Glycine N-Methyltransferase Deficiency via the GNMT Gene

Defects in the Glycine N-Methyltransferase (GNMT) enzyme have been shown to lead to persistent, isolated hypermethioninemia, which is the elevation of methionine in plasma without accompanying homocystinemia. This hypermethioninemia persists beyond the first months of life (Mudd et al. 2001). Very few patients have been described with defects in the GNMT enzyme. Clinically, the identified patients have presented with hepatomegaly (in one family) and chronic elevation of serum transaminases indicative of liver disease, but not attributable to typical causes of liver disease. Biochemically, all patients were found to have persistently elevated serum methionine levels with normal levels of plasma homocysteine, tyrosine and sarcosine. In addition, serum adenosylmethionine (AdoMet) was elevated while serum adenosylhomocysteine (AdoHcy) levels were normal (Mudd et al. 2001; Luka et al. 2002; Augoustides-Savvopoulou et al. 2003).

Onset appears to be during early childhood, although it is not currently known how early hypermethioninemia would be detected in GNMT deficient individuals. Due to the small number of cases reported, the long-term prognosis of the GNMT patients is currently unknown (Mudd et al. 2001; Luka et al. 2002; Augoustides-Savvopoulou et al. 2003).

The Glycine N-Methyltransferase enzyme is encoded by the GNMT gene, located on chromosome 6 at 6p12. To date, only three GNMT deficient patients have been reported in the literature and thus far, inheritance appears to be autosomal recessive. Two of the patients were Italian siblings, who were each found to be compound heterozygous for the missense variants Leu49Pro and His177Asn (Luka et al. 2002). The third patient was of Greek origin, and was found to be homozygous for the missense variant Arg140Ser (Augoustides-Savvopoulou et al. 2003).

The GNMT enzyme is present in large amounts in liver, pancreas and prostate, and appears to be primarily a cytosolic enzyme. GNMT is involved in methionine metabolism. The enzyme methionine adenosyltransferase I/III converts methionine to adenosylmethionine (AdoMet), which is then converted to adenosylhomocysteine (AdoHcy) via the action of the GNMT enzyme. Mutations in the GNMT gene that affect activity of the GNMT enzyme lead to accumulation of methionine and AdoMet in the plasma (Mudd et al. 2001; Luka et al. 2009).

At this time, the sensitivity of this test is difficult to estimate due to the low number of cases reported in the literature. Analytical sensitivity may be high as the only reported causative variants are detectable by sequencing (Luka et al. 2002; Augoustides-Savvopoulou et al. 2003).

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

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).