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Congenital Cataracts Sequencing Panel

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

NGS Sequencing

Test Code Test Copy GenesCPT Code Copy CPT Codes
1983 AGK 81479 Add to Order
BFSP1 81479
BFSP2 81479
CHMP4B 81479
CRYAA 81479
CRYAB 81479
CRYBA1 81479
CRYBA4 81479
CRYBB1 81479
CRYBB2 81479
CRYBB3 81479
CRYGB 81479
CRYGC 81479
CRYGD 81479
CRYGS 81479
CTDP1 81479
EPHA2 81479
EYA1 81406
FAM126A 81479
FOXE3 81479
FYCO1 81479
GALK1 81479
GCNT2 81479
GJA3 81479
GJA8 81479
HSF4 81479
LIM2 81479
MAF 81479
MIP 81479
MIR184 81479
NHS 81479
P3H2 81479
PAX6 81479
PITX3 81479
PXDN 81479
SIL1 81405
SLC16A12 81479
SLC33A1 81479
TDRD7 81479
VIM 81479
Full Panel Price* $1840.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
1983 Genes x (40) $1840.00 81405, 81406, 81479(x38) Add to Order
Pricing Comment

If you would like to order a subset of these genes contact us to discuss pricing.

Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

Whole exome sequencing identified pathogenic variants in 9 probands from 23 pedigrees affected by familial dominant cataract (39%) in CRYAA, CRYBB1, CRYBB3, CRYGC, CRYGD, GJA8 and MIP (Reis et al. 2013). Mutation screening in 25 Chinese families with congenital cataracts identified pathogenic variants in 10 families (40%) in 12 genes encoding crystallins (CRYAA, CRYAB, CRYBA1, CRYBB1, CRYBB2, CRYBB3, CRYBA4, CRYGS, CRYGC, CRYGD), and connexins (GJA3 and GJA8). Approximately 32% of the families had pathogenic variants in crystallin genes and 8% of the families had pathogenic variants in connexin genes (Sun et al. 2011).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 AGK$690.00 81479 Add to Order
CRYAB$690.00 81479
CTDP1$690.00 81479
EYA1$690.00 81405
FAM126A$690.00 81479
FOXE3$690.00 81479
GALK1$690.00 81479
NHS$690.00 81479
PAX6$690.00 81479
SIL1$690.00 81479
Full Panel Price* $840.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
600 Genes x (10) $840.00 81405, 81479(x9) Add to Order
Pricing Comment

# of Genes Ordered

Total Price

1

$690

2

$730

3

$770

4-10

$840

11-30

$1,290

31-100

$1,670

Over 100

Call for quote

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

To our knowledge, no studies have indicated what percentage of the cataract population has copy number variants or which genes have a high frequency of deletion/duplications. Copy number variants in AGK, BFSP1, CRYAB, EYA1, FAM126A, GCNT2, HSF4, NHS, PAX6, PITX3 and SIL1 have been reported to be causative to date (Human Gene Mutation Database).

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Clinical Features

Cataracts are defined 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).

Genetics

Only 10–25% of congenital cataracts are hereditary. Cataracts are most often inherited as an autosomal dominant trait. CC also exhibits 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 cataract 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 40 genetic loci, and over 25 of those are connected to pathogenic variants in specific genes. However, this number is constantly increasing. Among the candidate genes, the majority of the identified pathogenic variants (about half) are in crystallins (CRYAA, CRYAB, CRYBA1, CRYBB1, CRYBB2, CRYBB3, CRYBA4, CRYGS, CRYGC, CRYGD), followed by (about a quarter) lens-specific connexins (GJA3, GJA8). The remainder are divided among growth and Transcription Factors (HSF4, MAF, PITX3), Membrane Proteins aquaporin-0 (AQP0,also known as MIP), cytoskeletal structural proteins (beaded filament structural proteins BFSP1 and BFSP2) and others (FYCO1, GCNT2, HSF4, LIM2, SIL1, TDRD7, FOXE3, CHMP4B, EPHA2, SLC33A1, AGK) (Hejtmancik 2008). Pathogenic variants in CRYAB, CRYBB2, CRYBA4, CRYGS, CRYGC, FOXE3, PITX3, CHMP4B, GJA3, MIP, EPHA2, BFSP2, SLC33A1, MAF, CRYBA1 (also known as CRYBA3), GJA8, CRYAA, HSF4, CRYGB, EYA1, MIR184, PAX6, SLC16A12, VIM and CRYGD are inherited in an autosomal dominant manner. Pathogenic variants in AGK, CRYBB3, FYCO1, GCNT2, LIM2, SIL1, TDRD7, BFSP1, PXDN,CTDP1, FAM126A, GALK1, P3H2 and CRYBB1 are inherited in an autosomal recessive manner. Pathogenic variants in NHS gene causes an X-linked disorders. However, inheritance of the same variant in different families or within the same family can result in a varied clinical presentation of cataracts, which suggests the involvement of additional genes or modifying factors. On the other hand, identical clinical presentation of cataract also possible due to variants in completely different genes (Hejtmancik 2008; Santana and Waiswo 2011; Chen et al. 2011; Pras 2004; Haghighi et al. 2014).

