Highlights From the Annual Clinical Genetics Meeting

Siobhan Dolan, MD


April 07, 2003

In This Article

Hereditary Deafness

Newborn hearing screening has been adopted by many states and is being considered by many others. Many new families will have their newborn's hearing tested within the first day or two of life and turn to their ob/gyn for help in understanding the results. While this counseling is often undertaken by the pediatrician, it is helpful for ob/gyns to know some of the basic facts about the remarkable technologic advances that have allowed newborn hearing screening. It is also valuable to understand the implications of congenital deafness in order to assist patients as they learn about test results. Some cases of congenital deafness have causes that originated during pregnancy, such as cytomegalovirus (CMV). Ob/gyns may be called upon to order diagnostic testing for the mother during the work-up of congenital hearing loss.

Dr. Christine Petit (Institut Pasteur, Paris, France) delivered the Samuel Pruzansky Memorial Lecture entitled Hereditary Sensory Defects: From Genes to Pathogenesis.[6]

Deafness is the most frequent sensory defect in humans. It can happen at any age and with any degree of severity. The overall impact of deafness is greatly influenced by the severity of the hearing defect and the age of onset. Early-onset forms impede speech acquisition and reading. Late-onset forms can lead to social isolation. Severe to profound deafness affects 1 in 700 children at birth. One in 1000 children are affected before adulthood; 2.3% of the population between 60 and 70 years of age is affected by severe to profound deafness. In developed countries, the syndromic forms of deafness are almost exclusively of genetic origin. They account for about one third of the deafness cases at birth.

About 150 genes have been isolated that contribute to hereditary deafness. These genes are involved in a large variety of developmental processes. Isolated deafness can be due to environmental causes as well as genetic factors. Congenital inherited forms of deafness are monogenic defects that are autosomal recessive in 80% to 85% of cases. Young adult-onset forms are mainly autosomal dominant.

There are 35 genes that are responsible for 41 forms of hereditary deafness. These forms include:

  • 18 DFNA (autosomal dominant) (note: DFN is an acronym for DeaFNess)

  • 20 DFNB (autosomal recessive)

  • 1 DFN (X-chromosome)

  • 2 mitochondrial forms

Six of these genes underlie both autosomal dominant and autosomal recessive forms of deafness. Eleven of these genes underlie both isolated and syndromic forms of deafness. A defect in the GJB2 gene, which codes for connexin26 (CX26), a gap junction protein, is responsible for more than half the genetic cases of profound deafness in the United States. At least two thirds of the cases of isolated prelingual deafness are of genetic origin.

Thirteen genes are known to underlie a hair cell defect that interferes with hearing. In 1995, Usher syndrome type 1B was determined to result from a defect in the motor protein myosin VIIA, which directly interacts with vezatin. Myosin VIIA, through its binding to vezatin, is involved in the adhesion process and likely strengthens the hair.

Kallmann syndrome is defined by the association of anosmia and hypogonadism. Kallmann syndrome is manifest by absent or underdeveloped olfactory bulbs. It also has gonadotropin-releasing hormone (GnRH) deficiency. In 1991, KAL-1 was cloned and discovered to be the gene responsible for the X-linked form of the syndrome. KAL-1 is a loss of function mutation. KAL-2 was recently identified. This gene is transmitted in an autosomal dominant fashion and is often the result of a sporadic mutation.

There have been many obstacles to the cloning of the genes underlying isolated deafness in humans. Specifically, there have been particular difficulties around performing segregation analyses in these genes. Also, the molecular bases of inner ear functioning are unknown.

