The Academy Research Conference (ARC) 2018 provided an overview of progress in the field of genetics and hearing loss from both research and clinical perspectives. As chair of ARC 2018, I was joined by several knowledgeable individuals on the organizing committee, including Dr. Zarin Mehta from A.T. Sill University, Dr. Wendy Hanks from Pacific University, and Dr. Jonathan Whitton from Decibel Therapeutics. My thanks to them for their expert guidance. I would also like to thank Jennifer Shinn, University of Kentucky, as well as Joan Haller, director of meetings with the Academy and Heather Finney, meetings manager with the Academy, all of whom were instrumental in organizing this conference. 

The organizing committee chose speakers who were exceptionally qualified to address recent developments in gene discovery, testing, and therapeutics, based on their clinical and research expertise. The technological advances in the field of genetics and hearing loss over the past 35 years has been nothing short of amazing. 

In the 1980s, the tools of the trade for evaluating a genetic cause of hearing loss in a client consisted almost entirely of pedigree analysis and physical examinations looking for features that indicated a syndromic cause of hearing loss. This approach allowed geneticists to sometimes identify a specific syndrome, and sometimes identify nonsyndromic hearing loss inherited in a specific pattern. At that time, however, the molecular tools to identify causative genes did not exist. 

Beginning in the 1990s, significant progress was made in mapping and cloning of genes related to hearing loss, including the discovery in 1997 of a major contributor to genetic hearing loss, the GJB2 gene (Connexin 26). Since that time, progress in identifying genes related to hearing loss has been explosive and has expanded to include not only single genes inherited in Mendelian patterns that are common causes of congenital and early-onset hearing loss, but genes that contribute to multifactorial conditions such balance disorders, and noise-induced or age-related hearing loss. 

In the past decade, next generation DNA sequencing made its appearance, allowing the rapid sequencing of specific genes or the entire genome in individuals. In the past year or two, a new age in therapeutics has been heralded in the progress made in gene-editing technologies, including one in particular called CRISPR-Cas9. Soon, we may begin to see this technique applied to patients with hereditary forms of hearing loss. 

These innovations and more were addressed by the ARC 2018 speakers. These five speakers included otolaryngologists, medical geneticists, and a pediatric clinical geneticist who have devoted their careers to the clinical and molecular characterization of genetic forms of hearing loss and bringing new developments from the research bench to clinical practice. Together with eight poster presentations by clinicians, researchers, and students, ARC 2018 speakers masterfully conveyed the most recent discoveries in this field to the attendees. The following abstracts from each of the speakers summarize their presentations.

The Basics of Genetics for the Clinician

Marci Lesperance, MD, FACS, Professor and Division Chief, Pediatric Otolaryngology, University of Michigan Health System, Ann Arbor, Michigan

Approximately 50 percent of childhood sensorineural hearing loss (SNHL) is genetic in origin, and about 80 percent of genetic cases are inherited as autosomal recessive traits (Marazita et al, 1993). Autosomal dominant inheritance is estimated at 18 percent of cases, and the remainder have X-linked or mitochondrial inheritance. It is anticipated that the proportion of genetic cases will increase in the future, as medical treatments are developed that help prevent hearing loss due to environmental or acquired factors. The evaluation of the patient with sensorineural hearing loss should include review of the family history as well as any potential risk indicators for environmental hearing loss. 

Both computed tomography (CT) and magnetic resonance imaging (MRI) play a role in evaluation of temporal bone anatomy. CT provides excellent bony detail, does not require IV contrast, and is less likely to require sedation. MRI is preferable for evaluation of auditory nerve hypoplasia and aplasia, particularly in the setting of unilateral profound loss. However, MRI is more likely to require IV contrast and sedation and is typically more expensive.

The most common gene underlying recessive nonsyndromic SNHL is GJB2, which encodes the Connexin 26 protein (Estivill et al, 1998). The most common mutation in GJB2 (35delG) is associated with profound congenital SNHL, but it is important to recognize that patients with GJB2 mutations may present with mild or moderate hearing loss and even normal hearing, and that modifier genes exist (Hilgert et al, 2009).

