Congenital Hereditary Endothelial Dystrophy Type 2 (CHED2) and Harboyan Syndrome via the SLC4A11 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
1677 SLC4A11$1060.00 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 analysis in 25 patients from 20 families (consanguinity was noted in 9 out of 20 families) clinically diagnosed with CHED2 detected SLC4A11 mutations in 56% (14/25) of patients (Paliwal et al. 2010). Another study also identified SLC4A11 mutations in 83% (41/49) of the CHED2 affected patients from 35 families (consanguinity was noted in 23 out of 35 families) (Sultana et al. 2007).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 SLC4A11$990.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Features

Congenital hereditary endothelial dystrophy (CHED) is a rare inherited corneal disorder, which results from hypoplasia or degeneration and dysfunction of the endothelial cells. Clinically, CHED is characterized as bilateral, symmetrical, corneal opacification and nystagmus, without other anterior segment abnormalities. CHED is usually evident at birth or within the neonatal period (Vithana et al. 2006; Hemadevi et al. 2008). CHED is classified into CHED1 and CHED2, which are inherited in autosomal dominant and recessive manner, respectively. CHED1 differs from CHED2 in the age of onset (CHED1 manifests later in the life) and severity (CHED2 is more severe) (Sultana et al. 2007).

Harboyan syndrome (HS) is a rare disorder characterized as CHED accompanied by progressive, postlingual sensorineural deafness (Desir and Abramowicz 2008). The estimated prevalence rate for congenital corneal clouding is ~ 3 in 100,000 newborns. In a study which included 47 congenital corneal abnormalities cases, Peters anomaly accounted for 40% of the cases followed by sclerocornea (18%), limbal dermoid (15%), congenital glaucoma (7%), microphthalmia (4%), birth trauma, and metabolic disease (3%), etc. Genetic testing can be helpful in the differential diagnosis and appropriate treatment (Desir and Abramowicz 2008). Audiometry helps in the differential diagnosis between Harboyan syndrome and CHED2 as they both share the same ocular abnormalities. Corneal transplantation (penetrating keratoplasty) has been reported as definitive treatment (Desir and Abramowicz 2008).


CHED2 is inherited in an autosomal recessive manner and is caused by mutations in the SLC4A11 gene. The locus for CHED1 has been mapped to the pericentromeric region of chromosome 20, which is physically and genetically distinct from the CHED2 locus (Hand et al. 1999). SLC4A11, which encodes sodium bicarbonate transporter-like solute carrier family 4 member 11 protein, is expressed in several organs and tissues, including eyes, blood, lungs, ovaries, colon, mouth, embryonic tissue, pancreas, kidneys, skin, cranial nerves, prostate, and brain (Kodaganur et al. 2013). Corneal endothelium acts as barrier between the corneal stroma and the aqueous humor to regulate the water content in the cornea through membrane active transport mechanisms (Bonanno 2012). Loss of function mutations in SLC4A11 lead to the perturbation of the SLC4A11-mediated membrane active transport mechanism which leads to the CHED2 phenotype as well as HS (Aldahmesh et al. 2009). So far, about 85 SLC4A11 mutations (missense, nonsense, splicing, small and gross insertions and deletions) have been reported (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 SLC4A11. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

Indications for Test

All patients with symptoms suggestive of congenital corneal dystrophy are candidates.


Official Gene Symbol OMIM ID
SLC4A11 610206
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Genetic Counselors
  • Aldahmesh MA, Khan AO, Meyer BF, Alkuraya FS. 2009. Mutational Spectrum of SLC4A11 in Autosomal Recessive CHED in Saudi Arabia. Investigative Ophthalmology & Visual Science 50: 4142–4145. PubMed ID: 19369245
  • Bonanno JA. 2012. Molecular mechanisms underlying the corneal endothelial pump. Experimental Eye Research 95: 2–7. PubMed ID: 21693119
  • Desir J, Abramowicz M. 2008. Congenital hereditary endothelial dystrophy with progressive sensorineural deafness (Harboyan syndrome). Orphanet Journal of Rare Diseases 3: 28. PubMed ID: 18922146
  • Hand CK, Harmon DL, Kennedy SM, FitzSimon JS, Collum LM, Parfrey NA. 1999. Localization of the gene for autosomal recessive congenital hereditary endothelial dystrophy (CHED2) to chromosome 20 by homozygosity mapping. Genomics 61: 1–4. PubMed ID: 10512674
  • Hemadevi B, Veitia RA, Srinivasan M, Arunkumar J, Prajna NV, Lesaffre C, Sundaresan P. 2008. Identification of mutations in the SLC4A11 gene in patients with recessive congenital hereditary endothelial dystrophy. Arch. Ophthalmol. 126: 700–708. PubMed ID: 18474783
  • Human Gene Mutation Database (Bio-base).
  • Kodaganur SG, Kapoor S, Veerappa AM, Tontanahal SJ, Sarda A, Yathish S, Prakash DR, Kumar A. 2013. Mutation analysis of the SLC4A11 gene in Indian families with congenital hereditary endothelial dystrophy 2 and a review of the literature. Mol Vis 19: 1694–1706. PubMed ID: 23922488
  • Paliwal P, Sharma A, Tandon R, Sharma N, Titiyal JS, Sen S, Nag TC, Vajpayee RB. 2010. Congenital hereditary endothelial dystrophy - mutation analysis of SLC4A11 and genotype-phenotype correlation in a North Indian patient cohort. Mol Vis 16: 2955–2963. PubMed ID: 21203343
  • Sultana A, Garg P, Ramamurthy B, Vemuganti GK, Kannabiran C. 2007. Mutational spectrum of the SLC4A11 gene in autosomal recessive congenital hereditary endothelial dystrophy. Mol Vis 13: 1327–1332. PubMed ID: 17679935
  • Vithana EN, Morgan P, Sundaresan P, Ebenezer ND, Tan DTH, Mohamed MD, Anand S, Khine KO, Venkataraman D, Yong VHK, Salto-Tellez M, Venkatraman A, et al. 2006. Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2). Nat. Genet. 38: 755–757. PubMed ID: 16767101
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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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