Dr. Walter Nance (Virginia Commonwealth University, Richmond) discussed the genetic epidemiology of deafness. Incidence of profound deafness is about 1 per 1000 births. A lesser degree of hearing loss is found in an additional 1-2 cases/1000 births. Dr. Nance pointed out that about half the causes of profound hearing loss in infancy are environmental and half the causes are genetic. Among the environmental causes are prematurity, pharmacologic ototoxicity (streptomycin or gentamicin), congenital rubella syndrome, prenatal CMV infection, neonatal kernicterus, and postnatal infections such as meningitis. Of the genetic causes, 30% are syndromic such as Alport, Norrie, Usher, Pendred, Waardenburg, branchio-oto-renal, and Jervell and Lange-Nielsen (JLN) syndrome. The other 70% are nonsyndromic and follow autosomal dominant, autosomal recessive, X-linked, and mitochondrial inheritance patterns.

A report from an ACMG expert panel on the Genetic Evaluation Guidelines for the Etiologic Diagnosis of Congenital Hearing Loss appears in the May/June 2002 issue of Genetics in Medicine, available online at: http://www.acmg.net/resources/ policies/we0302000162.pdf

Dr. Nance talked about the JLN Syndrome, as it is arguably the most important form of deafness to identify. Children often present with deafness and syncope. There is a prolonged QT interval and risk of sudden death. The incidence of JLN among the deaf is about 1 in 500. Effective treatment is available in the form of beta-blockers and implantable defibrillators. Patients need to be under the care of an experienced cardiologist because of the grave risk of sudden death. JLN is caused by mutations in a potassium channel gene: KCNQ1 is located at 11p15 and is responsible for 90% of JLN cases. KCNE1, at 21q22.1, is responsible for about 10% of JLN cases. There are at least 2 other mutations that contribute to a few cases of JLN. Unfortunately, some patients with JLN still die before being diagnosed. Some heterozygotes are known to have prolonged QT interval and experience syncope but not deafness. These individuals are still at risk of sudden death.

Dr. Nance asked clinicians to consider the following:

  • Deaf subjects still die from undiagnosed JLN syndrome.

  • Geneticists are now becoming involved in care of deaf patients during early infancy.

  • Where an etiologic diagnosis cannot be found, obtain an EKG to rule out JLN.

Dr. Bronya Keats (Louisiana State University Health Sciences Center, New Orleans) discussed the genetic characterization of Usher syndrome.[7] She described it as an autosomal recessive disease characterized by sensorineural hearing loss and retinitis pigmentosa (RP). Usher syndrome accounts for more than 50% of deaf-blindness and 18% of RP. It may affect 3% to 6% of children born with severe to profound hearing loss. The prevalence is estimated to be 1-3 per 50,000.

Genetic hearing loss may be associated with eye disorders (Usher syndrome), endocrine disorders (Pendred syndrome), cardiac disorders (JLN), pigmentary disorders (Waardenburg), renal disorders (BOR and Alport), and musculoskeletal disorders (Stickler).

Dr. Keats spoke about the mouse models for Usher syndrome. She demonstrated that Usher syndrome is clinically and genetically heterogeneous, both locus and allelic heterogeneity. She also reviewed that some mutations in the Usher genes are associated with nonsyndromic hearing loss. The presentation demonstrated that alternatively spliced transcripts may contribute to variation in retinal and cochlear findings. Dr. Keats' work clearly demonstrates that mouse models are invaluable for studying human hearing loss.

Dr. Karl White (Utah State University, Logan) spoke on early hearing detection. Early hearing detection and intervention (EHDI) can be performed in 1 of 2 ways: otoacoustic emissions (OAE) or auditory brainstem response (AABR). Dr. White reported that both technologies work well, and about half of the states are using each technology in their newborn screening programs. Both technologies have low false-negative rates.

Dr. White pointed out that it is very important to detect profound hearing loss early in life. Deaf children have been shown to have delayed reading acquisition. In addition, the effects of unilateral hearing loss are substantial. Studies show that children with unilateral hearing loss show delayed math, language, and social skills at about the 25th to 30th percentile, which translates into a several-year delay during most of elementary school. Data also demonstrate that children identified earlier in life can benefit from interventions and do better in terms of achieving grade-level performance.