Enlarged vestibular aqueduct (EVA) syndrome is a common cause of SNHL identified in children who pass the newborn hearing screen. Approximately 25 percent of patients with bilateral EVA have biallelic mutations in the SLC26A4 gene, whereas 50 percent have monoallelic mutations without identifying a second mutation (Choi et al, 2009). A recent study identified a Caucasian EVA haplotype, which may explain the “missing” second mutation (Chattaraj et al, 2017). When this haplotype is found in trans with a pathological SLC26A4 allele, the penetrance of hearing loss is 85 percent. 

Congenital human cytomegalovirus (HCMV) infection is the most important acquired cause of childhood SNHL in the U.S. population. HCMV infection must be diagnosed in the first three weeks of life to confirm congenital exposure. Congenital HCMV infection is diagnosed based on maternal antibody conversion during pregnancy or by identifying virus in infant saliva, blood, or urine. Some states and centers have implemented HCMV screening for all newborns who refer on newborn hearing screening. Clinical trials are underway to assess the benefit of drug treatment (oral valgancyclovir) to prevent development or progression of SNHL in children with congenital HCMV infection.

The potential benefits of genetic evaluation and genetic testing include ascertaining the etiology of hearing loss, estimating recurrence risk, assessing prognosis for progression of hearing loss, and recognizing possible syndromes. Our focus group study found that patients are not always given sufficient information to make an informed decision (Lesperance et al, 2017). The audiologist is an important member of the health-care team to help elicit patient preferences and identify patients who are candidates for genetic evaluation. 


References

Marazita ML, Ploughman LM, Rawlings B, Remington E, Arnos KS, Nance WE. (1993) Genetic epidemiological studies of early–onset deafness in the U.S. school–age population. Am J Med Genet 46(5):486–491.

Estivill X, Fortina P, Surrey S, Rabionet R, Melchionda S, D’Agruma L, Mansfield E, Rappaport E, Govea N, Milà M, Zelante L, Gasparini P. (1998) Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet 351(9100):394–398. 

Hilgert N, Huentelman MJ, Thorburn AQ, et al. (2009) Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene. Eur J Hum Genet (17):517–524.

Choi BY, Stewart AK, Madeo AC, et al. (2009) Hypo-functional SLC26A4 variants associated with non-syndromic hearing loss and enlargement of the vestibular aqueduct: genotype-phenotype correlation or coincidental polymorphisms? Hum Mutat 30(4):599–608. 

Chattaraj P, Munjal T, Honda K, Rendtorff ND, Ratay JS, Muskett JA, Risso DS, Roux I, Gertz EM, Schäffer AA, Friedman TB, Morell RJ, Tranebjærg L, Griffith AJ. (2017) A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct. J Med Genet 54(10):665–673.

Lesperance MM, Winkler E, Melendez TL, Yashar BM. (2017) “My plate is full”: reasons for declining a genetic evaluation of hearing loss. J Genet Couns October 4:1–11.

Genetic Testing and Counseling for Hearing Loss in Era of Precision Medicine

Arti Pandya, MD, MBA, Associate Professor and Division Chief, Division of Genetics and Metabolism, Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, North Carolina

Hearing loss is one of the most common neurosensory deficit affecting one in 500 children, with profound hearing loss identified in one in 1,000 newborns (Morton and Nance, 2006). In the past two decades, we have witnessed remarkable progress in our ability to diagnose and evaluate individuals with hearing loss due to the explosion in knowledge and availability of newer technology. 

Our understanding of the genetic basis for congenital hearing loss has increased exponentially with the implementation of the Human Genome Project and completion of sequencing the human genome. There also has been simultaneous progress in early detection of hearing loss through the universal audiological newborn screening and in identifying a genetic etiology for a large proportion of children with profound loss. 

Currently there are more than 250 genes identified that are important in both nonsyndromic and syndromic forms of hearing loss. With the availability of technology to examine the entire coding region of the human genome and the recent initiative for precision medicine, there are definite opportunities to tailor the care and management of children and adults with hearing loss. 

