DOORS Syndrome and TBC1D24-related Epilepsy via the TBC1D24 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 | |
|---|---|---|---|---|---|
| 4261 | TBC1D24 | 81479 | 81479,81479 | $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
Variants in the TBC1D24 gene have recently been implicated in a number of neurological conditions with varied clinical presentations.
TBC1D24 variants were identified in patients with focal epilepsy and intellectual disability. Seizure onset occurred at 2 months of age and consisted of focal seizures with eye blinking and facial and hand twitching (Corbett et al. 2010). These seizures persisted throughout life and were sensitive to fever, but were well controlled with medication (Afawi et al. 2013). Mild developmental delay was noted in early development. There was borderline to moderate intellectual disability seen in adulthood, dysarthria, and ataxia. MRI revealed abnormal cortical thickening.
TBC1D24 has also been implicated in patients with progressive encephalopathy. Features included infantile onset myoclonic seizures, dystonia, and psychomotor delay (Guven and Tolun 2013). Variable features included postictal enduring hemiparesis, refractory seizures, bilateral optic atrophy, and macular degeneration. MRI revealed moderate cerebral atrophy and ventricular enlargement, both of which progressively declined as the patient aged. Death was reported in the first decade. Another study identified TBC1D24 variants in siblings with malignant migrating partial seizures of infancy (MMPSI)(Milh et al. 2013). These patients showed infantile onset of tonic-clonic seizures which increased in frequency until they approached status epilepticus. Psychomotor regression was seen after 3 months and was associated with hypotonia, loss of visual contact, and absence of prehension.
More recently, whole exome sequencing studies have identified TBC1D24 as a cause of deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome. The core features seen in TBC1D24 positive DOORS patients are intellectual disability, seizures, deafness, short distal phalanges and small or absent nails (Campeau et al. 2014). MRI in DOORS syndrome patients were heterogeneous, but revealed structural abnormalities in 50% of patients.
In addition to these conditions which feature seizures as a primary symptom, TBC1D24 variants can also cause autosomal recessive and autosomal dominant non-syndromic hearing loss (ARNSHL, ADNSHL) in the absence of seizures (Rehman et al. 2014; Azaiez et al. 2014; Zhang et al. 2014).
Genetics
DOORS syndrome and TBC1D24-related epilepsy are inherited in an autosomal recessive manner and are caused by variants in the TBC1D24 gene. Pathogenic missense, nonsense, splice site, and frameshift variants have been reported in TBC1D24 (Campeau et al. 2014). TBC1D24 encodes a protein with an N-terminal Tre2/Bub2/Cdc16 (TBC) domain which is shared by other Rab GTPase-activating proteins (Rab-GAPs). The TBC1D24 TBC domain lacks the arginine and glutamine residues required for GAP activity, suggesting it may not act as a Rab-GAP (Corbett et al. 2010). TBC1D24 is expressed in the brain and physically interacts with ADP ribosylation factor 6 (ARF6)- a GTP-binding protein involved in membrane exchange. Studies in rat neurons suggest that TBC1D24 positively regulates radial neuronal migration by maintaining ARF6 in an inactive state (Falace et al. 2014). Many reported variants in TBC1D24 disrupt its interaction with ARF6. Both loss of TBC1D24 function and expression of constitutively active ARF6 result in similar neuronal migration defects (Falace et al. 2014).
Clinical Sensitivity - Sequencing with CNV PG-Select
In a study of 26 families with DOORS syndrome, pathogenic TBC1D24 variants were identified in 9 (~35%) families (Campeau et al. 2014).
Testing Strategy
This test provides full coverage of all coding exons of the TBC1D24 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.
Indications for Test
TBC1D24 testing should be considered for patients with suspected DOORS syndrome and patients with infantile epilepsy and intellectual disability of unknown cause. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in TBC1D24.
TBC1D24 testing should be considered for patients with suspected DOORS syndrome and patients with infantile epilepsy and intellectual disability of unknown cause. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in TBC1D24.
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| TBC1D24 | 613577 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Diseases
| Name | Inheritance | OMIM ID |
|---|---|---|
| DOOR syndrome | AR | 220500 |
| Epileptic Encephalopathy, Early Infantile, 16 | AR | 615338 |
| Myoclonic Epilepsy, Familial Infantile | AR | 605021 |
Citations
- Azaiez H, Booth KT, Bu F, Huygen P, Shibata SB, Shearer AE, Kolbe D, Meyer N, Black-Ziegelbein EA, Smith RJH. 2014. TBC1D24 Mutation Causes Autosomal-Dominant Nonsyndromic Hearing Loss. Human Mutation 35: 819–823. PubMed ID: 24729539
- Campeau PM, Hennekam RC, The DOORS syndrome collaborative group. 2014. DOORS syndrome: Phenotype, genotype and comparison with Coffin-Siris syndrome: AMERICAN JOURNAL OF MEDICINE PART C (SEMINARS IN MEDICAL GENETICS). American Journal of Medical Genetics Part C: Seminars in Medical Genetics 166: 327–332. PubMed ID: 25169651
- Campeau PM, Kasperaviciute D, Lu JT, Burrage LC, Kim C, Hori M, Powell BR, Stewart F, Felix TM, Ende J van den, Wisniewska M, Kayserili H, et al. 2014. The genetic basis of DOORS syndrome: an exome-sequencing study. Lancet Neurol 13: 44–58. PubMed ID: 24291220
- Corbett MA, Bahlo M, Jolly L, Afawi Z, Gardner AE, Oliver KL, Tan S, Coffey A, Mulley JC, Dibbens LM, Simri W, Shalata A, et al. 2010. A Focal Epilepsy and Intellectual Disability Syndrome Is Due to a Mutation in TBC1D24. The American Journal of Human Genetics 87: 371–375. PubMed ID: 20797691
- Falace A, Buhler E, Fadda M, Watrin F, Lippiello P, Pallesi-Pocachard E, Baldelli P, Benfenati F, Zara F, Represa A, Fassio A, Cardoso C. 2014. TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway. Proceedings of the National Academy of Sciences 111: 2337–2342. PubMed ID: 24469796
- Guven A, Tolun A. 2013. TBC1D24 truncating mutation resulting in severe neurodegeneration. Journal of Medical Genetics 50: 199–202. PubMed ID: 23343562
- Milh M, Falace A, Villeneuve N, Vanni N, Cacciagli P, Assereto S, Nabbout R, Benfenati F, Zara F, Chabrol B, Villard L, Fassio A. 2013. Novel Compound Heterozygous Mutations in TBC 1 D 24 Cause Familial Malignant Migrating Partial Seizures of Infancy. Human Mutation 34: 869–872. PubMed ID: 23526554
- Rehman AU, Santos-Cortez RLP, Morell RJ, Drummond MC, Ito T, Lee K, Khan AA, Basra MAR, Wasif N, Ayub M, Ali RA, Raza SI, et al. 2014. Mutations in TBC1D24, a Gene Associated With Epilepsy, Also Cause Nonsyndromic Deafness DFNB86. The American Journal of Human Genetics 94: 144–152. PubMed ID: 24387994
- Zhang L, Hu L, Chai Y, Pang X, Yang T, Wu H. 2014. A Dominant Mutation in the Stereocilia-Expressing Gene TBC1D24 is a Probable Cause for Nonsyndromic Hearing Impairment. Human Mutation 35: 814–818. PubMed ID: 24729547
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.
- All testing must be ordered by a qualified healthcare provider.
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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