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HelpTest ID: NTC3Z NOTCH3 Gene, Full Gene Analysis, Varies
Ordering Guidance
Targeted testing for familial variants (also called site-specific or known variants testing) is available for the NOTCH3 gene. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.
Additional Testing Requirements
For cord blood specimens: Maternal cell contamination (MCC) studies are available. Order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on both the cord blood and maternal specimens under separate order numbers. Cord blood testing will proceed without MCC studies, but results may be compromised if MCC is present.
Shipping Instructions
Specimen Required
Patient Preparation: A previous hematopoietic stem cell transplant from an allogenic donor will interfere with testing. For information about testing patients who have received a hematopoietic stem cell transplant, call 800-533-1710.
Submit only 1 of the following specimens:
Specimen Type: Whole blood
Container/Tube:
Preferred: Lavender top (EDTA) or yellow top (ACD)
Acceptable: Green top (Sodium heparin)
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send whole blood specimen in original tube. Do not aliquot.
Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 4 days/Frozen 4 days
Additional Information:
1. Specimens are preferred to be received within 4 days of collection. Extraction will be attempted for specimens received after 4 days, and DNA yield will be evaluated to determine if testing may proceed.
2. To ensure minimum volume and concentration of DNA are met, the requested volume must be submitted. Testing may be canceled if DNA requirements are inadequate.
Specimen Type: Cord blood
Container/Tube:
Preferred: Lavender top (EDTA) or yellow top (ACD)
Acceptable: Green top (Sodium heparin)
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send cord blood specimen in original tube. Do not aliquot.
Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 4 days/Frozen 4 days
Additional Information:
1. Specimens are preferred to be received within 4 days of collection. Extraction will be attempted for specimens received after 4 days, and DNA yield will be evaluated to determine if testing may proceed.
2. To ensure minimum volume and concentration of DNA are met, the requested volume must be submitted. Testing may be canceled if DNA requirements are inadequate.
3. While a properly collected cord blood sample may not be at risk for maternal cell contamination, unanticipated complications may occur during collection. Therefore, maternal cell contamination studies are recommended to ensure the test results reflect that of the patient tested and are available at an additional charge. Order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.
Specimen Type: Saliva
Patient Preparation: Patient should not eat, drink, smoke, or chew gum 30 minutes prior to collection.
Supplies: Saliva Swab Collection Kit (T786)
Specimen Volume: 2 Swabs
Collection Instructions: Collect and send specimen per kit instructions.
Specimen Stability Information: Ambient (preferred) 30 days/Refrigerated 30 days
Additional Information: Saliva specimens are acceptable but not recommended. Due to lower quantity/quality of DNA yielded from saliva, some aspects of the test may not perform as well as DNA extracted from a whole blood sample. When applicable, specific gene regions that were unable to be interrogated will be noted in the report. Alternatively, additional specimen may be required to complete testing.
Specimen Type: Blood spot
Supplies: Card-Blood Spot Collection (Filter Paper) (T493)
Container/Tube:
Preferred: Collection card (Whatman Protein Saver 903 Paper)
Acceptable: PerkinElmer 226 filter paper or blood spot collection card
Specimen Volume: 2 to 5 Blood spots
Collection Instructions:
1. An alternative blood collection option for a patient older than 1 year is a fingerstick. For detailed instructions, see How to Collect a Dried Blood Spot Sample.
2. Let blood dry on the filter paper at ambient temperature in a horizontal position for a minimum of 3 hours.
3. Do not expose specimen to heat or direct sunlight.
4. Do not stack wet specimens.
5. Keep specimen dry
Specimen Stability Information: Ambient (preferred)/Refrigerated
Additional Information:
1. Blood spot specimens are acceptable but not recommended. Multiple extractions will be required to obtain sufficient yield for supplemental analysis, and there is significant risk for test failure due to insufficient DNA.
2. Due to lower concentration of DNA yielded from blood spot, some aspects of the test may not perform as well as DNA extracted from a whole blood sample. When applicable, specific gene regions that were unable to be interrogated will be noted in the report. Alternatively, additional specimen may be required to complete testing.
3. For collection instructions, see Blood Spot Collection Instructions
4. For collection instructions in Spanish, see Blood Spot Collection Card-Spanish Instructions (T777)
5. For collection instructions in Chinese, see Blood Spot Collection Card-Chinese Instructions (T800)
Specimen Type: Cultured fibroblasts
Source: Skin
Container/Tube: T-25 flask
Specimen Volume: 2 Flasks
Collection Instructions: Submit confluent cultured fibroblast cells from a skin biopsy. Cultured cells from a prenatal specimen will not be accepted.
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information:
1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks are required to culture fibroblasts before genetic testing can occur.
Specimen Type: Skin biopsy
Supplies: Fibroblast Biopsy Transport Media (T115)
Container/Tube: Sterile container with any standard cell culture media (eg, minimal essential media, RPMI 1640). The solution should be supplemented with 1% penicillin and streptomycin.
Specimen Volume: 4-mm Punch
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information:
1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks are required to culture fibroblasts before genetic testing can occur.