Hearing test on young girl imageThe first gene implicated in nonsyndromic human deafness, GJB2, was identified in 1997 (Kelsell et al, 1997). Sequence changes in GJB2, a gap junction beta 2 gene that codes for the protein Connexin 26 (Cx26), accounts for 50 percent to 80 percent of all profound recessive hearing loss. A single sequence change involving a deletion of a guanine nucleotide in a series of six Gs known as 35delG accounts for 70 percent of the pathologic alleles. 

Interestingly in at least 20 percent of individuals with a GJB2 related hearing loss, immediate family history is often negative and a detailed pedigree may help identify the genetic nature. Testing for mutations in GJB2 is available through several diagnostic laboratories and offered as part of the initial work up of all children diagnosed with hearing loss. A positive result helps in accurate counseling and avoids more expensive and invasive testing.

Today, more than 130 genes are associated with nonsyndromic hearing loss. In addition, more than 600 clinical syndromes include deafness and several of these have a gene identified as its cause; in many, deafness is the first presenting clinical feature. A thorough evaluation of the infant by a clinical geneticist helps rule out the more common syndromic forms of deafness such as Waardenburg syndrome, Branchio-Oto-Renal syndrome, etc.

This recent explosion in gene discovery for hearing loss is attributed to technological advances in massively parallel sequencing (MPS) also referred to as Next Generation Sequencing (NGS). Between 1995–2010, nearly 75 percent of the genes were identified using the more traditional methods such as linkage and homozygosity mapping, however since 2010, an additional 25 percent of genes have been identified in the short span, emphasizing the impact of these newer technologies in enhancing gene discovery (Atik et al, 2015).

A history of deafness segregating through maternal relatives should raise suspicion about mitochondrial inheritance and mutations in the MT-RNR1 (12SrRNA) mitochondrial gene predisposing to aminoglycoside ototoxicity. Molecular screening for mutations in the mitochondrial gene is offered, especially to infants from high-risk ethnic groups. A prior knowledge of this mutation in an infant or pregnant mother would allow prevention of hearing loss by avoiding nonjudicious use of aminoglycoside antibiotics.

The extreme genetic heterogeneity for hearing loss has precluded comprehensive genetic testing that is cost effective and easily accessible. Until a few years ago, testing was limited to the more common genetic forms of HL including the GJB2, GJB6, and select mitochondrial genes. This no doubt was helpful in those families where a pathogenic mutation was identified, and it helped stop the diagnostic odyssey, offer precise genetic counseling and recurrence risks, and prevent onset of HL if a mitochondrial A1555G change was detected prior to administration of aminoglycoside antibiotics (Pandya and Arnos, 2006). 

With the advent and availability of technology using massively parallel DNA sequencing, it is now possible to interrogate most genes identified for syndromic and nonsyndromic hearing loss using large gene panels (Shearer et al, 2011). Such platforms and panels are offered through a few laboratories in the United States; however, there remains variability in the number and types of genes included on these panels (Jasper et al, 2015). In addition, prospective studies and literature review to assess the sensitivity of panels using MPS suggest an overall diagnostic rate of 42 percent, with higher yield if an individual has bilateral AR NSHL vs milder forms of HL (Shearer et al, 2013; Shearer and Smith, 2015). 

No doubt, the current platforms of gene panels have facilitated dramatic improvements in the diagnostic yield, but there remains the need for diagnostic panels that are more comprehensive and include genes implicated in both syndromic and nonsyndromic hearing loss. Although one can consider using whole exome sequencing (WES) in lieu of using targeted gene panels for hearing loss, considerations favoring the latter approach include the high cost, and the identification of secondary findings unrelated to the presenting phenotype with WES (Shearer et al, 2013). Not only does having an etiologic diagnosis for HL provide knowledge about the natural history, progression of HL, associated organ system involvement and precise recurrence risk, but in the near future it will form the basis for novel gene- or mutation-specific treatment options to ameliorate or treat genetic HL.


