Genetic Testing

The requirements of our genetic testing battery

Diagnostic Evaluation Of Hearing Loss

After a hearing loss has been identified in a child, a comprehensive evaluation is begun to seek the cause. Most cases of hearing loss are from an obvious cause (i.e. ear infections) and no further diagnostic testing is needed. In most cases of sensorineural hearing loss, the cause is not obviously known and your ear specialist (pediatric otologist) will take a thorough medical history and perform a physical examination. Many different factors can cause SNHL with genetic causes accounting for over 50% of cases. Non-genetic (hereditary) factors that can be identified include infections (meningitis, cytomegalovirus [CMV], syphilis), hyperbilirubinemia (jaundice at birth), medications (aninoglycoside antibiotics and cisplatin chemotherapy), trauma (skull fractures), immune dysfunction (autoimmune inner ear disease) and blood dyscrasias (hypercoaguable states, sickle cell disease).

The appropriate evaluation for children diagnosed has long been controversial. It is well accepted that talking with and examining child and family are the most important tools to determine the cause of hearing loss. Many of the syndromes associated with SNHL can be diagnosed in this fashion. Further testing remains controversial. The debate centers on the yield and cost-effectiveness of specific tests in contrast with the risks of failing to identify a potentially significant disorder. Possible diagnostic tests include various urine and blood tests, electrocardiograms, and imaging studies. Recent studies have suggested that the high resolution CT scan ("CAT scan") is the test that has the best chance of identifying the reason for the SNHL.

Genetic hearing loss is related to the passage of traits through the family that cause hearing loss. The two main forms of genetic deafness are syndromic and non-syndromic. When hearing loss is present with other medical problems the condition is termed syndromic. Non-syndromic refers to the absence of other related medical conditions. Most genetic hearing loss is non-syndromic (70%) compared to syndromic (30%) causes. Table 1 describes common syndromes with their associated conditions.

Even if no other persons in the family may have hearing loss, genetic factors may play a role in your child's hearing loss. So a comprehensive evaluation by a pediatric otologists versed in molecular genetics is important. The Center for Hearing and Deafness Research is unique in that it combines the clinical and research expertise in the fields of hearing loss and molecular genetics to provide complete care to all pediatric patients. Figure 1 represents a flow diagram for the general evaluation of childhood hearing loss.

Common syndromes related to hearing loss

Genetic testing

Genetic testing is a process by which our unique genetic code is determined to discover the cause a particular disorder. It has been estimated that as many as 10,000 genes may be involved in how our ear works. But to date, less than 100 mutated genes have been associated with hearing loss and only several dozen have been completely characterized. Presently, 3 genes are available for routine screening and as technology and our knowledge improves, complete panels of all deafness related genes will be realized.

We are very excited here at Children's Hospital in Cincinnati at the formation of the Center of Hearing and Deafness Research to promote better diagnostic and treatment options for your child. We now have available genetic tests to help diagnose the cause of your child's hearing loss. Molecular diagnostic testing has revolutionized the ability to assist otologists in providing insight into the etiology of hearing impairment in children. Genetic factors play a role in over 50% of all childhood hearing impairment. State-of-the-art medical testing is now available for the most common causes of hereditary hearing impairment at the Center for Hearing and Deafness Research. In addition, families studies can now be performed for less common causes of hearing impairment.

Approximately one-third of all children with significant hearing loss will be positive for testing for the gene Connexin 26. It is now recommended that all children with hearing impairment be screened with this simple blood test. Besides being able to diagnose many of these children with a single test, this may prevent the need of other time consuming and expensive test that are routinely performed. This test can be performed through the main hospital, any of our satellite offices or by mail. The test turnaround time is approximately 2-3 weeks, is covered by nearly all insurance companies and the referring physicians will receive an interpretation of the laboratory results. We provide a thorough and clinically relevant report of the test results based on our extensive experience. We have recently found several important relationships between the type and amount of hearing loss and the genetic testing results (Arch Otolaryngol Head Neck Surg., in press)

We are also interested in better understanding the results of these tests through collaborative research efforts. We provide testing results for research studies on a contractual basis.

Complete medical consultation and genetic counseling is available through the collaborative efforts of the Center for Hearing and Deafness Research and the Division of Human Genetics at Cincinnati Children's Hospital. Click here for more information

Connexin 26

In light of the hundreds of mutations in dozens of genes associated with hearing impairment identified to date, the identification of the high frequency of 35delG mutations in the Connexin26 (Cx26) gene in this population has allowed for an excellent screening test. The proper role of this and other genetic tests has recently come to the forefront of testing for hearing impaired children. Our evaluation of these patients now relies heavily on the incorporation of molecular diagnostics testing. The flow diagram in the Figure summarizes our current paradigm for evaluating children with SNHL. All children with bilateral hearing impairment >40dB (greater than mild) undergo Cx26 mutation screening. The application of this technology for mild hearing loss is still under consideration. Although, recent data has shown that non-35delG Cx26 mutations (i.e. M34T) can cause mild forms of hearing impairment. A conservative approach would be to include these children in the recommendations for molecular testing. To date, cases of unilateral (one-sided) hearing impairment are not candidates for molecular testing. For those patients not having Cx26 mutations, we perform a modified evaluation including urinalysis (urine test), ECG (for bilateral severe-profound cases) and a CT scan of the ear bones. More extensive evaluations are performed on a case-by-case basis.

Besides being a more precise and cost effective mode of diagnosis, other benefits of understanding the reasons of hearing impairment include better counseling of the families for the risk of future children and one day the possibility of treating these DNA problems (gene therapy). Despite our improved techniques in audiological testing in the under 2 years of age group, the decision for early cochlear implantation can be difficult. For those young patients with audiological tested, but not confirmed profound hearing loss, Cx26 testing can provide more confidence in the diagnosis.

Pendred Syndrome

Pendred syndrome is reported to be the most common form of syndromic hearing impairment (hearing impairment with other medical problems), affecting up to 7.5% of all cases of hereditary hearing impairment. Pendred syndrome consists of congenital profound (very severe) sensorineural hearing loss with thyroid goiter (enlargement) and inner ear malformations on CT scan of the temporal (ear) bones. Although the latter 2 findings are inconsistently present with 83% of patients developing goiter (midline lower neck mass), 44% with hypothyroidism (low functioning thyroid gland) and 40-50% with temporal bone abnormality. Even the definitive laboratory test for Pendred syndrome, the perchlorate discharge test, has a 10% false negative rate (test is normal, but the patient has the defect). Likewise, enlarged vestibular aqueduct syndrome (EVA) is the most common inner ear anomaly diagnosed on x-ray, which may be found at random, in families or associated with Pendred syndrome. The defect in EVA is an enlargement of a duct (vestibular aqueduct) that is vital to the regulation of inner ear fluid.
Mutations in the gene pendrin (PDS) are the cause of Pendred syndrome, DFNB4 (nonsyndromic recessive hearing impairment-a form of Pendred syndrome with no thyroid goiter) and EVA. Routine screening of PDS is now also available. Its current role is for those hearing loss patients with an obvious goiter, inner ear malformations such as EVA or Mondini's dysplasia.

Branchio-oto-renal syndrome

Branchio-oto-renal syndrome (BOR) is an uncommon condition that presents with variable hearing loss, kidney abnormalities and various head and neck malformations (branchial cleft cysts, preauricular pit and tags, external ear deformities. Changes in the gene, EYA1, have been found to be the cause of BOR in about 20% of patients. Genetic testing this gene is also available at the Center.