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Cornelia de Lange Syndrome via the HDAC8 Gene

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

Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
895 HDAC8$810.00 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
One study identified HDAC8 mutations in five out of 154 individuals affected with CdLS syndrome without NIPBL mutations (Deardorff, M.A. et al. Nature 489(7415):313-317, 2012).

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Clinical Features
Cornelia de Lange syndrome (CdLS) is characterized by distinctive facial features, growth retardation, hirsutism, and upper limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly. Craniofacial features include synophrys, arched eyebrows, long eyelashes, small upturned nose, small widely spaced teeth, and microcephaly. IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS (Deardorff et al. GeneReview, 2011).
Genetics
CdLS can be caused by mutations in NIPBL, SMC1A, SMC3, RAD21 and HDAC8. HDAC8-related Cornelia de Lange syndrome (OMIM#300882) is inherited in an X-linked manner. Female carriers may show symptoms depending on X-inactivation (Mannini, L. et al. Hum Mutat Aug 29, 2013. [Epub ahead of print]). HDAC8 protein (Histone deacetylase 8 protein) coded by HDAC8, is an enzyme in the histone deacetylase family and plays a key role in transcriptional regulation by affecting the acetylation state of core histones in the nucleus of cells. It is also involved in the deacetylation of cohesin complex protein SMC3, regulating release of cohesin complexes from chromatin (Buggy, J.J. et al. Biochem J 350(1):199-205, 2000; Deardorff, M.A. et al. Nature 489(7415):313-317, 2012). To date, five mutations (four missense, 1 nonsense) have been found in patients with Cornelia de Lange syndrome and a splicing mutation has been found in a large Dutch family with intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual facial features. Some of these features overlap with Wilson-Turner syndrome (OMIM#309585) (Harakalova, M. et al. J Med Genet 49(8): 539-543, 2012).
Testing Strategy
The HDAC8 protein is coded by exons 1 to 7 and 9 to 12 of the HDAC8 gene (OMIM# 3002692) on chromosome Xq13.1. Testing involves PCR amplification from genomic DNA and bidirectional Sanger sequencing of the coding exons and ~20 bp of adjacent noncoding sequences. 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 symptoms consistent with Cornelia de Lange Syndrome, particularly with a family pattern consistent with X-linked inheritance, and the family members of patients who have known HDAC8 mutations.

Gene

Official Gene Symbol OMIM ID
HDAC8 300269
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Cornelia de Lange Syndrome and Wiedemann-Steiner Syndrome via the KMT2A Gene
Cornelia de Lange Syndrome via the NIPBL Gene
Cornelia de Lange Syndrome via the RAD21 Gene
Cornelia de Lange Syndrome via the SMC1A Gene
Cornelia de Lange Syndrome via the SMC3 Gene
Craniosynostosis and Related Disorders Sequencing Panel
Facial Dysostosis Related Disorders Sequencing Panel
Treacher Collins Syndrome/ Mandibulofacial Dysostosis/Miller syndrome/Acrofacial Dysostosis, Nagar Type Sequencing Panel

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Buggy, J.J. et al. (2000). "Cloning and characterization of a novel human histone deacetylase, HDAC8" Biochem J 350 Pt 1:199-205. PubMed ID: 10926844
  • Deardorff MA, Bando M, Nakato R, Watrin E, Itoh T, Minamino M, Saitoh K, Komata M, Katou Y, Clark D, Cole KE, Baere E De, et al. 2012. HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Nature 489: 313–317. PubMed ID: 22885700
  • Deardorff, M.A. et al.  2011. Cornelia de Lange Syndrome. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301283
  • Harakalova, M. et al. (2012). “X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face.”  J Med Genet 49(8): 539-543. PubMed ID: 22889856
  • Mannini L, Cucco F, Quarantotti V, Krantz ID, Musio A. 2013. Mutation Spectrum and Genotype-Phenotype Correlation in Cornelia de Lange Syndrome. Human Mutation 34: 1589–1596. PubMed ID: 24038889
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TEST METHODS

Bi-Directional Sanger Sequencing

Test Procedure

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 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 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 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

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 20 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.

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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.
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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