References

Atik T, Bademci G, Diaz-Horta O, Blanton SH, Tekin M. (2015) Whole-exome sequencing and its impact in hereditary hearing loss. Genetics Res 97:8.

Jasper KM, Jamshidi A, Reilly BK. (2015) Pediatric otolaryngology, molecular diagnosis of hereditary hearing loss: next-generation sequencing approach. Curr Opin Otolaryngol Head Neck Sur 23(6):480–484.

Kelsell DP, Dunlop J, Stevens HP, et al. (1997) Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 387(6628):80–83.

Morton CC, Nance WE. (2006) Newborn hearing screening—a silent revolution. New Eng J Med 354(20):2151–2164.

Pandya A, Arnos KS. (2006) Genetic evaluation and counseling in the context of early hearing detection and intervention. Sem Hear 27(3):205–212.

Shearer AE, Smith RJ. (2015) Massively parallel sequencing for genetic diagnosis of hearing loss: the new standard of care. Otolaryngol Head Neck Surg 153(2):175–182. 

Shearer AE, Black-Ziegelbein EA, Hildebrand MS, Eppsteiner RW, Ravi H, Joshi S, Guiffre AC, Sloan CM, Happe S, Howard SD, Novak B, Deluca AP, Taylor KR, Scheetz TE, Braun TA, Casavant TL, Kimberling WJ, Leproust EM, Smith RJ. (2013) Advancing genetic testing for deafness with genomic technology. J Med Gen 50(9):627–634.

Shearer AE, Hildebrand MS, Sloan CM Smith RJ. (2011) Deafness in the genomics era. Hear Res 282(1):1–9.

Age-Related Hearing Loss and Noise-Induced Hearing Loss—Old Problems and New Paradigms 

Lawrence R. Lustig, MD, and Howard W. Smith, Professor and Chair, Department of OtolaryngologyHead and Neck Surgery, Columbia University Vagelos College of Physicians and Surgeons, NewYork-Presbyterian/Columbia University Irving Medical Center

Presbycusis, or age-related hearing loss (ARHL), is a well-known phenomenon that will affect nearly every one of us. Forty percent of the hearing impaired are older than 65, and with our population aging every year, the number of people with ARHL will continue to increase. Studies in animal models, such as the C57 mouse, clearly have identified genetic factors associated with age-related hearing loss, where animals show loss of spiral ganglion neurons, hair cells, and other cellular structures within the cochlea. At least within the C57 mouse, the culprit seems to be a protein associated with the hair cell transduction channel, called cadhedrin 23. In contrast, large genome-wide associated studies have implicated proteins associated with spiral ganglion neurons as a possible cause of ARHL. Last, aging changes in mitochondria associated with specific genetic markers also have been associated with ARHL due to effects on the electron transport chain that lead to oxidative damage. 

Older hard-of-hearing asian woman and her daughter imageA seemingly different problem is noise-induced hearing loss (NIHL). Sounds exceeding 85 dB are potentially injurious to the cochlea, especially with prolonged exposure. Noise damage results in a number of injuries to the cochlea, including hair cells, while susceptibility to noise-induced hearing loss has been linked strongly to the efferent neuronal system within the cochlea. While it traditionally has been believed that hearing loss due to noise exposure does not progress once the exposure is discontinued, an accumulating body of research strongly suggests that early noise exposure predisposes to more accelerated age-related hearing loss and that even isolated “reversible” noise exposure can lead to significant neural damage. The increased prevalence of personal music systems and their ability to cause noise-induced hearing loss underscores the importance of this problem in society today.

Despite the growing body of evidence that noise-induced hearing loss accelerates age-related hearing loss, our treatments are still limited to hearing aids for mild to severe losses and cochlear implants for severe to profound losses. Newer technologies such as hybrid or electroacoustic stimulation that combine acoustic and electrical hearing are an additional option for some but are still limited by cochlear implant technology. However, with an improved understanding of the neurotrophic factors that allow spiral ganglion neuron regeneration and facilitate hair cell synapse formation, it is hoped that this can be exploited into new therapies to reverse the damage that is done by both noise exposure and age-related hearing loss. The current multicenter human gene therapy trial that is evaluating hair cell regeneration using the atoh 1 gene is the first step towards this goal of ultimately regenerating normal inner ear function.


