Galactosemia Type I (Classic and Variant Galactosemia) via the GALT Gene

Galactosemia is a defect in the metabolism of galactose resulting in elevated levels of galactose and derivatives such as galactose-1-phosphate and galactitol. Severity of this disorder is quite variable, though it is generally categorized into three groups based on patient phenotype (Berry 2014). The first is the most severe “classic” form with onset in early infancy, and is characterized by feeding difficulties, vomiting, diarrhea, jaundice, cataracts, hypotonia, hepatomegaly and sepsis. If the amount of lactose in the diet is not reduced in the first days of life, these symptoms progress to death. Even in surviving patients, ovarian failure and lifelong speech and cognitive disabilities are expected (Berry 2014; Fridovich-Keil and Walter 2014). The second phenotypic category is termed "clinical variant" galactosemia, which also presents early in infancy and is more common in African Americans and native Africans in South Africa (Crushell et al. 2009; Berry 2014; Fridovich-Keil and Walter 2014). These patients tend to present with feeding difficulties, which may include failure to thrive, and hepatocellular damage, such as cirrhosis and bleeding. In these patients, if a lactose-restricted diet is implemented within the first days of life, the severe neonatal complications are typically prevented and the patients do not appear to be at risk for long-term complications (Berry 2014). The third phenotypic category is termed "biochemical variant galactosemia", the most common form of which is "Duarte variant galactosemia". Biochemical variant galactosemia is currently not thought to result in clinical disease in most patients (Berry 2014; Fridovich-Keil et al. 2014).

Today in wealthy nations, nearly all cases of classic galactosemia are detected through routine neonatal screening. However, it may be more difficult to detect patients with clinical and biochemical variant galactosemias because the galactose level in such patients is not as high as in classic galactosemia patients, and results of breath testing may be normal (Berry 2014). In situations where the activity of the GALT enzyme is always tested or the patient is fed enough lactose, clinical and biochemical variant galactosemias should be detectable (Berry 2014; Fridovich-Keil et al. 2014).

Galactosemia is an autosomal recessive disorder. Pathogenic variants in the GALT gene are the primary genetic cause of galactosemia. Relatively small numbers of cases are caused by pathogenic variants in the GALK1 (galactokinase) and GALE (UDPgalactose-4’-epimerase) genes. GALT encodes the enzyme galactose-1-phosphate uridyltransferase. Over 300 causative GALT variants have been reported to date (Human Gene Mutation Database; ARUP GALT Database at http://arup.utah.edu/database/GALT/GALT_display.php). Roughly 70% of these variants are missense, although frameshift, nonsense, splicing, small insertions and deletion variants and gross deletions have all been reported. The Gln188Arg variant is the most common cause of classic galactosemia, comprising up to 50% of all causative alleles in U.S. classic galactosemia patients and higher fractions among patients with western European ancestry (Berry 2014). Other common variants associated with classic galactosemia are the Lys285Asn and Leu195Pro missense variants, and a 5.5 kb complex deletion common in individuals of Ashkenazi Jewish descent. The Ser135Leu variant is particularly common among patients with African ancestry and is associated with clinical variant galactosemia (Suzuki et al. 2001; Crushell et al. 2009), whereas a 4-bp deletion in the GALT promoter, termed c.-119_-116delGTCA or D2 allele, is currently considered to be the main cause of Duarte variant galactosemia (Berry 2014). The Asn314Asp missense variant is usually found on the D2 allele together with the c.-119_-116delGTCA promoter variant, but as this missense variant also occurs on functionally normal GALT alleles, it is no longer considered to be a contributing factor to Duarte variant galactosemia (Berry 2014).

Testing for the 5.5 kb GALT deletion is available separately.

Using DNA sequencing, Bosch et al. (2005) reported detection of 91% of causative variants in 106 consecutive galactosemia patients. Similarly, Kozák et al. (2000) reported detection of 96% of causative variants in 37 patients. More recently, Boutron et al. (2012) reported detection of 99% of causative variants in a cohort of 210 French families using direct sequencing.

While the great majority of GALT variants are expected to be detected via gene sequencing, several exonic or whole-gene deletions have been reported (Human Gene Mutation Database). In general, these deletions have been observed in a single patient, although a ~5.5 kb complex deletion is common in those of Ashkenazi Jewish descent (Barbouth et al. 2006; Coffee et al. 2006; Berry 2014). If desired, the specific Ashkenazi Jewish ~5.5 kb deletion can also be detected by our PCR-based deletion test.

This test provides full coverage of all coding exons of the GALT gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Our test covers the 4 bp deletion in the promoter region upstream of exon 1 (c.-119_-116 delGTCA) that has been shown to decrease enzyme activity in the Duarte allele (Elsas et al. 2001; Berry 2014).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).