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Test ID: NTC3Z NOTCH3 Gene, Full Gene Analysis, Varies


Ordering Guidance


Targeted testing (also called site-specific or known variant testing) is available for variants identified in this gene. See FMTT / Familial Variant, Targeted Testing, Varies.



Shipping Instructions


Specimen preferred to arrive within 96 hours of collection.



Specimen Required


Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

 

Submit only 1 of the following specimens:

 

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

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)/Refrigerated

 

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: Refrigerated (preferred)/Ambient

Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.

 

Specimen Type: Cultured fibroblast

Container/Tube: T-25 flask

Specimen Volume: 2 Flasks

Collection Instructions: Submit confluent cultured fibroblast cells from a skin biopsy from another laboratory. Cultured cells from a prenatal specimen will not be accepted.

Specimen Stability Information: Ambient (preferred)/Refrigerated (<24 hours)

Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to -4 weeks is required to culture fibroblasts before genetic testing can occur.

 

Specimen Type: Blood spot

Container/Tube:

Preferred: Collection card (Whatman Protein Saver 903 Paper)

Acceptable: PerkinElmer 226 (formerly Ahlstrom 226) filter paper or blood spot collection card

Specimen Volume: 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 Dried Blood Spot Samples.

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. Due to lower concentration of DNA yielded from blood spot, it is possible that additional specimen may be required to complete testing.

2. For collection instructions, see Blood Spot Collection Instructions

3. For collection instructions in Spanish, see Blood Spot Collection Card-Spanish Instructions (T777)

4. For collection instructions in Chinese, see Blood Spot Collection Card-Chinese Instructions (T800)

 

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: 1 Swab

Collection Instructions: Collect and send specimen per kit instructions.

Additional Information: Due to lower concentration of DNA yielded from saliva, it is possible that additional specimen may be required to complete testing.

Specimen Stability Information: Ambient 30 days


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) (T826)

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 pathogenic 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

Testing Algorithm

For skin biopsy or cultured fibroblast specimens, fibroblast culture testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.

Method Name

Sequence Capture and Targeted Next-Generation Sequencing followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing

Reporting Name

NOTCH3 Gene, Full Gene Analysis

Specimen Type

Varies

Specimen 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. 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, migraine 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 a pathognomonic 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 pathogenic variants typically result in either loss of 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 pathogenic 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 (ACMG) 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 May;17(5):405-424

2. Ferrante E, Cudrici C, Boehm M: CADASIL: new advances in basic science and clinical perspectives. Curr Opin Hematol. 2019 May; 26(3):193-198

3. Rutten J, Van Eijsden B, 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 Mar; 21(3):676-682

4. Canalis E: The skeleton of lateral meningocele syndrome. Front Genet. 2021 Jan 14;11620334

Day(s) Performed

Varies

Report Available

28 to 42 days

Test 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
Mayo Clinic Laboratories | Genetics and Genomics Additional Information:

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