Camurati-Engelmann Disease (CED) via the TGFB1 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
787 TGFB1$690.00 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
This test is predicted to detect disease mutations in >90% of individuals with a clinical diagnosis of CED (Janssens et al. Nat Genet 26:273–275, 2000; Kinoshita et al. Nat Genet 26:19–20, 2000; Campos-Xavier et al. Hum Genet 109:653–658, 2001; Mumm et al. Am J Hum Genet 69S:593, 2001; Wallace et al. Am J Med Genet 129A:235–247, 2004; Janssens et al. J Med Genet 43:1–11, 2006).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 TGFB1$690.00 81479 Add to Order
Pricing Comment

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Over 100

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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Features
Camurati-Engelmann disease (OMIM#131300) is characterized by hyperostosis of the long bones and the skull, proximal muscle weakness, severe limb pain, a wide-based, waddling gait, and joint contractures. Facial features such as frontal bossing, enlargement of the mandible, proptosis, and cranial nerve impingement resulting in facial palsy are seen in severely affected individuals later in life (Wallace & Wilcox. GeneReview. 2010). Rare manifestations include anemia, anorexia, hepatosplenomegaly, decreased subcutaneous tissue, atrophic skin, hyperhidrosis of the hands and feet, delayed dentition, extensive caries, delayed puberty, and hypogonadism (Gupta & Cheikh. Endocr Pract. 11:399–407, 2005).
Camurati-Engelmann disease is inherited in an autosomal dominant manner with reduced penetrance. TGFB1 is the only gene known to be associated with CED. TGFB1 encodes transforming growth factor beta-1 (TGF-β1), a large precursor molecule and a multifunctional peptide that controls proliferation, differentiation, and other functions in many cell types. TGF-β1 preprotein contains a signal peptide of 29 amino acids that is proteolytically cleaved. TGF-β1 is further cleaved after amino acid 278 to form latency-associated peptide (LAP) and active TGF-β1. LAP dimerizes with interchain disulfide links at Cys223 and Cys225. TGF-β1 can be secreted as an inactive small latent complex that consists of a mature TGF-β1 homodimer non-covalently associated with an LAP homodimer. The majority of pathogenic TGFB1 mutations in individuals with CED lead to single amino-acid substitutions near the site of interchain disulfide bonds between the LAP homodimers. Three mutations in exon 4 (p.Arg218Cys, p.Arg218His, p.Cys225Arg) account for ~80% of the total mutations observed in CED (Campos-Xavier et al. Hum Genet 109:653–658, 2001). These mutations may disrupt dimerization of LAP and binding to active TGF-β1, leading to increased active TGF-β1 release from the cell (Janssens et al. J Biol Chem 278:7718–7724, 2003; Kinoshita et al. Am J Med Genet 127A:104–107, 2004).
Testing Strategy
This test involves bidirectional sequencing using genomic DNA of all coding exons of the TGFB1 gene plus ~10 bp of flanking non-coding DNA on each side. 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
Candidates for this test are patients with clinical and radiographic findings consistent with CED and family members of patients who have a known TGFB1 mutation.


Official Gene Symbol OMIM ID
TGFB1 190180
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Camurati-Engelmann Disease 131300


Genetic Counselors
  • Campos-Xavier, B., (2001). "Phenotypic variability at the TGF-beta1 locus in Camurati-Engelmann disease." Hum Genet 109(6): 653-8. PubMed ID: 11810278
  • Gupta, S., Cheikh, I. E. (2005). "Camurati-Engelmann disease in conjunction with hypogonadism." Endocr Pract 11(6): 399-407. PubMed ID: 16638728
  • Janssens, K., (2000). "Mutations in the gene encoding the latency-associated peptide of TGF-beta 1 cause Camurati-Engelmann disease." Nat Genet 26(3): 273-5. PubMed ID: 11062463
  • Janssens, K., (2003). "Transforming growth factor-beta 1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein." J Biol Chem 278(9): 7718-24. PubMed ID: 12493741
  • Janssens, K., (2006). "Camurati-Engelmann disease: review of the clinical, radiological, and molecular data of 24 families and implications for diagnosis and treatment." J Med Genet 43(1): 1-11. PubMed ID: 15894597
  • Kinoshita, A., (2000). "Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease." Nat Genet 26(1): 19-20. PubMed ID: 10973241
  • Kinoshita, A., (2004). "TGFB1 mutations in four new families with Camurati-Engelmann disease: confirmation of independently arising LAP-domain-specific mutations." Am J Med Genet A 127A(1): 104-7. PubMed ID: 15103729
  • Mumm, S.R. (2001). "Camurati-Engelmann diesease: New mutation in the latency-associated peptide of the transforming growth factor b-1 gene."." Am J Hum Genet 69S: 593."
  • Stephanie E Wallace (2010). "Camurati-Engelmann Disease."
  • Wallace, S. E., (2004). "Marked phenotypic variability in progressive diaphyseal dysplasia (Camurati-Engelmann disease): report of a four-generation pedigree, identification of a mutation in TGFB1, and review." Am J Med Genet A 129A(3): 235-47. PubMed ID: 15326622
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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.

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.
  • 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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