Consulted References for ARC Presentation 

Ciorba A, Hatzopoulos S, Bianchini C, Aimoni C, Skarzynski H, Skarzynski PH. (2015) Genetics of presbycusis and presbystasis. Intl J Immunopathol Pharmacol 28:29–35.

Department of Labor, OSHA (1981). Occupational noise exposure: hearing conservation amendment. Fed Reg 46:4078–4180.

Dillon CF, Gu Q, Hoffman HJ, Ko CW. (2010) Vision, hearing, balance, and sensory impairment in Americans aged 70 years and over: United States, 1999–2006. NCHS Data Brief:1–8.

Fernandez KA, Jeffers PW, Lall K, Liberman MC, Kujawa SG. (2015) Aging after noise exposure: acceleration of cochlear synaptopathy in recovered ears. J Neuroscience 35:7509-20.

Gates GA, Cooper JC, Kannel WB, Miller NJ. (1990) Hearing in the elderly: the Framingham cohort, 1983–1985. Part I. Basic audiometric test results. Ear Hear 11:247–56.

Goman AM, Lin FR. (2016) Prevalence of hearing loss by severity in the United States. Am J Public Health 106:1820–1822.

Havlik R. (1986) Aging in the eighties: impaired senses for sound and light in persons age 65 years and over. Preliminary data from the supplement on aging to the National Health Interview Survey: United States, January–June 1984. Advance data from vital and health statistics, #125. Hyattsville, MD: National Center for Health Statistics, Publication no. DHHS (PHS) 86–1250.

Izumikawa M, Minoda R, Kawamoto K, Abrashkin KA, Swiderski DL, Dolan DF, Brough DE, Raphael Y. (2005) Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nature Med 11:271–276.

Kujawa SG, Liberman MC. (2015) Synaptopathy in the noise-exposed and aging cochlea: primary neural degeneration in acquired sensorineural hearing loss. Hear Res 330:191–199.

Liberman MC. (2017) Noise-induced and age-related hearing loss: new perspectives and potential therapies. F1000Research 6, 927.

Liberman MC, Kujawa SG. (2017) Cochlear synaptopathy in acquired sensorineural hearing loss: Manifestations and mechanisms. Hear Res 349:138–147.

Lin FR, Yaffe K, Xia J, Xue QL, Harris TB, Purchase-Helzner E, Satterfield S, Ayonayon HN, Ferrucci L, Simonsick EM, Health ABCSG. (2013) Hearing loss and cognitive decline in older adults. JAMA Intern Med 173:293–299.

Sakat MS, Kilic K, Bercin S. (2016) Pharmacological agents used for treatment and prevention in noise-induced hearing loss. Eur Arch Otorhinolaryngol 273:4089–4101.

Sliwinska-Kowalska M, Zaborowski K. (2017) WHO Environmental Noise Guidelines for the European Region: A Systematic Review on Environmental Noise and Permanent Hearing Loss and Tinnitus. Int J Environ Res Pub Health 14.

Sulkowski W, Owczarek K, Olszewski J. (2017) Contemporary noise-induced hearing loss (NIHL) prevention. Otolaryngol Pol 71:1–7.

Genetic Associations with Vestibular Disorders and Unilateral Hearing Loss 

Kelley Dodson, MD, FACS, Associate Professor, Residency Program Director, Pediatric Otolaryngology, Congenital and Genetic Hearing Loss, Otology, and General Otolaryngology, Virginia Commonwealth University, Richmond, Virginia

The genetics of vestibular dysfunction and unilateral hearing loss are an emerging area of active investigation. Embryologic development of the ear is complex and closely regulated by a number of genes. Defects in any of these processes may lead to hearing loss, vestibular dysfunction, or both. Outer and middle-ear development arises from the first and second branchial arches, while the inner ear arises from neuroepithelium from the otic placode. The vestibular portion of the inner ear is subdivided into the endolymphatic duct and sac, the vestibule (utricle and saccule), and the semicircular canals. 

