CROHN DISEASE - NOD2 SUSCEPTIBILITY MUTATIONS
Gene Symbol: NOD2
Chromosomal Locus 16q12.1
Protein: Nucleotide-Binding Oligomerization Domain Protein 2 or Caspase Recruitment Domain-Containing Protein 15
Pseudonyms: CARD15, Inflammatory Bowel Disease, IBD, Ulcerative Colitis
TURNAROUND TIME: 3 weeks
TESTING METHODOLOGY: Polymerase chain reaction (PCR) followed by sequencing of 3 exons (containing the 4 susceptibility mutations) in the gene.
- Collect: Prefer two 5ml whole blood EDTA (lavender top) tube.
- Min. Collection: 0.7 ml whole blood EDTA.
- Transport: blood EDTA at Room Temp shipped regular next day air (No Saturday delivery; store specimen at 4° C and ship Monday).
- Stability: Ambient: up to 7 days; Refrigerated: 2 weeks. Frozen: unacceptable
- Unacceptable Conditions: Serum. Frozen or severely hemolyzed blood. Clotted blood.
- Prenatal testing: Direct: 5ml direct unspun amniotic fluid or 15mg CVS tissue with a backup flask growing. Culture: confluent T25 flask. Maternal blood sample is required for maternal cell contamination studies.
Counseling and informed consent are recommended for genetic testing. A consent form
is available as a resource but not required.
Incidence: Less than 1 in 500.
Inheritance: Autosomal dominant but penetrance increases with multiple susceptibility mutations.
Disease Characteristics: Crohn disease and ulcerative colitis are the common inflammatory bowel diseases and have overlapping clinical characteristics. Crohn disease is an inflammatory process that can affect any part of the gastrointestinal tract resulting in pain, blockage, fistulas and scarring. Within 10 years of onset 60% of patients with Crohn disease will need surgical treatment. Risk for colon cancer is also increased. The pathogenesis of Crohn disease involves both environmental and genetic factors. Since the condition is both chronic and progressive early intervention is very valuable in clinical management. Changes in diet, life style, and medications are all effective components in improving the course of the disease.
Crohn disease symptoms can overlap with Blau syndrome which is also caused by mutations in the NOD2 gene. Blau syndrome is classically characterized by early-onset granulomatous arthritis, uveitis and skin rash with camptodactyly but it often displays only one symptom or has a unique presentation.
Molecular Genetic Mechanism: The genetics of the NOD2 gene and Crohn disease are complex. Crohn disease mapping studies have identified the NOD2/CARD15 gene as the primary locus. Four autosomal dominant, susceptibility variants have been observed in the NOD2/CARD15 gene; R702W, G908R, 3020insC (1007fs) and IVS8+158. Approximately 60% of the Crohn disease population has one or more of these predisposing loci; 17% are homozygote for one of these markers. Other rarer variants throughout the NOD2/CARD15 gene have also been associated with Crohn disease.
Clinical Sensitivity: up to 60%
Analytical Sensitivity: 99%.
Test Limitations: Mutations that are not in the 3 coding sequences that contain the susceptibility mutations of the NOD2 gene will not be detected.
INDICATIONS FOR USE:
- To help confirm a clinical diagnosis of Crohn disease.
- To determine whether a patient may respond well to Crohn disease medications.
- To determine whether a patient may clinically respond well to lifestyle changes.
- To identify children at risk so that treatment can begin much earlier in the course of the disease (normally diagnosis is made after considerable damage has been done).
- To help differentiate Crohn disease from ulcerative colitis patients.
- To help differentiate Blau and Crohn syndrome patients.