See individual gene test descriptions for information on molecular biology of gene products.

Testing Strategy

For this NGS test, the full coding regions, plus ~20 bp of non-coding DNA flanking each exon, are sequenced for each of the genes listed below. Sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization method, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for any regions not captured or with insufficient number of sequence reads. All pathogenic, undocumented and questionable variant calls are confirmed by Sanger sequencing.

This panel provides full coverage of aforementioned area of the indicated genes.

Indications for Test

Patients with multiple types of cataract such as aculeiform, crystalline, frosted, needle-shaped, fasciculiform, congenital cerulean, nonnuclear polymorphic congenital, central nuclear, lamellar, and punctate and with microcornea.

Diseases

Name Inheritance OMIM ID
Anterior Segment Mesenchymal Dysgenesis AD 107250
Aphakia, Congenital Primary AR 610256
Branchiootorenal Syndrome 1, with or without Cataracts AD 113650
Cataract 10 AD 600881
Cataract 11 AD 610623
Cataract 12 AD 611597
Cataract 13 AR 116700
Cataract 14 AR 601885
Cataract 15 AD 615274
Cataract 16 AR 613763
Cataract 17 AD,AR 611544
Cataract 18 AR 610019
Cataract 19 AR 615277
Cataract 2 AD 604307
Cataract 20 AD 116100
Cataract 21 AD 610202
Cataract 22 AD,AR 609741
Cataract 23 AD 610425
Cataract 3 AD 601547
Cataract 30 AD 116300
Cataract 31 AD 605387
Cataract 33 AR 611391
Cataract 36 AR 613887
Cataract 38 AR 614691
Cataract 39 AD 615188
Cataract 4 AD 115700
Cataract 47 AD 612018
Cataract 5 AD 116800
Cataract 6 AD 116600
Cataract 9 AD 604219
Cataract, Congenital, X-Linked AD 302200
Cataract, Zonular Pulverulent 1 AD 116200
Congenital Aniridia AD 106210
Congenital Cataracts, Facial Dysmorphism, And Neuropathy AR 604168
Congenital Cataracts, Hearing Loss, and Neurodegeneration AR 614482
Corneal Opacification and Other Ocular Anomalies AR 269400
Deficiency Of Galactokinase AR 230200
EDICT Syndrome AR 614303
Hypomyelination And Congenital Cataract AD 610532
Marinesco-Sjogren Syndrome AR 248800
Myopia, High, with Cataract And Vitreoretinal Degeneration AR 614292
Nance-Horan Syndrome XL 302350
Sengers syndrome AR 212350

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Axenfeld-Rieger Syndrome Sequencing Panel
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Branchiootorenal syndrome via the EYA1 Gene
Cataract 10, Multiple Types (CTRCT10) via the CRYBA1 Gene
Cataract 17, Multiple Types (CTRCT17) via the CRYBB1 Gene
Cataract 22, Multiple Types (CTRCT22) via the CRYBB3 Gene
Cataract 23 (CTRCT23) via the CRYBA4 Gene
Cataract 3, Multiple Types (CTRCT3) via the CRYBB2 Gene
Cataract 9, Multiple Types (CTRCT9) via the CRYAA Gene
Cataract Type 11 via the PITX3 Gene
Cataract Type 14 via the GJA3 Gene
Cataract Type 2 (CTRCT2) via the CRYGC Gene
Cataract Type 39 via the CRYGB Gene
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Congenital Cataracts and Ayme-Gripp Syndrome via the MAF Gene
Congenital Cataracts Facial Dysmorphism Neuropathy (CCFDN) Syndrome via the CTDP1 Gene
Congenital Cataracts via the BFSP1 Gene
Dilated Cardiomyopathy Sequencing Panel with CNV Detection
Distal Hereditary Myopathy Sequencing Panel
Galactosemia Type II via the GALK1 Gene
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Hypomyelination and Congenital Cataract (HCC) via the FAM126A Gene
Marinesco-Sjogren Syndrome via the SIL1 Gene
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Myofibrillar Myopathy Sequencing Panel
Myofibrillar Myopathy via the CRYAB Gene
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Pure Hereditary Spastic Paraplegia Sequencing Panel with CNV Detection
Sengers Syndrome via the AGK Gene
Septo-optic Dysplasia Spectrum Sequencing Panel
X-Linked Intellectual Disability Sequencing Panel with CNV Detection
X-linked Nance-Horan Syndrome and Congenital Cataract via the NHS Gene

