Molybdenum Cofactor Deficiency via the GPHN Gene
- Summary and Pricing
- Clinical Features and Genetics
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The great majority of tests are completed within 18 days.
Clinical sensitivity cannot be estimated precisely because only a small number of patients have been reported. However, clinical sensitivity appears to be low.
Molybdenum cofactor deficiency is an inborn error in metabolism caused by pathogenic variants in the enzymes responsible for molybdenum cofactor biosynthesis. As a result, several molybdenum cofactor-dependent enzymes (sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase) are nonfunctional. Patients with molybdenum cofactor deficiency excrete elevated levels of sulfite, thiosulfate, S-sulfocysteine, xanthine, and hypoxanthine while uric acid levels are low (Johnson and Duran, 2014). Clinical presentations in molybdenum cofactor deficiencies and isolated sulfite oxidase deficiency are almost indistinguishable. Considerable variability and age of onset for molybdenum cofactor deficiency exists. However, typically presentation will occur shortly after birth with severe convulsions that are difficult to suppress (Reiss et al., 2001. PubMed ID: 11095995; Reiss et al., 2011. PubMed ID: 22040219; Johnson and Duran, 2014). Patients with molybdenum cofactor deficiency also have dysmorphic features that include long face with puffy cheeks, widely spaced eyes, elongated palpebral fissures, thick lips, a long philtrum, and a small nose, which can resemble perinatal asphyxia. Patients also present with psychomotor retardation, ophthalmologic abnormalities such as lens dislocation, peripheral hypertonicity, and axial hypotonia (Johnson and Duran, 2014).
All molybdenum cofactor deficiencies are inherited in an autosomal recessive manner. Reported pathogenic variants in GPHN include a missense variant and a gross deletion of exons 2-3 (Reiss et al., 2001. PubMed ID: 11095995; Reiss et al., 2011. PubMed ID: 22040219). Copy number variants (CNVs) in GPHN in the heterozygous state have been associated with neurodevelopmental disorders such as autism, schizophrenia, and epilepsy (Lionel et al., 2013. PubMed ID: 23393157). However, these variants in the heterozygous state are not causative for molybdenum cofactor deficiency. MOCS1 and MOCS2 pathogenic variants are the more common cause of molybdenum cofactor deficiency (Reiss and Hahnewald, 2011. PubMed ID: 21031595).
The GPHN gene encodes the gephyrin protein which has surprising dual functions in cofactor synthesis as well as synaptic receptor clustering. The gephyrin protein contains two domains (E and G) that are necessary for the activation and insertion of molybdenum into molybdopterin (Reiss et al., 2001. PubMed ID: 11095995). The reported pathogenic variants for molybdenum cofactor deficiency have been observed in both domains. Gephyrin also belongs to a group of cytoskeletal elements that are critical for receptor-associated synaptic localization and organization (Reiss et al., 2001. PubMed ID: 11095995).
Testing is accomplished by amplifying all coding exons and ~20 bp of adjacent noncoding sequence, then determining the nucleotide sequence using standard 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 pathogenic variants or to confirm research results.
Indications for Test
Patients with molybdenum cofactor deficiency excrete elevated levels of sulfite, thiosulfate, S-sulfocysteine, xanthine, and hypoxanthine while uric acid levels are low. Patients that biochemically and clinically fit molybdenum cofactor deficiency with no molecular diagnosis after MOCS1 and MOCS2 genetic testing.
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- Genetic Counselor Team - firstname.lastname@example.org
- McKenna Kyriss, PhD - email@example.com
- Johnson and Duran, 2014. Molybdenum Cofactor Deficiency and Isolated Sulfite Oxidase Deficiency. Online Metabolic & Molecular Bases of Inherited Disease, New York, NY: McGraw-Hill.
- Lionel et al., 2013. PubMed ID: 23393157
- Reiss and Hahnewald, 2011. PubMed ID: 21031595
- Reiss et al., 2001. PubMed ID: 11095995
- Reiss et al., 2011. PubMed ID: 22040219
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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- A completed requisition form must accompany all specimens.
- Billing information along with specimen and shipping instructions are within the requisition form.
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(Delivery accepted Monday - Saturday)
- Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
- For small babies, we require a minimum of 1 ml of blood.
- Only one blood tube is required for multiple tests.
- Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
- During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
- In cold weather, include an unfrozen ice pack in the shipping container as insulation.
- At room temperature, blood specimen is stable for up to 48 hours.
- If refrigerated, blood specimen is stable for up to one week.
- Label the tube with the patient name, date of birth and/or ID number.
(Delivery accepted Monday - Saturday)
- Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
- For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
- DNA may be shipped at room temperature.
- Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
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(Delivery preferred Monday - Thursday)
- PreventionGenetics should be notified in advance of arrival of a cell culture.
- Culture and send at least two T25 flasks of confluent cells.
- Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
- Send specimens in insulated, shatterproof container overnight.
- Cell cultures may be shipped at room temperature or refrigerated.
- Label the flasks with the patient name, date of birth, and/or ID number.
- We strongly recommend maintaining a local back-up culture. We do not culture cells.