Initial efforts around EHDI were aimed at identifying "high-risk" children and screening these children. Early data showed that only 50% of children with congenital hearing loss exhibited high-risk indicators. As technology has evolved to enable bedside newborn hearing screening, universal newborn hearing screening has become widely accepted. Concurrently, equipment and techniques for diagnostic testing of hearing loss in infants continue to improve. There still is a need for pediatric audiologists in many states.

Thirty-seven states now offer universal newborn hearing screening. The American College of Medical Genetics (ACMG) and the March of Dimes (MOD) have endorsed universal newborn hearing screening. The American Academy of Pediatrics (AAP) guidelines suggest that newborn hearing screening be performed in the context of the medical home before 1 month. (The concept of medical home was established by the AAP and requires that each child in the United States have a primary care provider who manages care in a culturally competent way.) The guidelines suggest that diagnostic testing should be performed by 3 months of age, and intervention should be undertaken by 6 months.

Dr. White gave a status report of the EHDI programs in the United States. Approximately two thirds of US newborns are currently being screened. Newborn screening programs still have work to do in terms of assuring that all babies who have positive screens receive diagnostic testing. Some states report that only about half of children with positive screens actually receive their diagnostic testing.

Current follow-up systems are designed to serve infants with bilateral profound hearing loss, but don't seem to do as well in terms of children who are mildly affected. Studies have shown that babies with isolated profound hearing loss are not always getting referred to genetics counselors. The benefits can include not only understanding the reproductive implications for the family, but also providing further information, anticipatory guidance, and support services, as well as parent contacts and referrals. The National Center for Hearing Assessment and Management at Utah State University has a Web site available at: www.infanthearing.org. Information for parents is available at www.babyhearing.org.

In summary, newborn hearing screening is beneficial, feasible, effective, and inexpensive. EHDI programs are expanding rapidly, but significant issues remain to be addressed. Better understanding about the genetics of congenital hearing loss will dramatically improve EHDI programs.

Dr. Charles Berlin (Louisiana State University Health Sciences Center) spoke on the diagnosis and management of auditory neuropathy/dyssynchrony.[8] Dr. Berlin showed multiple visual demonstrations and animations that demonstrate how hearing is accomplished. These are available on the Web at: www.kresgelab.org. Dr. Berlin reminds us to treat the child, not the test results!

Dr. Kathleen Arnos (Galludet University, Washington, DC) gave a talk entitled "Communicating Culture and Attitude Towards Newborn Screening and Genetic Testing: Implications for Genetic Counseling."[9] Dr. Arnos covered some of the very important issues around genetic counseling for individuals with hereditary deafness. In the United States, 90% of culturally deaf people will marry another deaf person. Of this group, 20% preferred to have deaf children, 10% preferred to have hearing children, and 70% stated no preference. This information is relevant as an ob/gyn tries to perform nondirective counseling regarding prenatal diagnosis. It is important to keep in mind that hearing couples may be interested in diagnosing deafness in a fetus and see deafness as a problem. By contrast, deaf couples may be interested in propagating deafness as it offers an entrée into deaf culture that the parents may be very much a part of. While the ethics of using genetic information to select for a deaf child have been debated, it is nevertheless important to consider the various perspectives that exist around deafness. Ultimately, families, and specifically women, maintain the freedom to make complicated choices regarding pregnancy and prenatal diagnosis, and, by providing up-to-date medical information, ob/gyns can help their patients make informed decisions.

Communication technology has helped the deaf community intensely. Email and instant-messaging pagers are widely used. Cochlear implants is a technology that was initially not well received by the deaf community. Things are changing and more children are having cochlear implants and mainstreaming in to the educational system. This has already substantially reduced the size of the deaf community.

In summary, although most deaf babies are born to hearing parents, they do grow up and many choose to become part of the deaf culture. Cultural differences have important implications for genetic counseling. It's important to avoid making assumptions about the desires of hearing patients as well as deaf patients.


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