If you’re not offering a certain genetic test to determine the cause of sensorineural hearing loss (SNHL) in children, you should consider it, or refer your pediatric patients to specialists experienced with such diagnostics, according to a growing body of literature that underscores the value of genetic testing to determine the cause of SNHL in these patients.
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June 2013The latest such study comes from the University of Miami. Writing in the November 2012 issue of Otolarynology—Head and Neck Surgery, researchers led by Xue Zhong Liu, MD, PhD, professor of otolaryngology, human genetics and pediatrics and director of research at the University of Miami Health System, showed that screening for common mutations in GJB2 and GB26 should be an early step in the diagnostic evaluation of pediatric hearing loss (Otolaryngol Head Neck Surg. 2012;147:932-936). These genes encode the proteins connexin 26 and 30, which form gap junctions, channels that allow potassium molecules to move between cells and enable normal hearing. Faulty connexin proteins disrupt the potassium recycling pathway and production of electrochemical signals, resulting in hearing loss.
About half of all congenital hearing loss is inherited, caused by mutations in more than 100 culprit genes but, in developed countries, 40 percent of hearing loss is caused by changes in GJB2. They are the most common cause in all ethnic groups, except those of African descent. GJB2, a relatively small and easy gene to test, can yield results that may spare some children from unnecessary, costly tests, some of which carry risks from radiation, noted the University of Miami researchers and other experts on genetic testing for hearing loss. Tests for these and other genes give some parents answers about causes of hearing loss, how it may progress, whether other medical problems may result and the chance of recurrence in siblings.
A Look at Real-Life Testing
Dr. Liu and his team wanted to determine the diagnostic yield of targeted genetic testing in both adult and pediatric populations with SNHL to develop effective testing strategies in their clinic. They screened blood from 221 adults and 163 pediatric patients with non-syndromic SNHL who visited the University of Miami Ear Institute between 2001 and 2010. The researchers screened for
mutations in GJB2 and GJB6, plus three mitochondrial DNA mutations that can cause deafness when patients with these genetic abnormalities take the antibiotic gentamicin. The researchers also collected patients’ family histories and audiometric testing data.
The researchers found mutations in the most common recessive deafness genes, GJB2 and GJB6, in 14 percent of pediatric patients and 1 percent of adults. Thirteen percent of the children were also carriers of single mutations, indicating that they may play some role in deafness, the authors noted. Three percent of the adults had mitochondrial DNA mutations, but none of the children did.
Dr. Liu and his team propose a testing scenario in which children with SNHL first have tests for both GJB2/GJB6 mutations and cytomegalovirus, the most common cause of hearing loss in children, before CT scans. The researchers recommend against such testing in adults because it has very low yield, except in cases with strong family history.
Avoiding Unnecessary Tests
While GJB2 had been considered a first-line genetic test for children with SNHL prior to their study, the University of Miami researchers aimed to see how it could become part of a more efficient diagnostic strategy for their adult and pediatric clinic patients, said Dr. Liu. “This study strengthened our strategy, which is to screen for common genes first. That way, we can exclude 20 to 30 percent of cases. It’s very cost effective,” he said. Identifying children with GJB2 mutations before running other tests can in some cases prevent the need for certain non-genetic tests, especially CT scans, which also deliver high doses of radiation.
That’s because GJB2 testing can rule out genetic syndromes, which cause up to 30 percent of hearing loss cases. Without evidence of a mutation that causes faulty connexin, there’s an argument for ordering several costly non-genetic tests up front, including a CT scan, lab tests, an EKG and an eye exam, said Anil Lalwani, MD, professor and vice chair for research, chief of the division of otology, neurotology and skull base surgery and director of the cochlear implantation program in the department of otolaryngology–head and neck surgery at Columbia University in New York City. Among the more common conditions are Stickler syndrome, which involves eye and joint issues, and Waardenburg syndrome, the characteristics of which include joint and skin problems. Pendred syndrome involves the thyroid, while Usher syndrome includes blindness.
Other research groups have previously recommended delaying CT scans intended to look at ear structure until a child’s GJB2 status is known, said Craig Buchman, MD, chief of the division of otology, neurology and skull base surgery at the University of North Carolina School of Medicine in Chapel Hill (Laryngoscope: 2009;119:554-558 and 2011;121:630-635). That’s because patients with faulty connexin 26 generally have negative imaging tests, he said, so CT scans may needlessly expose children to radiation or anesthesia.
However, the decision not to order a CT scan before or after GJB2 test results isn’t so simple. A substantial number of patients with GJB2 mutations receive cochlear implants and will need imaging prior to surgery, Dr. Buchman said. “You will know by the degree of hearing loss,” he said, adding that it may sometimes be better to order imaging and genetic tests together.
Counseling Counts
All of the specialists interviewed for this article offer GJB2 testing to families of all pediatric patients. After explanation of the process and benefits of testing, most families are interested, they report. Those benefits, Dr. Buchman said, include the peace of mind that comes from knowing the cause is genetic rather than the result of something the mother did during pregnancy. Genetic testing for both GJB2 and syndromic hearing loss has identified other serious problems, can say how serious the hearing loss may ultimately be and identifies risk of recurrence. “These are all positive pieces of information,” said Dr. Buchman.
Proper counseling by otolaryngologists is a key part of the genetic testing process. Rick Friedman, MD, PhD, an otologist/
neurotologist at the House Clinic and principal investigator for Genetics of Hereditary Ear Disorders research at the House Research Institute in Los Angeles, emphasized the need to discuss the GJB2 test thoroughly when it is offered, adding that it often yields negative results. “It’s important to discuss the test and counsel parents about what a positive or negative result implies for family,” he said. For example, a positive result can give information about recurrence risk. Genetic testing usually does not change hearing loss treatment, which generally involves hearing aids or cochlear implants regardless of the cause, he added.
Families don’t always choose genetic testing, said Dr. Lalwani. Such decisions often result from lack of insurance coverage but are sometimes based on ethnic customs and religious beliefs.
Looking to More Genes and the Future
Genetic testing offers a valuable opportunity to better tailor care to individual children’s needs and will enable families to take advantage of future interventions to restore hearing, said Richard Smith, MD, director of the Iowa Institute of Human Genetics and professor and vice chair of the department of otolaryngology–head and neck surgery at the University of Iowa Carver College of Medicine in Iowa City. Researchers are now developing therapies that “will be predicated on knowing the exact genetic cause of hearing loss,” some of which have already reversed hearing loss in mice, he said.
Dr. Liu is looking ahead to the day when sequencing all of the protein-
coding genes with whole exome sequencing, and even the entire genome, may inform care for hearing loss. With National Institutes of Health grants, he has developed a 64-gene panel test for causes of deafness; he is also identifying and setting up a database of new genes and their function in human hearing loss and has made additional changes to the testing scenario described in his paper. GJB2 and GJB6 are still the first tests, along with mitochondrial DNA for patients with a maternal family history. If no cause is identified, patients get the panel test. If that is negative, they are eligible for either whole exome sequencing or whole genome sequencing.
Dr. Liu hopes his use of these technologies can spot new genetic causes and diagnose them in patients. Noting widespread predictions that the cost of sequencing a genome will soon drop to $1,000, he predicts that the technology will “change our way of testing and medical practice.”
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