Specimen Type: Extracted DNA
Container/Tube:
Preferred: Screw Cap Micro Tube, 2 mL with skirted conical base
Acceptable: Matrix tube, 1 mL
Collection Instructions:
1. The preferred volume is at least 100 mcL at a concentration of 75 ng/mcL.
2. Include concentration and volume on tube.
Specimen Stability Information: Frozen (preferred) 1 year/Ambient/Refrigerated
Additional Information: DNA must be extracted in a CLIA-certified laboratory or equivalent and must be extracted from a specimen type listed as acceptable for this test (including applicable anticoagulants). Our laboratory has experience with Chemagic, Puregene, Autopure, MagnaPure, and EZ1 extraction platforms and cannot guarantee that all extraction methods are compatible with this test. If testing fails, one repeat will be attempted, and if unsuccessful, the test will be reported as failed and a charge will be applied. If applicable, specific gene regions that were unable to be interrogated due to DNA quality will be noted in the report.
Forms
1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file.
The following documents are available:
-Informed Consent for Genetic Testing (T576)
-Informed Consent for Genetic Testing (Spanish) (T576)
2. Molecular Genetics: Neurology Patient Information
3. If not ordering electronically, complete, print, and send a Neurology Specialty Testing Client Test Request (T732) with the specimen.
Useful For
Establishing a molecular diagnosis in individuals with features of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and NOTCH3-related disorders
Identifying disease-causing variants within the NOTCH3 gene known to be associated with CADASIL and NOTCH3-related disorders, allowing for predictive testing of at-risk family members
Genetics Test Information
This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in the NOTCH3 gene associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and other NOTCH3-related disorders. See Method Description for additional details.
Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, familial screening, recurrence risk assessment, and genetic counseling for NOTCH3-related disorders.
Reflex Tests
| Test ID | Reporting Name | Available Separately | Always Performed |
|---|---|---|---|
| CULFB | Fibroblast Culture for Genetic Test | Yes | No |
| MATCC | Maternal Cell Contamination, B | Yes | No |
Testing Algorithm
Skin biopsy:
For skin biopsy or cultured fibroblast specimens, fibroblast culture will be performed at an additional charge. If viable cells are not obtained, the client will be notified.
Cord blood:
For cord blood specimens that have an accompanying maternal blood specimen, maternal cell contamination studies will be performed at an additional charge.
Method Name
Sequence Capture and Targeted Next-Generation Sequencing (NGS) followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing
Reporting Name
NOTCH3 Gene, Full Gene AnalysisSpecimen Type
VariesSpecimen Minimum Volume
See Specimen Required
Specimen Stability Information
| Specimen Type | Temperature | Time |
|---|---|---|
| Varies | Varies | |
Clinical Information
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disorder and common genetic cause of stroke and dementia in adults. The onset of clinical symptoms typically occurs in mid-adulthood and may include recurrent ischemic stroke and transient ischemic attacks, cognitive decline that progresses to dementia, migraines with aura, and psychiatric disturbances. Symmetric and progressive white matter hyperintensities, lacunes of presumed vascular origin, and subcortical infarcts are characteristic neuroimaging findings. Granular osmophilic material (GOM) detected by electron microscopy on skin fibroblasts is considered an indicative finding for CADASIL.
Disease-causing variants in the NOTCH3 gene cause CADASIL. Most individuals with CADASIL inherit the condition from a parent, but rare de novo variants have been reported. The family history may appear negative due to variable expressivity of the condition and failure to recognize symptoms in other affected family members. Further, NOTCH3 is comprised of repetitive epidermal growth factor-like repeat (EGFr) domains. Reported disease-causing variants typically result in either loss or gain of cysteine residues within EGFr domains; those impacting EGFr domains 1-6 are fully penetrant, while those impacting EGRr domains 7-34 may be associated with mild disease or incomplete penetrance.
Heterozygous disease-causing variants in NOTCH3 also cause autosomal dominant lateral meningocele syndrome (LMS). LMS is a rare condition associated with multiple lateral meningoceles, hearing loss, developmental delay, hypotonia, joint hyperlaxity, and variable additional congenital malformations. LMS typically occurs due to a de novo disease-causing variant, but rare instances of inheritance from an affected parent have been reported.
Reference Values
An interpretive report will be provided.
Interpretation
All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Clinical Reference
1. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424
2. Ferrante EA, Cudrici CD, Boehm M. CADASIL: new advances in basic science and clinical perspectives. Curr Opin Hematol. 2019;26(3):193-198
3. Rutten JW, Van Eijsden BJ, Duering M, et al. The effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1-6 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7-34 pathogenic variant. Genet Med. 2019;21(3):676-682
4. Canalis E. The skeleton of lateral meningocele syndrome. Front Genet. 2021;11620334
Day(s) Performed
Varies
Report Available
14 to 21 daysTest Classification
This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.CPT Code Information
81479
88233-Tissue culture, skin, solid tissue biopsy (if appropriate)
88240-Cryopreservation (if appropriate)
LOINC Code Information
| Test ID | Test Order Name | Order LOINC Value |
|---|---|---|
| NTC3Z | NOTCH3 Gene, Full Gene Analysis | 103950-2 |
| Result ID | Test Result Name | Result LOINC Value |
|---|---|---|
| 616564 | Test Description | 62364-5 |
| 616565 | Specimen | 31208-2 |
| 616566 | Source | 31208-2 |
| 616567 | Result Summary | 50397-9 |
| 616568 | Result | 82939-0 |
| 616569 | Interpretation | 69047-9 |
| 616570 | Resources | In Process |
| 616571 | Additional Information | 48767-8 |
| 616572 | Method | 85069-3 |
| 616573 | Genes Analyzed | 82939-0 |
| 616574 | Disclaimer | 62364-5 |
| 616575 | Released By | 18771-6 |
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