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Test ID: DRD4O    
Dopamine Receptor D4 Genotype (DRD4), Saliva

Useful For Suggests clinical disorders or settings where the test may be helpful

Influencing the target dose of methylphenidate treatment for patients with attention deficit/hyperactivity disorder

 

Determining possible cause for poor response to methylphenidate in treated patients with attention deficit/hyperactivity disorder

 

Genotyping patients who prefer not to have venipuncture done

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

The dopamine receptor D4 gene (DRD4) is located near the telomeric region of chromosome 11q and is a highly variable gene. A 48-base pair (bp) variable number tandem repeat (VNTR) polymorphism in exon 3 of DRD4, which ranges from 2 to 11 repeats, creates a 32- to 176-amino acid variation in the third intracellular loop on the dopamine receptor. The frequency of these alleles is shown in Table 1. The DRD4 7-repeat allele (7R) has functional consequences and is associated with lower affinity for dopamine receptor agonists and reduced signal transduction (eg, cAMP levels) compared to the more common DRD4 4-repeat allele (4R). The effect of other copy number repeats is not as well defined to date, however, and VNTRs with 6 or fewer repeats are grouped as 4R and those with 7 or more repeats as 7R.

 

Frequency of alleles with various DRD4 exon 3 48-bp repeats: 

Allele/Number of Repeats (R)

Allelic Frequency (%)

2R

8.8

3R

2.4

4R

65.1

5R

1.6

6R

2.2

7R

19.2

8R

0.6

9R

<0.1

10R

<0.1

11R

<0.1

 

The DRD4 protein is expressed in a number of brain regions, with higher levels of expression in the prefrontal cortex, where animal models suggest that it inhibits neuronal firing.

                                

Attention Deficit/Hyperactivity Disorder (ADHD):

Several studies have found associations between the DRD4 7R allele and ADHD.(1,2) Similarly, a long form (240-bp variant) of a DRD4 promotor repeat polymorphism is associated with ADHD susceptibility, possibly due to linkage disequilibrium with the DRD4 7R allele.(3)

 

Pharmacogenetics:

Several studies demonstrate that the presence of the DRD4 7R allele, alone or in combination with the SLC6A4 long/long promotor polymorphism of the serotonin transporter, is associated with lower responsiveness of ADHD to methylphenidate (eg, Ritalin, Concerta), the main treatment for ADHD.(4) Methylphenidate dosage may have to be increased to effectively treat individuals with the DRD4 7R allele. Attempts to find an association between DRD4 genotype and the variability of response to antipsychotic drugs, especially clozapine, have been largely unsuccessful or have yielded conflicting results.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Note that in patients who have received heterologous blood transfusions before a saliva sample was acquired, the saliva samples may contain donor DNA. Return to recipient genotype usually occurs after 6 weeks. Similarly, saliva samples obtained from patients after allogeneic blood or marrow transplantation can contain donor DNA. In both cases, this may result in genotyping results that reflect the genotype of the recipient, the donor, or a blend of the donor and recipient. Results obtained under these circumstances may not accurately reflect the recipient’s genotype.

 

This test does not detect polymorphisms other than the exon 3 variable number tandem repeat (VNTR).

 

The DRD4 VNTR alleles are not correlated with the variability of antipsychotic drug response; this test should not be ordered for that purpose.

Clinical Reference Provides recommendations for further in-depth reading of a clinical nature

1. Ding Y, Chi HC, Grady D, et al: Evidence of positive selection acting at the human dopamine receptor D4 gene locus. Proc Natl Acad Sci U S A 2002;99(1):309-314

2. Online Inheritance in Man. Viewed on 4/01/2008 at URL: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=126452

3. Kustanovich V, Ishii J, Crawford L, et al: Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5. Mol Psychiatry 2004;9(7):711-717

4. Hamarman S, Fossella J, Ulger C, et al: Dopamine receptor 4 (DRD4) 7-repeat allele predicts methylphenidate dose response in children with attention deficit hyperactivity disorder: a pharmacogenetic study. J Child Adolesc Psychopharmacol 2004;14(4):564-574

Special Instructions and Forms Describes specimen collection and preparation information, test algorithms, and other information pertinent to test. Also includes pertinent information and consent forms to be used when requesting a particular test