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Chen J. et al. 2011. American journal of human genetics. 88: 827-38. PubMed ID: 21636066
  • Francis P.J., Moore A.T. 2004. Current opinion in ophthalmology. 15: 10-5. PubMed ID: 14743013
  • Haghighi A. et al. 2014. Orphanet journal of rare diseases. 9: 119. PubMed ID: 25208612
  • Hejtmancik J.F. 2008. Seminars in cell & developmental biology. 19: 134-49. PubMed ID: 18035564
  • Lambert S.R., Drack A.V. 1996. Survey of ophthalmology. 40: 427-58. PubMed ID: 8724637
  • Pras E. et al. 2004. Investigative ophthalmology & visual science. 45: 1940-5. PubMed ID: 15161861
  • Reis L.M. et al. 2013. Human genetics. 132: 761-70. PubMed ID: 23508780
  • Santana A., Waiswo M. 2011. Arquivos brasileiros de oftalmologia. 74: 136-42. PubMed ID: 21779674
  • Stambolian D. et al. 1990. American journal of human genetics. 47: 13-9. PubMed ID: 1971992
  • Sun W. et al. 2011. Molecular vision. 17: 2197-206. PubMed ID: 21866213
  • Toutain A. et al. 1997. Human genetics. 99: 256-61. PubMed ID: 9048931
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TEST METHODS

NextGen Sequencing using PG-Select Capture Probes

Test Procedure

We use a combination of Next Generation Sequencing (NGS) and Sanger sequencing technologies to cover the full coding regions of the listed genes plus ~20 bases of non-coding DNA flanking each exon.  As required, genomic DNA is extracted from the patient specimen.  For NGS, patient DNA corresponding to these regions is captured using an optimized set of DNA hybridization probes.  Captured DNA is sequenced using Illumina’s Reversible Dye Terminator (RDT) platform (Illumina, San Diego, CA, USA).  Regions with insufficient coverage by NGS are covered by Sanger sequencing.  All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.

For Sanger sequencing, Polymerase Chain Reaction (PCR) is used to amplify targeted regions.  After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Patient DNA sequence is aligned to the genomic reference sequence for the indicated gene region(s). All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories, listed below, per ACMG Guidelines (Richards et al. 2015).

(1) Pathogenic Variants
(2) Likely Pathogenic Variants
(3) Variants of Uncertain Significance
(4) Likely Benign Variants
(5) Benign, Common Variants

Human Genome Variation Society (HGVS) recommendations are used to describe sequence variants (http://www.hgvs.org).  Rare variants and undocumented variants are nearly always classified as likely benign if there is no indication that they alter protein sequence or disrupt splicing.

Analytical Validity

As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.   

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available.  Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When Sanger sequencing does not reveal any difference from the reference sequence, or when a sequence variant is homozygous, we cannot be certain that we were able to detect both patient alleles.  Occasionally, a patient may carry an allele which does not amplify, due to a large deletion or insertion.   In these cases, the report will contain no information about the second allele.  Our Sanger and NGS Sequencing tests are generally not capable of detecting Copy Number Variants (CNVs).

We sequence all coding exons for each given transcript, plus ~20 bp of flanking non-coding DNA for each exon.  Test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions or any currently uncharacterized alternative exons.

In most 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 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.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes from whole blood).   Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Rare, low probability interpretations of sequencing results, such as for example the occurrence of de novo mutations in recessive disorders, are generally not included in the reports.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics.  However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

Deletion/Duplication Testing Via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options


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.
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.

SPECIMEN TYPES
WHOLE BLOOD

(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.

DNA

(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.

CELL CULTURE

(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.
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