Dizziness is one of the most common symptoms of aging and may be peripheral or central. Hereditary or familial vestibular disorders are often classified into those with and those without hearing loss; alternatively, they may be grouped into those which are episodic versus progressive. Those without hearing loss include familial vestibular migraine, familial episodic ataxias, and familial CANVAS. Those with hearing loss include familial Meniere’s disease, and genetic syndromic and non-syndromic hearing loss disorders associated with vestibular dysfunction including enlarged vestibular aqueduct syndrome, Usher syndrome, DNFA 9, DFNA 11 and DFNA 15. The most common form of autosomal recessive deafness, DFNB1, caused by mutations in Connexin 26, also may have vestibular components. 

Unilateral hearing loss affects up to 5 percent of school-aged children and can result in significant social, educational, and behavioral consequences. Longitudinal studies of children with unilateral hearing loss over time show continued areas of academic weakness and poor school performance. Up to 30 percent of infants with congenital unilateral hearing loss have a Joint Committee on Infant Hearing risk factor and co-occurring birth defects are not uncommon. The most common risk factors were craniofacial anomalies, family history of hearing loss, and stigmata of syndromes associated with hearing loss. Genetic studies of unilateral hearing loss have demonstrated sequence variants in common deafness genes, suggesting a possible gene-environmental interaction for this condition. In summary, both familial vestibular disorders and unilateral hearing loss are both areas of active investigation to study risk factors, genetic contributions, and potential treatment options. 


Consulted References for ARC Presentation 

Appelbaum EN, Howell JB, Chapman D, Pandya A, Dodson KM. (2018) Analysis of risk factors associated with unilateral hearing loss in children who initially passed newborn hearing screening. Int J Ped Otorhinolaryngol March.

Bisdorff A, Bosser G, Gueguen R, Perrin P. (2013) The epidemiology of vertigo, dizziness, and unsteadiness and its links to co-morbidities. Front Neurol 22(4):29. 

Dodson KM, Georgolios A, Barr N, Nguyen B, Sismanis A, Arnos KS, Norris VW, Chapman D, Nance WE, Pandya A. (2012) Etiology of unilateral hearing loss in a national hereditary deafness repository. Am J Otolaryngol 33(5):590–594.

Lieu JE, Tye-Murray N, Karzon RK, Piccirillo JF. (2010) Unilateral hearing loss is associated with worse speech-language scores in children. Peds 125(6):e1348–1355

Lieu JE, Tye-Murray N, Fu Q. (2012) Longitudinal study of children with unilateral hearing loss. Laryngoscope 122(9):2088–2095. 

Requena T, Espinosa-Sanchez JM, Lopez-Escamez JA. (2014) Genetics of dizziness: cerebellar and vestibular disorders. Curr Opin Neurol 27(1):98–104.

Roman-Naranjo P, Gallego-Martinez A, Lopez Escamez JA. (2018) Genetics of vestibular syndromes. Curr Opin Neurol 31(1):105–110.

Yelverton JC, Dominguez LM, Chapman DA, Wang S, Pandya A, Dodson KM. (2013) Risk factors associated with unilateral hearing loss. JAMA Otolaryngol Head Neck Surg139(1):59–63.

From Etiologic Diagnoses to Personalized Therapies for Hearing Loss 

Cynthia Casson Morton, PhD, William Lambert Richardson Professor of Obstetrics, Gynecology and Reproductive Biology and Professor of Pathology, Harvard Medical School, Boston, MA; Kenneth J. Ryan MD Distinguished Chair in Obstetrics and Gynecology and Director of Cytogenetics, Brigham and Women’s Hospital, Boston, MA; Chair in Auditory Genetics, Division of Evolution and Genomic Science, University of Manchester, Manchester Academic Health Science Centre, Manchester, England

Implementation of universal newborn hearing screening (UNHS) began in the United States in the 1990s (JCIH, 1994) with a goal of identifying all newborns with moderate-to-profound deafness through physiologic evaluations of auditory function in response to sound. The astonishing spread of universal programs to screen newborns for hearing throughout the world has truly been a revolution in health care. Early detection and habilitation of deafness through UNHS is notable for enormous personal, societal and economic benefit. Better hearing for persons of all nations is an achievable, important goal, given that a disabling hearing impairment affects about 4 percent of the world’s population, with two-thirds of such persons living in developing countries.

