deficiencies are all inherited in an autosomal recessive manner.

Regarding GALT deficiency galactosemia, the prevalence of classic galactosemia is 1 in 10,000–48,000, the prevalence of clinical variant galactosemia is unknown, and the prevalence of Duarte variant galactosemia is approximately 1 in 16,000.

The overall incidence of GALE deficiency is unknown. The generalized form is very rare. The peripheral form is more common in African Americans, compared to other ethnic groups.

The prevalence of GALK is not well-known. The birth incidence for GALK deficiency is approximately 1 in 150,000 or greater in most parts of Europe, USA, and Japan.

This test may be appropriate for:

  • patients with abnormal newborn screening for galactosemia
  • patients with elevated galactose-1-phosphate, total galactose, or urine galactitol
  • patients who present with neonatal sepsis and congenital cataracts

For considerations for testing please refer to:

  1. American College of Medical Genetics. NBS ACT Sheet. Classical Galactosemia. Accessed February 2016.
  2. American College of Medical Genetics. NBS ACT Sheet. Primary or Secondary Hypergalactosemia. Accessed February 2016.
  3. Berry GT, Walter JH. Inborn metabolic diseases: diagnosis and treatment. 5th ed. Heidelberg: Springer; 2012. Chapter 7, Disorders of Galactose Metabolism; p. 141–150.
  4. Berry, GT. Classic Galactosemia and Clinical Variant Galactosemia. 2000 Feb 04. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301691
  5. Bosch, AM, et al. Clinical features of galactokinase deficiency: a review of the literature. J. Inherit. Metab. Dis. 2002; 25(8):629-34. PMID: 12705493
  6. Bosch, AM, et al. Identification of novel mutations in classical galactosemia. Hum. Mutat. 2005; 25(5):502. PMID: 15841485
  7. Bosch, AM. Classical galactosaemia revisited. J. Inherit. Metab. Dis. 2006; 29(4):516-25. PMID: 16838075
  8. Duarte Galactosemia. Accessed February 2016.
  9. Kolosha, V, et al. Novel mutations in 13 probands with galactokinase deficiency. Hum. Mutat. 2000; 15(5):447-53. PMID: 10790206
  10. Medical Home Portal. Galactosemia. Accessed February 2016.
  11. Park, HD, et al. Molecular and biochemical characterization of the GALK1 gene in Korean patients with galactokinase deficiency. Mol. Genet. Metab. 2007; 91(3):234-8. PMID: 17517531

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
GALE NM_000403.3
GALK1 NM_000154.1
GALT* NM_000155.3

GALT: Analysis includes the 5 kb deletion NM_000155.3:c.[-1039_753del; 820+50_*789delinsGAATAGACCCCA] as well as the Duarte variant NM_000155.3: c.-119_-116delGTCA.