Feb 2019 The Hearing Journal

Kathleen Arnos, PhD, and Ian Krantz, MD, have been on the frontlines of a revolution. Arnos is a recently retired professor of biology and the director of the Genetics Program at Gallaudet University in Washington, DC, and Krantz is an attending physician in the division of genetics at the Children's Hospital of Philadelphia (CHOP). Both have been immersed in relatively new developments in the field of genetic testing as it relates to hearing loss.

Arnos began her career path in human genetics, with a research focus on hereditary deafness, in the early 1980s.

genetic2“For 35 years, I worked within the Deaf community studying various aspects of hereditary deafness,” said Arnos, whose interest in this area was initially sparked by learning sign language. “Amazing progress has been made in the last years in understanding the causes of hereditary deafness and the optimal approaches for genetic evaluation, testing, and counselling for hereditary deafness. It has been a thrill to be a part of it.”

Krantz described his research in the area of elucidating the underlying genetic causes of syndromic and non-syndromic birth differences as difficult when he started out 25 years ago, when families were often left with more questions than answers. “At that time, there were essentially no genetic tests for hearing loss, so all the information that we could give was based on clinical exams and guess work,” said Krantz, adding that in the late ’90s, hearing loss genes were beginning to be identified with more accuracy. Krantz started the Genetics of Hearing Loss Clinic at CHOP in 1996 to meet the demand of interested families. The clinic initially met once a month, but it rapidly grew over the years into a double-booked weekly clinic. “As we saw more families with hearing loss, we embarked on a research study that has been ongoing for over 20 years now to identify new genetic causes, improve diagnostics, and hopefully identify novel ways to treat hearing loss in the future,” he said, pointing to the Human Genome Project that sequenced the entire human genome and was completed in 2003.

Genetic hearing loss research has been one of the main benefactors of the breakthroughs, as the initial human genome took over 10 years to sequence at a cost of over $1 billion, while today an entire genome can be sequenced in a matter of days for under $1,000, said Krantz, adding: “Hearing loss is one of the most genetically heterogeneous diagnoses in humans, with hundreds of genes that can each result in hearing loss when changed or mutated.” 


While a high percentage of patients who have genetic causes of hearing loss can be directly identified by genetic tests, the revolutionary developments in the field can have a ripple effect on clinical audiology practices. Sherri Jones, PhD, the chair of the department of special education and communication disorders at her alma mater, the University of Nebraska-Lincoln, underscored the importance of a diagnosis providing answers for the patient and family members/caregivers.

“A diagnosis can provide information that allows the clinician to be proactive with management strategies, for example, genetic diagnoses that include progressive hearing loss would enable the clinician to counsel the patient regarding the expected progression of hearing loss and map out a strategy for follow-up testing and intervention, including devices, educational strategies, etc.”

Krantz, who holds a Distinguished Chair position in the department of pediatrics at CHOP, sees a direct connection from the research realm to the work of audiology professionals as being able to rapidly test an individual with hearing loss.

He outlined five scenarios that emphasise the importance of the research-audiology link:

  1. Finding out early that a child who presents with apparent isolated hearing loss actually has changes in an Usher syndrome gene that also impacts vision.
  2. Allowing for a determination by an audiologist if there are any treatments or management options.
  3. Allowing for an accurate recurrence risk counselling for affected individuals and family members.
  4. Finding an answer may allow for the avoidance of unnecessary additional clinical testing. For example, finding that the cause of a child's hearing loss is attributed to changes in the GJB2 gene (which causes isolated non-syndromic hearing loss) would eliminate the need for additional, costly tests such as an MRI of the temporal bones, an EKG to rule out cardiac rhythm difference, a renal ultrasound, and kidney and thyroid function tests.
  5. Understanding the underlying molecular etiology for an individual's hearing will also allow clinicians and affected individuals to know if any new hearing treatments that may emerge will apply to them, as many of the new therapies that investigators are working on will be very specific to the molecular cause of an individual's hearing loss.

Indeed, genetic diagnosis plays a critical role in ongoing decision-making and patient care, and has become a critical part of the diagnostic workup and management of an individual with hearing loss for all of the above reasons. Using genetics in the diagnostic evaluation of individuals with hearing loss has been at the forefront of integration of genetics into clinical care.

“Since such a high percentage of hearing loss has a genetic contribution and hearing loss is so genetically heterogeneous, there is increasing evidence to show that a genetics-first approach in the workup of hearing loss has many benefits and is a cost-effective way to manage the clinical care of individuals with hearing loss,” said Krantz.

Arnos also sees audiology professionals as crucial partners with the genetic research community.

“There is no doubt that ensuring that genetic testing is more consistently used with audiologic newborn hearing screening will improve identification and outcomes of newborns with hearing loss,” she said. “Parents (and practitioners too) may assume that genetic testing is relevant only for families who have a child with hearing loss and are considering having additional children, but clearly genetic testing and evaluation has become part of the diagnostic process of a child with hearing loss.” 


Krantz recalls the case of a patient we will call “Alex,” who had bilateral sensorineural hearing loss. He was evaluated by genetics when he was 6 years old, and genetic testing at that time did not reveal an answer. “When he returned for re-evaluation at 12 years of age, he had developed visual loss and balance problems,” said Krantz. “Full exome sequencing allowed us to establish a diagnosis of a rare recessive disorder called Brown-Vialetto-Van Laere syndrome that is caused by mutations in the SLC52A2 gene.”

The disorder is caused by an inability to transport an essential vitamin, riboflavin, into cells. It's a progressive neurologic disorder that presents in childhood with hearing loss and progresses to more severe neurologic involvement that can result in early deaths from respiratory failure.

