Glutathione Synthetase Deficiency via the GSS Gene

Glutathione synthetase deficiency is the most common inborn error of the synthesis of glutathione. According to clinical severity, the disease has been classified as mild, moderate or severe (Njålsson 2005; Ristoff and Larsson. 2007). The mild form is alternatively termed hemolytic anemia due to glutathione synthetase deficiency, with only the presentation of hemolytic anemia. The moderate form usually presents with severe chronic metabolic acidosis and 5-oxoprolinuria with mild or moderate hemolytic anemia in the neonatal stage. In addition to all manifestations of the moderate form, patients with severe glutathione synthetase deficiency typically develop progressive neurological symptoms including psychomotor retardation, mental retardation, seizures, spasticity, ataxia, and intention tremor. Some patients also have recurrent bacterial infections. Retinal dystrophy has been also found in some adult patients. Other less frequent clinical manifestations include antenatal cerebral haemorrhage, low levels of cysteinyl leukotrienes and multiple malformations. Age at onset of the disease ranges from the first days of life to childhood (Simon et al. 2009). Early death in the neonatal stage due to infection and electrolyte imbalance has been reported in about 25% of patients with glutathione synthetase deficiency.

Glutathione synthetase deficiency is an autosomal recessive disorder caused by defects in the GSS gene (Shi et al. 1996). GSS has 12 coding exons that encode glutathione synthetase, the enzyme catalyzing the last step of glutathione synthesis. The majority of GSS defects are missense and splicing site mutations, accounting for approximately 60% and 28% of all documented pathogenic alleles respectively (Human Gene Mutation Database). Small deletion/insertions and one nonsense mutation have been also found in GSS, but much less frequently. Although GSS defects have been found across the whole coding region of the gene, the majority of missense mutations are clustered at the region of exons 5 to 10 (Dahl et al. 1997; Njålsson 2005). The mild form of the disease is correlated with pathogenic mutations affecting enzymatic stability (Njålsson 2005).

Biallelic GSS mutations were found in the coding exons and exon-intron boundaries of the gene in about 77% (23 out of 30) of patients with glutathione synthetase deficiency (Njålsson et al. 2003).

This test provides full coverage of all coding exons of the GSS 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).

In addition, we also target-sequence the following documented pathogenic mutations that cannot be detected via the above sequencing: c.-9+5G>A and c.129+1663 A>G (Human Gene Mutation Database).

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).