Infant hearing test imageEtiologies for congenital deafness are heterogeneous and include genetic and environmental causes (e.g., infectious, hypoxia, trauma, ototoxic medications), but genetic causes are the major contributor in developed countries (Morton and Nance, 2006). The prevalence of deafness is known to increase in childhood and has been attributed largely to an increasing percentage of environmental causes. For every 10 infants with permanent hearing loss at birth (1–2 per thousand), similar losses develop in another 5 to 9 children before the age of nine years. A portion of this increase represents children lost to follow up after not passing UNHS, and newborns with mild-to-moderate deafness. Clearly, certain limitations exist in current UNHS, among which is an etiologic diagnosis to empower personalized therapies.

Impressive improvements in molecular technologies in concert with expansion of genetic diagnoses and genetics-informed therapies have led to initiatives to address implementation of genomic sequencing into newborn screening. Application in UNHS for genetic deafness is of especial interest given the unparalleled genetic heterogeneity (>600 clinical syndromes with deafness) and lack of an etiologic focus in UNHS, which compromises optimal habilitation. In particular, early diagnosis of a syndromic form of deafness that appears as a form of congenital nonsyndromic deafness (e.g., Usher, Jervell, and Lange Nielsen) would be of great value. 

Due to its diagnostic rate, genetic testing is the first line test in evaluation of a child with bilateral sensorineural deafness. To address incorporating genetic screening into UNHS, several groups have studied the utility of limited panels of genes or variants to augment UNHS in large cohorts (Wu et al, 2017). In addition, the studies have variously included cytomegalovirus testing and follow up. A consistent finding is identification of a delayed onset of deafness in newborns who passed UNHS and who also have well-known pathogenic variants, accounting for a portion of the missing etiologies of childhood deafness. Although whole genome sequencing (WGS) (Shen and Morton, 2016) is an attractive future platform for facilitating diagnoses of congenital disorders including structural variants, a near term goal for implementation of genetic testing into UNHS for a specific population is likely to be a limited screen on a single platform with the most frequently encountered pathogenic variants.

SEQaBOO (Sequencing a Baby for an Optimal Outcome) Boston and SEQaBOO Manchester are sister pilot demonstration projects of implementing WGS in UNHS. Both projects will survey knowledge and attitudes about genetics and genomics in parents of newborns who did not pass UNHS, and will follow families with annual surveys to assess evolving parental knowledge and attitudes and the child’s health (hearing status and speech and language development). A goal of SEQaBOO Boston is to provide otologists genomic results at the one-month diagnostic audiology test for assessment of desired changes in medical management with genetic results at the initial encounter, while delivering standard-of-care management. SEQaBOO Manchester will inform families of potential eligibility to enroll in the 100K Genomes Project for WGS in the rare disease category.


References

Joint Committee on Infant Hearing. Position Statement. (1994) Accessed at www.jcih.org/JCIH1994.pdf.

Morton CC, Nance WE. (2006) Newborn hearing screening—a silent revolution. N Engl J Med 354:2151–2164.

Shen J, Morton CC. (2016) Next-generation newborn hearing screening. In: Vona B, Haaf T, eds. Monographs in Human Genetics: Genetics of Deafness, pp. 30–39.

Wu CC, Tsai CH, Hung CC, et al. (2017) Newborn genetic screening for hearing impairment: a population-based longitudinal study. Genet Med 19:6–12.

Conclusion

The theme of next year’s Academy Research Conference will be advances in amplification, focusing on the latest advances in the selection and fitting of hearing aids as well as evidence-based research as it relates to best practices and improvement in quality of life for all individuals living with hearing loss. ARC 2019 will be held on March 27 in Columbus, Ohio.