Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (451 page)

   Molecular testing—the CFTR gene is the only gene known to be associated with the CFTR-related disorders, CF, and CAVD.

   Diagnostic testing for symptomatic individuals should be performed if needed for family studies, for confirmation of diagnosis when results from the other tests are unavailable or uninformative, and for epidemiologic purposes. Some CF patients may have unidentified mutations when tested by a target mutation panel and may need sequencing of the whole gene and/or testing for deletion/duplication.

   Carrier testing in at-risk relatives and their reproductive partners is recommended. Also carrier testing for pregnant or planning pregnancy women is offered.

   Prenatal testing is recommended for pregnancies at risk for CF when the parental mutations are known and for pregnancies in which fetal echogenic bowel has been identified.

   Preimplantation genetic diagnosis for pregnancies at increased risk for CF is possible when the parental mutations are known.

   Transepithelial nasal potential difference (NPD) measurements are recommended to confirm the diagnosis of CF in symptomatic individuals with borderline or nondiagnostic sweat tests in whom only one or no CFTR disease–causing mutation has been detected.

   Other Considerations

Individuals who test negative in carrier testing for a panel of CFTR mutations have their carrier risk reduced (though not eliminated). Carrier risk before testing and residual risk after carrier testing are calculated by the laboratories based on the patient’s family history and mutation detection rate of the testing panel and carrier frequency, which depends on the patient’s ethnicity. An increased prevalence of CFTR mutations has been noted in individuals with idiopathic pancreatitis, bronchiectasis, allergic bronchopulmonary aspergillosis, and chronic rhinosinusitis. At present, DNA testing is of unknown and unclear utility for these conditions.

Suggested Reading

Moskowitz SM, Chmiel JF, Sternen DL, et al. CFTR-related disorders. In: Pagon RA, Adam MP, Bird TD, et al., eds.
GeneReviews
^™
[Internet]
. Seattle, WA: University of Washington, Seattle; 2001:1993– 2013 [Updated 2008 Feb 19]. Available from:
http://www.ncbi.nlm.nih.gov/books/NBK1250/

   
DISORDERS OF HEARING AND VISION

DEAFNESS, AUTOSOMAL RECESSIVE 1 (DFNB1)

OMIM #220290

   Definition

Nonsyndromic hearing loss and deafness (DFNB1; NSHL) is characterized by autosomal inheritance of congenital, nonprogressive, mild to severe sensorineural hearing impairment and is unaccompanied by other medical abnormalities. Autosomal recessive deafness-1A (DFNB1A) is caused by mutations in the GJB2 gene (13q11-q12) encoding the gap junction beta-2 protein connexin-26 (CX26) or compound heterozygote mutations in both the GJB2 and the allelic gap junction beta-6 protein GJB6 gene encoding connexin-30. NSHL from homozygous mutations in only the GJB6 gene is rare.

   Relevant Tests and Diagnostic Value

   Sequencing of the entire coding regions of
GJB2
and
GJB6
detects more than 99% of autosomal recessive deafness-causing mutations in these genes. Testing should include detection of the splice site mutation in exon 1 of
GJB2
and large deletions in
GJB6
by assays such as PCR or MLPA.