Familial Dysautonomia via the IKBKAP Gene - Targeted Variants Analysis

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
847 IKBKAP$440.00 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 sequencing test will identify all previously reported pathogenic variants in the IKBKAP gene.

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Clinical Features
Familial dysautonomia (FD), also known as Riley–Day syndrome and hereditary sensory autonomic neuropathy type III, is characterized by hypotonia, gastrointestinal dysfunction, vomiting crises, recurrent pneumonia, altered sensitivity to pain, taste and temperature perception, absence of fungiform papillae on the tongue, decreased or absent deep tendon reflexes, absence of overflow tears, and cardiovascular instability (Shohat and Halpern 2010). These congenital symptoms result from the abnormal development and survival of the sensory and autonomic systems, which leads to progressive neurological abnormalities FD almost exclusively occurs in individuals with Ashkenazi Jewish (AJ) ancestry. Penetrance is complete, although there is variable expressivity (Axelrod 2005). The incidence of FD among individuals with AJ heritage is 1:3600 births, and has an estimated carrier frequency of 1/30. Someone who is not of AJ ancestry has a carrier risk of less than 1:150 (Slaugenhaupt et al. 2001).
FD is inherited in an autosomal recessive manner. It is caused by pathogenic variants in the IKBKAP gene, which encodes a component of the Elongator complex. The complex allows for permissive chromatin structure for efficient mRNA elongation during transcription (Shohat and Halpern 2010). Two pathogenic variants account for more than 99% of affected individuals. (1) The c.2204+6T>C variant is a founder mutation that is responsible for disease in individuals with AJ heritage. It causes skipping of exon 20 resulting in a truncated IKAP protein (Dietrich et al. 2011). The abnormal transcript is tissue specific, as the abnormal transcript is found in the brain but not in lymphoblasts and fibroblasts (Slaugenhaupt et al. 2001). (2) The c.2087G>C (p.Arg696Pro) variant has been reported in the AJ population but is not as common as the intronic variant, and has not been reported in the homozygous state. Another variant c.2741C>T (p.Pro914Leu) has been reported in an individual with FD who inherited the variant from a non-AJ parent along with the common pathogenic variant from their AJ parent (Leyne et al. 2003). The missense variants appear to disrupt phosphorylation (Gold-von Simson and Axelrod 2006).
Testing Strategy
The elongator complex protein 1 is encoded by 36 exons (2-37) of the IKBKAP gene on chromosome 9q31. This test involves bidirectional Sanger sequencing using genomic DNA of selected exons /intron (exon 19, intron 20 and exon 26) for the c.2087G>C (p.Arg696Pro), c.2204+6T>C, and c.2741C>T (p.Pro914Leu) variants. We will also sequence any single exon (Test #100) in family members of patients with known mutations or to confirm research results or test only the two Ashkenazi pathogenic variants (Test #200).
Indications for Test
Candidates for this test are patients clinically diagnosed with Familial Dysautonomia or carrier testing in family members. This test is specifically designed for heritable germline mutations.


Official Gene Symbol OMIM ID
IKBKAP 603722
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Familial Dysautonomia 223900

Related Test

Familial Dysautonomia via the IKBKAP Gene - Full Gene Sequencing


Genetic Counselors
  • Axelrod FB. 2005. Familial dysautonomia: a review of the current pharmacological treatments. Expert Opin Pharmacother 6: 561–567. PubMed ID: 15934882
  • Dietrich P, Yue J, E. S, Dragatsis I. 2011. Deletion of Exon 20 of the Familial Dysautonomia Gene Ikbkap in Mice Causes Developmental Delay, Cardiovascular Defects, and Early Embryonic Lethality. PLoS ONE 6: e27015. PubMed ID: 22046433
  • Gold-von Simson G, Axelrod FB. 2006. Familial Dysautonomia: Update and Recent Advances. Current Problems in Pediatric and Adolescent Health Care 36: 218–237. PubMed ID: 16777588
  • Leyne M, Mull J, Gill SP, Cuajungco MP, Oddoux C, Blumenfeld A, Maayan C, Gusella JF, Axelrod FB, Slaugenhaupt SA. 2003. Identification of the first non-Jewish mutation in familial Dysautonomia. American Journal of Medical Genetics 118A: 305–308. PubMed ID: 12687659
  • Shohat M, Halpern GJ. 1993. Familial Dysautonomia. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle,. PubMed ID: 20301359
  • Slaugenhaupt SA, Blumenfeld A, Gill SP, Leyne M, Mull J, Cuajungco MP, Liebert CB, Chadwick B, Idelson M, Reznik L. 2001. Tissue-Specific Expression of a Splicing Mutation in the IKBKAP Gene Causes Familial Dysautonomia. The American Journal of Human Genetics 68: 598–605. PubMed ID: 11179008
  • Slaugenhaupt SA, Blumenfeld A, Gill SP, Leyne M, Mull J, Cuajungco MP, Liebert CB, Chadwick B, Idelson M, Reznik L. 2001. Tissue-Specific Expression of a Splicing Mutation in theIKBKAP Gene Causes Familial Dysautonomia. The American Journal of Human Genetics 68: 598–605. PubMed ID: 11179008
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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 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.
  • 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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