Phosphoglycerate Dehydrogenase Deficiency and Neu-Laxova Syndrome 1 via the PHGDH Gene
- Summary and Pricing
- Clinical Features and Genetics
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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).
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).
Testing is accomplished by amplifying each coding exon of the PHGDH gene and ~20 bp of adjacent noncoding sequence, then determining the nucleotide sequence using standard Sanger dideoxy sequencing methods and a capillary electrophoresis instrument. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.
Indications for Test
PHGDH sequencing test is recommended for patients suspected to have phosphoglycerate dehydrogenase deficiency or Neu-Laxova syndrome 1.
|Official Gene Symbol||OMIM ID|
|Neu-Laxova syndrome 1||256520|
|Phosphoglycerate Dehydrogenase Deficiency||601815|
- Genetic Counselor Team - email@example.com
- Li Fan, MD, PhD, FCCMG, FACMG - firstname.lastname@example.org
- Acuna-Hidalgo R. et al. 2014. American Journal of Human Genetics. 95: 285-93. PubMed ID: 25152457
- Human Gene Mutation Database (Bio-base).
- Jaeken J. et al. 1996. Archives of Disease in Childhood. 74: 542-5. PubMed ID: 8758134
- Klomp L.W. et al. 2000. American Journal of Human Genetics. 67: 1389-99. PubMed ID: 11055895
- Shaheen R. et al. 2014. American Journal of Human Genetics. 94: 898-904. PubMed ID: 24836451
- Tabatabaie L. et al. 2009. Human Mutation. 30: 749-56. PubMed ID: 19235232
Bi-Directional Sanger Sequencing
Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org). As required, DNA is extracted from the patient specimen. PCR is used to amplify the indicated exons plus additional flanking non-coding sequence. After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions. In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.
As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.
Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).
In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.
Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.
In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.
In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.
Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.
Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.
Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.
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