Epilepsy and Intellectual Disability in Females via the PCDH19 Gene
Summary and Pricing 
Test Method
Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes| Test Code | Test Copy Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 4207 | PCDH19 | 81405 | 81405,81479 | $990 | Order Options and Pricing |
Pricing Comments
Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.
Turnaround Time
3 weeks on average for standard orders or 2 weeks on average for STAT orders.
Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.
Targeted Testing
For ordering sequencing of targeted known variants, go to our Targeted Variants page.
Clinical Features and Genetics
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).
Genetics
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).
Clinical Sensitivity - Sequencing with CNV PG-Select
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) .
Testing Strategy
This test provides full coverage of all coding exons of the PCDH19 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.
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.
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.
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| PCDH19 | 300460 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Disease
| Name | Inheritance | OMIM ID |
|---|---|---|
| Epileptic Encephalopathy, Early Infantile, 9 | XL | 300088 |
Citations
- 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
Ordering/Specimens
Ordering Options
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myPrevent - Online Ordering
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Requisition Form
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- Billing information along with specimen and shipping instructions are within the requisition form.
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For Requisition Forms, visit our Forms page
If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.
Specimen Types
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