Armed with the diagnosis, there was hope. Treating it with high doses of riboflavin can potentially halt progression of these symptoms and if started pre-symptomatically, can potentially prevent any symptoms from manifesting. “Since this is a recessive condition, with both of Alex's parents being carriers, we were able to test Alex's asymptomatic sister ‘Hanna’ who was also found to have both mutations,” said Krantz. “Both Alex and Hanna were started on high-dose riboflavin to halt Alex's progression and hopefully prevent symptoms from arising in Hanna”.

“Someday in the future, when all newborns are screened for these types of genetic changes, we may be able to prevent these types of treatable forms of hearing loss from happening.” Arnos outlined the case of a 4-month-old infant. She was born to a full term and healthy weight, and had no family history of hearing loss. However, based on a “refer” status for hearing screen prior to discharge, subsequent audiologic testing revealed a severe to profound sensorineural hearing loss. At the suggestion of the audiologist, her parents followed up with genetic evaluation and counselling, which revealed that she had gene mutations that cause Jervell and Large-Nielsen syndrome—a condition that causes hearing loss as well as life-threatening heart arrhythmia. The family was then referred to a cardiologist for follow-up treatment.

“This case illustrates current standard practice for genetics referral and testing for newborns identified with hearing loss,” said Arnos. “Within the next ten years, a more comprehensive newborn hearing screen that includes physiologic (audiologic), genetic, and cytomegalovirus testing may be standard practice.”


The advancements in genetic research have been rapid in the last few decades, but they are not without continued challenges for researchers, audiologists, counsellors, and families. “The main challenges in genetic diagnostics of hearing loss is the high degree of genetic heterogeneity,” said Krantz, adding that “lots of genes cause hearing loss.” So many genes and mutations in these genes are novel or unique to a family, which means there is often a need for genetics expertise to help determine if a given change is actually responsible for an individual's hearing loss.

“At CHOP, we have one of the most comprehensive hearing loss gene screening panels called the Audiome, an exome-based test that allows us to evaluate over 120 known hearing loss genes. And if we do find an answer for a family in these genes, we can look at the rest of the 20,000 genes for an answer,” said Krantz. “Another issue encountered in genetic testing in general is the issue of uncertainty—sometimes a result is unclear as to whether it is really the cause of the hearing loss. Other family members often need to be tested to help clarify the pathogenicity of some identified variants/mutations.”

As genetic testing becomes more complex, families looking to take full advantage of the diagnostic tool are not always met with open arms. “From my point of view, one challenge is the cost of genetic testing, which can be quite high depending on the testing panel used,” said Arnos. “Although such testing is often covered by insurance, not all families have equal access to health insurance.”

Emma Bedoukian, one of the genetic counsellors at CHOP who works closely with both Krantz and families in the hearing loss clinic, deals with the complex fallout of the results. “When results are positive, parents may be happy, relieved, or even angry,” she said. “Some are happy to have a genetic etiology as it provides a clear cut reason for the hearing loss that can be utilised to guide future decisions for the patient and for themselves (cochlear implants, need for MRI, in vitro fertilisation with preimplantation genetic diagnosis, etc.). Some families are angry that a genetic cause is identified because–I think—it then becomes more real or like they will be blamed. Some families like a genetic etiology, knowing then that it wasn't something they did during the pregnancy.”

Bedoukian also pointed to “syndromic” results that could indicate health concerns beyond hearing loss. While these may arm families with knowledge, other emotions—described by Bedoukian as “fear, blame, concern, grief, and more”—create additional challenges. “Some are happy with a negative gene panel (showing no gene mutations that cause the hearing loss) because they have at least ruled out the known syndromic forms of hearing loss (at least the ones with known genetic etiologies). Some are upset that there is no answer yet, and they don't know true recurrence risks or what to expect of their child as they get older.”

However, as Jones warned, genetic testing does not always identify the cause, saying: “The majority of hereditary hearing loss is through recessive inheritance where there is no family history of hearing loss, so consideration of a genetic cause may be overlooked.” She knows this directly through her own research, which has examined the functional consequences of genetic mutations on auditory and vestibular functions in mutant mouse models. “Our work has shown that genetic mutations can have differential effects on the cochlea and the vestibular organs,” she said. “Functional changes in hearing do not always predict functional changes in the vestibular system. Indeed, the inner ear vestibular system can be quite resilient to genetic mutations. And, our work has suggested that genetics plays a role in vestibular ageing that is different from that in age-related hearing loss.”

For families, this is the greatest fear of all—the fear of the unknown—that is magnified with the natural frustration of where to go next. “Sometimes genetic testing results reveal variants of unknown clinical significance,” said Bedoukian. “A variant of unknown clinical significance is a genetic change that, based on the currently available knowledge, cannot be interpreted as pathogenic or benign. Some parents are confused by the ambiguity of genetic testing results like this.”

As the science rapidly improves, however, there will be more firm answers arming those in the field with knowledge. “The clinicians may feel strongly they are—or aren't—the answer, but without more time and science on our side, we cannot confirm either way immediately,” said Bedoukian. “This means that variants of unknown significance often are without repercussion, and no action can be taken in many instances if results are not confirmed to be pathogenic.”

For all the advancements, Arnos foresees more down the road. “There are many genetic causes of hearing loss that have yet to be identified,” she noted. “I know of several families who clearly have a genetic form of hearing loss because multiple family members are affected, but the existing genetic testing panels have been unable to identify the specific genetic etiology for them. This can be frustrating for families. That being said, our knowledge and the diagnostic power of these testing panels is improving all the time.”

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26-01-2021 08:13


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