Congenital Cataracts and Ayme-Gripp Syndrome via the MAF Gene
- Summary and Pricing
- Clinical Features and Genetics
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The great majority of tests are completed within 18 days.
Predicting clinical sensitivity for the MAF gene is challenging due to genetic heterogeneity of cataracts and also due to the limited number of MAF-associated cataract cases. Ayme-Gripp syndrome is a rare disorder. Hence, predicting the clinical sensitivity is difficult. However, in one study, seven de novo MAF variants were identified in 8 unrelated patients diagnosed with the Ayme-Gripp syndrome (Niceta et al. 2015).
Cataracts are described as opacification of the crystalline lens of the eye that result in abnormal refraction index and light scattering. Congenital cataracts (CC) are a serious and leading cause of reversible blindness in childhood. They account for one-tenth of the cases of childhood blindness (Francis and Moore 2004). Estimated prevalence rate is 1.2 - 6.0 per 10,000 live births. Early diagnosis and surgery and optical correction have resulted in an improved outcome for infants with either unilateral or bilateral cataracts (Lambert and Drack 1996). Ayme-Gripp syndrome is not limited to eye lens defects, and includes deafness, intellectual disability, seizures, Down syndrome-like facies, short stature, and mental retardation (Niceta et al. 2015).
Only 10–25% of congenital cataracts are hereditary. Cataracts are most often inherited as an autosomal dominant trait. Congenital cataracts also exhibit autosomal recessive or X-linked inheritance (Hejtmancik 2008). X-linked cataract is seen in Nance-Horan syndrome (NHS), which is an especially rare disorder. NHS has cataracts along with prominent dental findings, dysmorphic features, and intellectual disability (Toutain et al. 1997; Stambolian et al. 1990). Currently, isolated or primary cataracts have been mapped to about 39 genetic loci, and over 25 of those are connected to pathogenic variants in specific genes. However, this number is constantly increasing (Hejtmancik 2008).
Pathogenic variants in MAF are causative for autosomal dominant syndromic and nonsyndromic cataracts (Niceta et al. 2015; Jamieson et al. 2002). MAF is a basic region leucine zipper (bZIP) transcription factor, which is expressed in vertebrate lens fiber cells and persists throughout lens development. MAF proteins have N-terminal transactivation domain, C-terminal DNA-binding domain, extended homology, basicmotif and leucine-zipper regions (Jamieson et al. 2002; Kawauchi et al. 1999). So far missense variants and one complex genomic rearrangement have been shown to be causative for both syndromic and nonsyndromic cataracts (Human Gene Mutation Database). De novo heterozygous missense variants affecting highly conserved residues of the gsk3 (serine/threonine kinase) phosphorylation motifs within the transactivation domain are shown to cause Ayme´-Gripp Syndrome (Niceta et al. 2015).
This test involves bidirectional DNA Sanger sequencing of all coding exons and ~10 bp of flanking noncoding sequence of the MAF gene. We will also sequence any single exon (Test #100) in family members of patients with known mutations or to confirm research results.
Indications for Test
All patients with symptoms suggestive of Congenital Cataracts and Ayme-Gripp syndrome are candidates.
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- Genetic Counselor Team - firstname.lastname@example.org
- Madhulatha Pantrangi, PhD - email@example.com
- Francis P.J., Moore A.T. 2004. Current opinion in ophthalmology. 15: 10-5. PubMed ID: 14743013
- Hejtmancik J.F. 2008. Seminars in cell & developmental biology. 19: 134-49. PubMed ID: 18035564
- Human Gene Mutation Database (Bio-base).
- Jamieson R.V. et al. 2002. Human Molecular Genetics. 11: 33-42. PubMed ID: 11772997
- Kawauchi S. et al. 1999. The Journal of Biological Chemistry. 274: 19254-60. PubMed ID: 10383433
- Lambert S.R., Drack A.V. 1996. Survey of ophthalmology. 40: 427-58. PubMed ID: 8724637
- Niceta M. et al. 2015. American Journal of Human Genetics. 96: 816-25. PubMed ID: 25865493
- Stambolian D. et al. 1990. American journal of human genetics. 47: 13-9. PubMed ID: 1971992
- Toutain A. et al. 1997. Human genetics. 99: 256-61. PubMed ID: 9048931
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 10 bases of non-coding DNA flanking the exon are sequenced.
As of February 2018, we compared 26.8 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 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.
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 10 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.
myPrevent - Online Ordering
- The test can be added to your online orders in the Summary and Pricing section.
- Once the test has been added log in to myPrevent to fill out an online requisition form.
- A completed requisition form must accompany all specimens.
- Billing information along with specimen and shipping instructions are within the requisition form.
- All testing must be ordered by a qualified healthcare provider.
(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.