TGFBI-Associated Corneal Dystrophies via the TGFBI Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1680 TGFBI$1020.00 81479 Add to Order
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 18 days.

Clinical Sensitivity

A mutation spectrum analysis identified TGFBI mutations in 80% of corneal dystrophy patients (50/61). Approximately 50% (24/50) of these patients had mutations at Arg124 and Arg 555 amino acids, which indicates the mutation hotspot (Munier et al. 2002). Analytical sensitivity is expected to be high as all the reported TGFBI mutations are detectable by direct sequencing of genomic DNA, and no gross deletions have been reported so far (Human Gene Mutation Database).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 TGFBI$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Features

Corneal dystrophies (CDs) are rare inherited disorders. Clinically, CDs are characterized as loss of corneal transparency and impaired refraction, which may be caused by a progressive accumulation of deposits (which can be amyloid, hyaline or a combination) on different layers of the cornea. With disease progression, visual acuity gradually decreases and can lead to visual impairment (Correa-Gomez et al. 2007; Klintworth 2009). CDs are non-inflammatory corneal diseases that are classified into three groups based on the sole or predominant anatomical location of the deposits. The three groups are anterior CDs, stromal CDs and posterior CDs. Most CDs exhibit autosomal dominant inheritance with a high degree of penetration. However, CDs present marked inter-and intra-familial variation in clinical expressivity (Klintworth 2009; Munier et al. 2002). CDs are typically evident in first or second decades of life, and manifestations are restricted to the cornea (Zenteno et al. 2006; Klintworth 2009).


CDs are genetically heterogeneous (Poulaki and Colby 2008). The Stromal CDs ( defined as all lattice CD types (LCDI, LCDIIIA, LCDI/IIIA and LCDIV), granular Groenouw type I (GCDI), and Avellino (ACD)) and the anterior CDs (defined as Thiel-Behnke dystrophy corneal dystrophy of Bowman layer type II (CDB2) and Reis-Bucklers (anterior CD)) are autosomal dominant and caused by mutations in the TGFBI (previously known as BIGH3, beta ig-h3) gene (Stewart et al. 1999; Takács et al. 2007). TGFBI is the Tissue Growth Factor Beta-Induced gene, which is located on chromosome 5q31. TGFBI encodes a protein called “keratoepithelin”, which is preferentially expressed on the extracellular surface of corneal epithelial cells, and might share β1integrin immunologic properties (Escribano et al. 1994). β1integrin is shown to be important for both the adhesion/migration and proliferation/differentiation of T cells (Maguire 1995). Mutation analyses of TGFBI suggests mutation hot spots at two arginine codons Arg124 and Arg 555 due to CpG dinucleotide transitions (Munier et al. 1997; Korvatska et al. 1998; Munier et al. 2002; Yang et al. 2010). So far, over 60 pathogenic variations in TGFBI (missense, nonsense, small insertions/duplications) have been reported in TGFBI-associated CDs (Human Gene Mutation Database).

Testing Strategy

This test involves bidirectional DNA Sanger sequencing of all coding exons and ~10 bp of flanking noncoding sequence of the TGFBI gene. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.

Indications for Test

All patients with symptoms suggestive of Corneal dystrophies are candidates.


Official Gene Symbol OMIM ID
TGFBI 601692
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Genetic Counselors
  • Correa-Gomez V, Villalvazo-Cordero L, Zenteno JC. 2007. The TGFBI A546D mutation causes an atypical type of lattice corneal dystrophy. Mol Vis 13: 1695–1700. PubMed ID: 17893671
  • Escribano J, Hernando N, Ghosh S, Crabb J, Coca-Prados M. 1994. cDNA from human ocular ciliary epithelium homologous to beta ig-h3 is preferentially expressed as an extracellular protein in the corneal epithelium. J. Cell. Physiol. 160: 511–521. PubMed ID: 8077289
  • Human Gene Mutation Database (Bio-base).
  • Klintworth GK. 2009. Corneal dystrophies. Orphanet Journal of Rare Diseases 4: 7. PubMed ID: 19236704
  • Korvatska E, Munier FL, Djemai A, Wang MX, Frueh B, Chiou A-Y, Uffer S, Ballestrazzi E, Braunstein RE, Forster RK, others. 1998. Mutation hot spots in 5q31-linked corneal dystrophies. The American Journal of Human Genetics 62: 320–324. PubMed ID: 9463327
  • Maguire JE, Danahey KM, Burkly LC, Seventer GA Van. 1995. T cell receptor-and beta 1 integrin-mediated signals synergize to induce tyrosine phosphorylation of focal adhesion kinase (pp125FAK) in human T cells. The Journal of experimental medicine 182: 2079–2090. PubMed ID: 7500053
  • Munier FL, Frueh BE, Othenin-Girard P, Uffer S, Cousin P, Wang MX, Héon E, Black GC, Blasi MA, Balestrazzi E, others. 2002. BIGH3 mutation spectrum in corneal dystrophies. Investigative ophthalmology & visual science 43: 949–954. PubMed ID: 11923233
  • Munier FL, Korvatska E, Djemaï A, Paslier D Le, Zografos L, Pescia G, Schorderet DF. 1997. Kerato-epithelin mutations in four 5q31-linked corneal dystrophies. Nat. Genet. 15: 247–251. PubMed ID: 9054935
  • Poulaki V, Colby K. 2008. Genetics of anterior and stromal corneal dystrophies. Semin Ophthalmol 23: 9–17. PubMed ID: 18214787
  • Stewart HS, Ridgway AE, Dixon MJ, Bonshek R, Parveen R, Black G. 1999. Heterogeneity in granular corneal dystrophy: identification of three causative mutations in the TGFBI (BIGH3) gene-lessons for corneal amyloidogenesis. Hum. Mutat. 14: 126–132. PubMed ID: 10425035
  • Takács L, Losonczy G, Matesz K, Balogh I, Sohajda Z, Tóth K, Fazakas F, Vereb G, Berta A. 2007. TGFBI (BIGH3) gene mutations in Hungary—report of the novel F547S mutation associated with polymorphic corneal amyloidosis. Mol Vis 13: 1976–1983. PubMed ID: 17982422
  • Yang J, Han X, Huang D, Yu L, Zhu Y, Tong Y, Zhu B, Li C, Weng M, Ma X. 2010. Analysis of TGFBI gene mutations in Chinese patients with corneal dystrophies and review of the literature. Molecular vision 16: 1186. PubMed ID: 20664689
  • Zenteno JC, Ramirez-Miranda A, Santacruz-Valdes C, Suarez-Sanchez R. 2006. Expanding the mutational spectrum in TGFBI-linked corneal dystrophies: identification of a novel and unusual mutation (Val113Ile) in a family with granular dystrophy. Mol Vis 12: 331–335. PubMed ID: 16636649
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  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.

Analytical Validity

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).

Analytical Limitations

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.

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.

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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.
  • 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.
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