Phosphoglycerate Dehydrogenase Deficiency and Neu-Laxova Syndrome 1 via the PHGDH Gene

Phosphoglycerate dehydrogenase deficiency is a rare inborn error of the amino acid L-serine biosynthesis that is characterized by congenital microcephaly, severe psychomotor retardation, hypertonia, intractable seizures, and growth retardation. Enzyme assays show significant decreased activity of 3’-phosphoglycerate dehydrogenase in patient fibroblasts (Klomp et al 2000). The major biochemical abnormalities associated with this disease are low concentrations of L-serine, D-serine, and glycine in cerebrospinal fluid. This deficiency is severe, but potentially treatable (Jaeken et al 1996).

Neu-Laxova syndrome 1 is a rare inborn disorder characterized by a recognizable pattern of malformations leading to prenatal or early postnatal lethality. The main features of the disease include significant fetal growth restriction, microcephaly, distinct facial appearance, ichthyosis and skeletal anomalies. Neu-Laxova syndrome 1 represents the severe end of serine-deficiency disorders (Shaheen et al 2014; Acuna-Hidalgo et al. 2014).

Phosphoglycerate dehydrogenase deficiency is inherited in an autosomal recessive manner and caused by pathogenic variants in the PHGDH gene encoding this enzyme. Pathogenic variants reported in the PHGDH gene include missense, nonsense and one small deletion (Klomp et al 2000; Tabatabaie et al 2009). Missense pathogenic variants either primarily affect substrate or cofactor binding and result in very low residual enzymatic activity. Some even lead to almost undetectable enzyme activities (Tabatabaie et al 2009). Large deletions and duplications have not been discovered yet. Disease severity correlates with the degree of PHGDH inactivation.

Neu-Laxova syndrome 1 is inherited in an autosomal recessive manner. Neu-Laxova syndrome 1 and phosphoglycerate dehydrogenase deficiency are allelic disorders. The reported cases of Neu-Laxova syndrome 1 are caused by homozygous missense variants in PHGDH gene (Shaheen et al 2014; Acuna-Hidalgo et al. 2014).

For the PHGDH gene, clinical sensitivity in large cohort of patients with phosphoglycerate dehydrogenase deficiency or Neu-Laxova syndrome 1 is unavailable in the literature due to reports only of individual cases. No large deletions and duplications have been reported (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the PHGDH gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.