WFS1
The Clinical Diagnostics Service of the Molecular Otolaryngology Research Laboratory is a Joint Commission-approved CLIA-accredited diagnostic laboratory that offers mutation screening of several genes.

DFNA6/14/38 (OMIM#: 600965) and Wolfram Syndrome (OMIM#: 222300)
DFNA6/14/38
Three overlapping DFNA loci have been mapped to 4p16 - DFNA6, DFNA14 and DFNA38 (Lesperance 1995, Van Camp 1999, Young 2001). All are associated with mutations in WFS1(OMIM# 606201). Now referred to as the DFNA6/14/38 locus, the phenotype is very distinctive and is characterized by low frequency hearing loss that rises to normal in the high frequencies. Some persons report tinnitus, but not vertigo.

Wolfram Syndrome 
Mutations in WFS1 also cause Wolfram Syndrome (OMIM# 222300), a recessively inherited disorder with a phenotype that includes diabetes insipidus, diabetes mellitus, optic atrophy and deafness (also known as DIDMOAD syndrome). Studies have shown an association betweenWFS1 mutations and diabetes mellitus and psychiatric illness.

WFS1
The gene, WFS1, contains 8 exons; exons 2 -7 encode the 890 amino acid protein Wolframin. The majority of mutations causing low frequency hearing loss are in the C-terminal portion of the protein; mutations causing Wolfram Syndrome are spread throughout the gene (Cryns et al., 2003). A listing of mutations identified in WFS1 can be found on the WFS1 Gene Mutation and Polyporphism Database.

MORL screening methodology
Screening for WFS1 is performed by DHPLC and sequencing. Oligonucleotide primers have been designed to amplify each coding exon (2-8). Amplified samples are resolved by DHPLC; abnormal elution profiles are sequenced to identify the specific mutation. Because exon 8 of WFS1 (aa 289-891) contains many non-disease causing polymorphisms, it is sequenced directly using overlapping primer sets.

DHPLC profile of WFS1, Exon 5

Legend: Profiles in brown contains mutations; profile in purple is wild type.

Sensitivity
Sensitivity is greater than 98%.

Turn-around time
Turn around time is approximately 3 months.

Cost: $500

Indications for screening
Families segregating aut0somal dominant non-syndromic deafness with low frequency hearing loss and preserved high frequency hearing.:

 GeneTests  GeneReviews – Deafness and Hereditary Hearing Loss

References
Lesperance, M. M. et al.: A gene for autosomal dominant nonsyndromic hereditary hearing impairment maps to 4p16.3. Hum. Molec. Genet. 4: 1967-1972, 1995.
PubMed ID: 8595423 
 

Van Camp, G. et al.: A gene for autosomal dominant hearing impairment (DFNA14) maps to a region on chromosome 4p16.3 that does not overlap the DFNA6 locus. J. Med. Genet. 36: 532-536, 1999.
PubMed ID: 10424813