Molecular Pathogenesis

The mechanism of pathogenesis of the GALT D₂ allele was a point of some confusion in the past (reviewed in Carney et al [2009]), likely reflecting the complex nature of the allele and the fact that the linked 4-bp promoter deletion (c.-119_-116delGTCA) was not initially recognized. The consensus is now that this 4-bp promoter deletion is actually the causal variant, leading to slight impairment of expression of what is a fully functional GALT protein.

The mechanism of pathogenesis of different GALT pathogenic variants as a cause of classic / clinical variant galactosemia is described in Classic Galactosemia and Clinical Variant Galactosemia.

Gene structure. See Classic Galactosemia and Clinical Variant Galactosemia for information about GALT. See also Table A, Gene.

Benign variants

• Duarte variant (D₂) allele. Some consider the D₂ variant allele itself to be benign. Five sequence changes are found together on the D₂ allele.
  • Four are noncoding nucleotide variants that are unique to the D₂ allele (see Table 3).
  • Of primary importance is a 4-bp deletion in the GALT promoter region (c.-119_-116delGTCA) that slightly impairs gene expression (reviewed in Carney et al [2009]).
  • The three remaining variants unique to D₂ are c.378-27G>C, c.508-24G>A, and c.507+62G>A.
  • The fifth sequence change is the missense variant c.940A>G (p.Asn314Asp, also called N314D); while always on the D₂ allele, c.940A>G also occurs on other functionally normal GALT alleles (reviewed in Carney et al [2009]).
• Los Angeles (or D₁) variant allele results in no diminution of GALT enzyme activity and is considered benign. Note: The Los Angeles (LA) GALT variant (D₁) has the identical c.940A>G missense variant as the D₂ variant but does not have the c.-119_-116delGTCA promoter deletion. Instead, it has the silent variant c.652C>T (p.Leu218=, also called L218L) on the same allele. See Classic Galactosemia and Clinical Variant Galactosemia. The D₁ variant allele does not cause galactosemia and is associated with normal or slightly increased erythrocyte GALT enzyme activity (reviewed in Carney et al [2009]).

Interpretation of molecular genetic test results. Although rare, some individuals with Duarte variant galactosemia are homozygous for c.940A>G (p.Asn314Asp, also called N314D) and heterozygous for a pathogenic GALT variant, indicating that the pathogenic variant coexists in these individuals with either a D₂ or D₁ allele on the same chromosome.

Also, rarely, some individuals with classic galactosemia (who by definition have biallelic GALT pathogenic variants) may also have either a D₂ or D₁ allele on the same chromosome as one or both pathogenic GALT variants.

Therefore, demonstrating the presence of the D₂ variant – or any of the individual GALT sequence changes associated with a D₂ allele (e.g., c.940A>G, p.Asn314Asp, or N314D) – does not confirm a diagnosis of Duarte variant galactosemia or rule out a diagnosis of classic galactosemia. The presence of GALT variants must always be interpreted in conjunction with GALT enzyme activity levels.

Of note, the parents of a child with an identified D₂ GALT variant allele and a GALT pathogenic variant allele can undergo molecular genetic testing themselves to determine whether each parent carries one variant, or whether both GALT variants are found in one parent while the other parent carries neither variant.

• If each parent carries one variant found in the child, the D₂ and pathogenic GALT variants identified in the child are on separate chromosomes consistent with a diagnosis of Duarte variant galactosemia in the child.
• If one parent carries both the D₂ and pathogenic GALT variants identified in the child while the other parent carries neither, the D₂ and pathogenic GALT variants in the child most likely coexist on the same chromosome consistent with a diagnosis of unaffected galactosemia carrier rather than Duarte variant galactosemia in the child. In this scenario, the child would also be expected to show a GALT enzyme activity level close to 50% of control.

Pathogenic variants. See Classic Galactosemia and Clinical Variant Galactosemia for information on other GALT alleles.

Normal gene product. The normal human GALT protein contains 379 amino acids and functions as a homodimer with two active sites [Wedekind et al 1995, Holden et al 2003].

A GALT allele with only the c.940A>G (p.Asn314Asp) variant is thought to produce a fully functional protein (reviewed in Carney et al [2009]).

Abnormal gene product. Abnormal gene products associated with different pathogenic alleles of GALT are described in Classic Galactosemia and Clinical Variant Galactosemia.