the AJMG SEQUENCE
Researchers use bloodspots to identify genetic hearing loss
Study indicates testing scenario has potential
Bloodspot-based genetic testing for common GJB2 alleles as second tier test for newborn hearing screening (NHS) may reduce the number of children with hearing loss who don't receive follow-up services, say University of Minnesota researchers.
Genetic causes contribute to over one half of all cases of hearing loss in infants and autosomal recessive mutations in the GJB2 gene are one of the most common culprits in North America. Meanwhile, about 43% of infants referred by newborn screening for hearing loss are lost to follow up and possibly, early habilitation that could improve language skills, note researchers (Schimmenti et al., 2011).
Their research, published in the December 2011 Genetics in Medicine, presents proof of the concept that genetic testing of bloodspots is feasible way to quickly identify infants with genetic causes of hearing loss. Researchers and advocates in the hearing loss community have been actively discussing use of newborns' bloodspots for genetic testing for several years, says Karl White, PhD, Professor of Psychology and Founding Director of the National Center for Hearing Assessment and Management at Utah State University. “The issue hasn't been the ability to do it, but whether it's economically and practically feasible,” he says.
The researchers were able to perform genetic testing at a cost of about $5 per infant, according to Lisa A. Schimmenti, MD, the study's first author and Associate Professor of Pediatrics at the University of Minnesota.
The research team sought to determine whether genetic testing would identify hearing loss among infants who failed the NHS or with biallelic GJB2 mutations undetected by the NHS. They analyzed 2,364 bloodspots that were stripped of identifying information from 2 groups of newborns. The “refer” group included bloodspot cards submitted to the Minnesota Department of Health from infants who failed the NHS in both ears. The “pass” group included newborn bloodspot cards from simultaneously selected random controls from infants who passed NHS in both ears.
The research team sought to determine whet her genetic test ing would identify hearing loss among infants who failed the NHS orwith biallelic GJB2 mutations undetected by the NHS.
The researchers analyzed all of the blood spots for c.35delG, c.167delT, c.235delC, and p.V37I mutations in GJB2, and re-analyzed a subset with conventional Sanger sequencing to search for additional alleles.
In the refer group, researchers identified 22 spots of 1,177 with biallelic mutations in GJB2, representing a prevalence of GJB2-related hearing loss in infants who fail the NHS of approximately 1 in 50. In the pass group, the researchers identified only 1 spot of 1177 with biallelic mutations in GJB2, showing that GJB2-related hearing loss rarely occurs in this group.
“These findings provide strong evidence that when a newborn is found to refer by NHS, it is probable that a child will have GJB2-related hearing loss. This evidence provides impetus to support follow-up diagnostic audiometric evaluation and subsequent genetics evaluations for infants who refer by NHS,” the researchers write.
Obstacles to Research
Dr. Schimmenti says she hopes to study the degree to which identified infants with hearing loss receive follow-up services. She adds, however, that the political climate surrounding retention of newborn screening bloodspots in her state makes this research unlikely in the near future. Following a January Minnesota Supreme Court ruling that newborn screening samples cannot be stored or used for anything except diagnosis without parents' informed consent, the state's newborn screening program will now destroy bloodspots after 71 days and related infant data after 24 months.
What they reported was not bedside testing, but in my opinion, that's what's needed for this procedure to be practical and timely.
—Karl White, PhD
But Dr. White still sees potential in testing scenarios like the Minnesota researchers', even if a state destroys bloodspots. “What they reported was not bedside testing, but in my opinion, that's what's needed for this procedure to be practical and timely,” he says. He adds that knowledge of a genetic mutation that predicts hearing loss would allow states to prioritize follow-up services for the more than 40% of children with hearing loss that are currently lost to follow-up, and give important information for medical management. Bedside testing of bloodspots is practically feasible—if not politically—because it would occur before an infant leaves the hospital. “I don't see suits over retention interfering if you get informed consent,” Dr. White says.
He envisions even broader screening with a panel of up to 10 of the most commonly occurring mutations associated with hearing loss. “That would be a tremendous step forward if you could make it an inexpensive, practical, and timely test in other hospital settings,” he says.
Genetic testing for hearing loss may be feasible for state panels, says Ian Krantz, MD, Associate Professor at the Perelman School of Medicine at the University of Pennsylvania and the Children's Hospital of Philadelphia, but he questions whether it is warranted. “Hearing loss is so heterogeneous,” he says. “To me, the issue researchers are trying to stress is the ability to identify specific genetic causes of hearing loss,” he adds. “I don't know if a targeted approach (e.g. screening of one of the over 300 genes known to cause hearing loss) is useful for hearing loss as you will miss a lot of kids. Newborn hearing screening, while not perfect, is still much better at capturing the majority of kids with hearing loss early.”
Another issue is that getting quality follow-up services presents challenges to many families. One is finding a pediatric audiologist amidst a shortage of these specialists, especially in rural areas. Another is coverage for multi-disciplinary evaluations. Although the Individuals with Disabilities Education Act directs states to pay for them, “many children aren't referred to services until they have diagnosed hearing loss,” White says. While almost all state Medicaid plans pay for hearing aids, many don't consider digital hearing aids a “medical necessity,” so many children get analog aids that lack the features they need.
Most state Medicaid plans do cover cochlear implants, but reimburse so poorly that hospitals and surgeons lose money on the surgery, Dr. White says.