Epilepsy and Intellectual Disability in Females via the PCDH19 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
636 PCDH19$870.00 81405 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

PCDH19 mutations have been identified in approximately 10% of females that present with clustered febrile seizures during infancy and that tested negative for SCN1A variants (Marini et al. 2010; Depienne et al. 2011) .

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 PCDH19$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Features

Female restricted epilepsy with mental retardation (EFMR; OMIM:300088) is a neurocognitive disorder that primarily affects females. Onset of epilepsy occurs during infancy or early childhood and patients present with clusters of focal febrile seizures. Seizures can manifest as periods of staring with motor arrest or bilateral clonic jerking and are often accompanied by fearful screaming (Marini et al. 2012). The seizures themselves are short in duration, but seizure clusters can be prolonged, lasting for weeks (Higurashi et al. 2013). Interictal EEG recordings reveal focal poly-spike and wave discharges on a slow background. Seizure frequency decreases with age and often seizures remit during adolescence (Depienne et al. 2011). Most patients have normal motor skills and can walk without assistance (Higurashi et al. 2013). EFMR patients display a range of intellectual disability from mild to severe. Psychiatric features commonly seen in EFMR include aggression, depression and obsessive behavior. Approximately 25% of EFMR patients fit the criteria for having an autism spectrum disorder (Camacho et al. 2012).


EFMR is inherited in a female-centric X-linked dominant manner and is caused by mutations in the PCDH19 gene. EFMR predominantly affects females due to a process termed 'cellular interference' where populations of cells expressing wild type PCDH19 and cells expressing mutant PCDH19 are required to observe a disease phenotype (Wieland et al. 2004; Depienne et al. 2009). Since females carry two X chromosomes and X-inactivation is random, females are mosaic for PCDH19 expression. A rare male that was mosaic for a PCDH19 mutation was identified to have an epilepsy phenotype (Depienne et al. 2009). PCDH19 mutations can be inherited from unaffected males, inherited from mildly affected females or arise de novo. Penetrance of PCDH19 mutations is nearly 100% in females (Dimova et al. 2012). Missense, nonsense, frameshift and splice site mutations as well as large deletions have been reported in the PCDH19 gene (Marini et al. 2012; Vincent et al. 2012). Many of the identified PCDH19 mutations are clustered in exon 1, which encodes the large cytoplasmic domain of the protocadherin protein (Depienne et al. 2009).

PCDH19 encodes a protocadherin protein. Protocadherins belong to the cadherin family of proteins. Cadherins have well-defined roles in cell adhesion. The exact role of protocadherins is unclear, but studies suggest that the large extracellular domain of protocahderins form homophillic interactions with other cadherin proteins to mediate cell adhesion (Emond et al. 2011). Studies in a zebrafish model demonstrate that PCDH19 is required for proper cell migration during neural development (Biswas et al. 2010). PCDH19 mRNA levels have also been shown to decrease in the rat hippocampus in response to electroconvulsive shock and it has been suggested PCDH19 plays a role in responding to stimuli and shaping neural circuitry (Kim et al. 2010).

Testing Strategy

This test involves bidirectional Sanger sequencing using genomic DNA of all coding exons of the PCDH19 gene plus ~20 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

 PCDH19 testing should be considered in females with epilepsy and intellectual disability of unknown cause. In addition, PCDH19 sequencing should be considered in females with a diagnosis for Dravet syndrome but for which no SCN1A mutation was identified.


Official Gene Symbol OMIM ID
PCDH19 300460
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Epileptic Encephalopathy, Early Infantile, 9 300088

Related Tests

Epilepsy: Dravet Syndrome Sequencing Panel
X-Linked Intellectual Disability Sequencing Panel


Genetic Counselors
  • Biswas S, Emond MR, Jontes JD. 2010. Protocadherin-19 and N-cadherin interact to control cell movements during anterior neurulation. The Journal of Cell Biology 191: 1029–1041. PubMed ID: 21115806
  • Camacho A, Simón R, Sanz R, Viñuela A, Martínez-Salio A, Mateos F. 2012. Cognitive and behavioral profile in females with epilepsy with PDCH19 mutation: Two novel mutations and review of the literature. Epilepsy & Behavior 24: 134–137. PubMed ID: 22504056
  • Depienne C, Trouillard O, Bouteiller D, Gourfinkel-An I, Poirier K, Rivier F, Berquin P, Nabbout R, Chaigne D, Steschenko D, Gautier A, Hoffman-Zacharska D, et al. 2011. Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females. Human Mutation 32: E1959–E1975. PubMed ID: 21053371
  • Depienne C. et al. 2009. Plos Genetics. 5: e1000381. PubMed ID: 19214208
  • Dimova PS, Kirov A, Todorova A, Todorov T, Mitev V. 2012. A Novel PCDH19 Mutation Inherited From an Unaffected Mother. Pediatric Neurology 46: 397–400. PubMed ID: 22633638
  • Emond MR, Biswas S, Blevins CJ, Jontes JD. 2011. A complex of Protocadherin-19 and N-cadherin mediates a novel mechanism of cell adhesion. The Journal of Cell Biology 195: 1115–1121. PubMed ID: 22184198
  • Higurashi N, Nakamura M, Sugai M, Ohfu M, Sakauchi M, Sugawara Y, Nakamura K, Kato M, Usui D, Mogami Y, Fujiwara Y, Ito T, et al. 2013. PCDH19-related female-limited epilepsy: Further details regarding early clinical features and therapeutic efficacy. Epilepsy Research 106: 191–199. PubMed ID: 23712037
  • Kim SY, Mo JW, Han S, Choi SY, Han SB, Moon BH, Rhyu IJ, Sun W, Kim H. 2010. The expression of non-clustered protocadherins in adult rat hippocampal formation and the connecting brain regions. Neuroscience 170: 189–199. PubMed ID: 20541594
  • Marini C, Darra F, Specchio N, Mei D, Terracciano A, Parmeggiani L, Ferrari A, Sicca F, Mastrangelo M, Spaccini L, Canopoli ML, Cesaroni E, et al. 2012. Focal seizures with affective symptoms are a major feature of PCDH19 gene-related epilepsy: PCDH19-Related Epilepsy. Epilepsia 53: 2111–2119. PubMed ID: 22946748
  • Marini C, Mei D, Parmeggiani L, Norci V, Calado E, Ferrari A, Moreira A, Pisano T, Specchio N, Vigevano F, Battaglia D, Guerrini R. 2010. Protocadherin 19 mutations in girls with infantile-onset epilepsy. Neurology 75: 646–653. PubMed ID: 20713952
  • Vincent A, Noor A, Janson A, Minassian B, Ayub M, Vincent J, Morel C. 2012. Identification of genomic deletions spanning the PCDH19 gene in two unrelated girls with intellectual disability and seizures. Clinical Genetics 82: 540–545. PubMed ID: 22091964
  • Wieland I, Jakubiczka S, Muschke P, Cohen M, Thiele H, Gerlach KL, Adams RH, Wieacker P. 2004. Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome. Am. J. Hum. Genet. 74: 1209–1215. PubMed ID: 15124102
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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.

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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