By the end of this lecture, learners will be able to: explain the differences between syndromic and non syndromic hearing loss, recognize that children with congenital hearing loss without a known cause are appropriate candidates for genetic testing, understand tiered genetic testing and targeted syndrome genetic testing and when each is the most appropriate to order, articulate the benefits of genetic counseling and testing for hearing loss for children and their families. There are a number of causes of congenital pediatric hearing loss. The causes of hearing loss fall into two categories; either acquired or genetic. Acquired hearing loss includes exposure to ototoxic drugs, infections such as cytomegalovirus, head trauma, noise exposure, and complications during birth. While many of these causes will be explored later on in the course, this video will only focus on the genetic basis of congenital hearing loss. Fifty percent of congenital hearing loss cases are due to genetic reasons. Genetic hearing loss is described as being either syndromic or non-syndromic. Syndromic hearing loss means that hearing loss is a symptom of an underlying genetic condition, and that the child has other symptoms besides hearing loss. Examples of genetic syndromes that present with hearing loss are Usher Syndrome and Waardenburg syndrome. Syndromic hearing loss accounts for 30 percent of genetic hearing loss cases. Some syndromes have settled features, especially in childhood, and thus it may not be obvious early in life that a child has an underlying genetic condition that contributes to their hearing loss. It is also important to keep in mind that many of these syndromes have highly variable phenotypes. Looking at a family history may not illuminate the possibility of hereditary hearing loss. An example of this variability is Waardenburg syndrome. The symptoms of this condition include changes in pigmentation in an individual's hair, skin, and eyes, and only 20 to 50 percent of individuals with Waardenburg syndrome present with hearing loss. Therefore, from only looking at a family history, it may not be apparent that a syndrome associated with hearing loss is being passed down, as conditions can have highly variable presentations even within families. Referral to a genetics team can help illuminate the possibility of a genetic syndrome through a dysmorphology exam. All in all, if information about the other systems affected by a genetic syndrome is not elicited, a diagnosis could be missed. The other type of genetic hearing loss is non-syndromic, and accounts for 70 percent of genetic hearing loss cases. Non-syndromic hearing loss means that the hearing loss is isolated and not a part of an underlying genetic syndrome. The most common cause of genetic non-syndromic hearing loss are mutations in the GJB2 gene, which is responsible for making the protein, connexin 26. Connexin 26 is found in the inner ear and plays a role in cochlear function. Over 150 deafness causing variants in GJB2 have been identified. Non-syndromic hearing loss resulting from GJB2 variance is typically present at birth and is bilateral. So who should have genetic testing for hearing loss, and when should they have it? As mentioned in previous lessons, all newborns undergo newborn screening. This is baby's first genetic test. Part of newborn screening is to assess for hearing loss that may be present at birth. The American College of Medical Genetics and Genomics recommends that all infants who are diagnosed with congenital hearing loss via the newborn screen should be evaluated by a genetics team. Additionally, children and teenagers who display hearing loss later on in childhood, in adolescence, should be evaluated for syndromic conditions. If upon evaluation, a hearing loss causing genetic syndrome is suspected, genetic testing targeted towards that syndrome can be done. The genetic counselor can order testing for the genes that are responsible for the suspected syndrome. If a syndrome is not clearly indicated, genetic testing can take a different graph. In this case, testing should follow a two tiered approach. First, the child should be tested for changes or mutations in genes commonly linked to hearing loss, like GJB2, to detect the most common genetic causes of non syndromic congenital hearing loss. If no gene mutations are identified, the second tier test that should be conducted is a next-generation sequencing gene panel. This panel contains a large number of other genes associated with hearing loss. All of these genes are analyzed for mutations that cause the gene to malfunction. Genetic testing produces three different results: positive, negative, or inconclusive. A positive result indicates that a pathogenic mutation was identified in one of the genes analyzed and provides an explanation for the child's hearing loss. A negative result means that a known pathogenic mutation was not identified in any of the genes analyzed. An inconclusive result known as a variant of uncertain significance indicates that a mutation was found in one or multiple of the genes analyzed. But it is unknown if this change is linked to hearing loss or is benign. Additionally, genetic testing is appropriate even for children who have tested positive for cytomegalovirus, a common cause of acquired hearing loss, as a positive CMV test does not rule out the possibility of a genetic cause of hearing loss. Even a negative or uncertain genetic testing result does not mean that the hearing loss isn't genetic. Researchers are discovering more genes connected to hearing loss every day. The child might have a genetic component to hearing loss, but at the time of testing, research and technology has not yet advanced enough to recognize it. It is important that these children continue to follow up with the genetics team who will continue to evaluate them over the years. As medicine progresses, new testing may become available or previously uncertain results interpreted in a new way. A genetic counselor will be able to make a family aware of this new information. So what are the benefits for children and families that genetic testing can provide? Genetic testing can possibly answer patient's question of how and why a child has congenital hearing loss. It can identify or rule out comorbidities from a syndrome that may require specialty care, and also allow for planning for the future in regard to a child's educational and medical needs. They can also provide parents with recurrence risk information if they are planning on having more children. Recurrence risk can vary upon the mutational basis of the child's hearing loss, and genetic testing can better illuminate this risk. A genetic counselor's able to interpret the genetic testing results and communicate the information to families, making them an integral part of the child's health care team. That concludes our discussion of the genetics of congenital pediatric hearing loss. Remember, a child may have a syndrome and present with only hearing loss at birth. So to rule out syndromic hearing loss, refer for a clinical genetic evaluation. By knowing the genetic etiology of a child's hearing loss or by ruling it out, genetic testing can be very beneficial for a child's care and the family's future planning.
