Molybdenum Cofactor Deficiency Type A via the MOCS1 Gene
- Summary and Pricing
- Clinical Features and Genetics
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In the largest report of biochemically confirmed molybdenum cofactor deficient patients, ~58% were found to have variants in the MOCS1 gene, ~38% in MOCS2, and 2% in GPHN (Reiss and Johnson, 2003. PubMed ID: 12754701). Analytical sensitivity should be near 100% because all reported pathogenic variants are detectable by sequencing.
Molybdenum cofactor deficiency type A is an inborn error in metabolism that results in defective synthesis of the molybdopterin cofactor required for the function of the sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase enzymes. Patients with molybdenum cofactor deficiency excrete elevated levels of sulfite, thiosulfate, S-sulfocysteine, taurine, xanthine, and hypoxanthine, while also exhibiting hypouricemia (Johnson and Duran 2014). Isolated deficiency of the xanthine dehydrogenase or aldehyde oxidase enzymes is a benign biochemical condition in most patients, while sulfite oxidase deficient patients present with a severe disease course. Clinical presentations in isolated sulfite oxidase deficiency and molybdenum cofactor deficiencies are almost indistinguishable (Mendel, 2009. PubMed ID: 19623604; Johnson and Duran, 2014).
Many times molybdenum cofactor deficiency will be misdiagnosed as infantile encephalopathy due to the brain anomalies and neurologic symptoms. Typically, presentation will occur early after birth with severe convulsions that are difficult to suppress (Reiss et al., 1998. PubMed ID: 9731530; Johnson and Duran, 2014). Pathological studies have shown there is marked neuronal loss and demyelination in the white matter accompanied by gliosis and diffuse spongiosis. Patients with milder clinical symptoms and later onset (6-15 months) have also been reported, although less than 10% of patients fall into this group. In many cases, an infection will trigger the first symptoms in later onset patients (Johnson and Duran, 2014). Patients with molybdenum cofactor deficiency or isolated sulfite oxidase 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). Irreversible neurological damage occurs due to sulfite toxicity and/or sulfate deficiency, and most patients die during the neonatal period or early childhood (Reiss et al., 1998. PubMed ID: 9731530; Macaya et al., 2005. PubMed ID: 16429380).
All molybdenum cofactor deficiencies are inherited in an autosomal recessive manner. Molybdenum cofactor deficiency type A is caused by pathogenic variants in the MOCS1 gene, which is located on chromosome 6 at 6p21.2. Reported pathogenic variants in this gene include missense and nonsense variants, splice variants, and small in-frame or frameshift deletions and duplications (Reiss and Johnson, 2003. PubMed ID: 12754701; Reiss and Hahnewald, 2011. PubMed ID: 21031595; Human Gene Mutation Database). One case of molybdenum cofactor deficiency due to a homozygous MOCS1 missense variant was shown to be a result of maternal uniparental isodisomy (Gümüs et al., 2010. PubMed ID: 20573177).
The MOCS1 gene encodes both the MOCS1A protein and the MOCS1AB fusion protein, which are generated via alternative splicing (Gray and Nicholls, 2000. PubMed ID: 10917590; Reiss, Johnson., 2003. PubMed ID: 12754701; Arenas et al., 2009. PubMed ID: 19544009; Reiss and Hahnewald, 2011. PubMed ID: 21031595). In the MOCS1AB fusion protein, only the MOCS1B portion is active (Arenas et al., 2009. PubMed ID: 19544009). Nomenclature of variants in the MOCS1 gene is complicated by the various alternative splicing mechanisms and multiple proteins encoded by this gene. Sequence variants in this gene are therefore best described using the accepted terminology reported by Reiss and Hahnewald (2011). Using this nomenclature, the three most commonly reported variants are c.956G>A (p.Arg319Gln), c.418+1G>A (both variants affect the MOCS1A protein) and c.1523_1524del (which affects the MOCS1B portion of the fusion protein) (Reiss and Johnson, 2003. PubMed ID: 12754701; Reiss and Hahnewald, 2011. PubMed ID: 21031595).
Biosynthesis of the molybdopterin cofactor begins with the conversion of guanosine triphosphate (GTP) to a precursor molecule designated Precursor Z. The MOCS1A and MOCS1B proteins are responsible for this step in molybdopterin biosynthesis (Arenas et al., 2009. PubMed ID: 19544009; Johnson and Duran, 2014).
This test involves bidirectional Sanger sequencing using genomic DNA of all coding exons of the MOCS1 gene plus ~20 bp of flanking non-coding DNA on each side. 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. Family members of patients who have known MOCS1 pathogenic variants are also good candidates. We will also sequence the MOCS1 gene to determine carrier status.
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- Arenas et al., 2009. PubMed ID: 19544009
- Gümüs et al., 2010. PubMed ID: 20573177
- Gray and Nicholls, 2000. PubMed ID: 10917590
- Human Gene Mutation Database (Bio-base).
- Johnson and Duran, 2014. Molybdenum Cofactor Deficiency and Isolated Sulfite Oxidase Deficiency. Online Metabolic & Molecular Bases of Inherited Disease, New York, NY: McGraw-Hill.
- Macaya et al., 2005. PubMed ID: 16429380
- Mendel, 2009. PubMed ID: 19623604
- Reiss and Hahnewald, 2011. PubMed ID: 21031595
- Reiss and Johnson, 2003. PubMed ID: 12754701
- Reiss et al., 1998. PubMed ID: 9731530
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.
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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.
- We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.
(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.