A focus group study of consumer attitudes toward genetic testing and newborn screening for deafness.

PURPOSE: Progress in identifying genes for deafness together with implementation of universal audiologic screening of newborns has provided the opportunity for more widespread use of molecular tests to detect genetic forms of hearing loss. Efforts to assess consumer attitudes toward these advances have lagged behind. METHODS: Consumer focus groups were held to explore attitudes toward genetic advances and technologies for hearing loss, views about newborn hearing screening, and reactions to the idea of adding molecular screening for hearing loss at birth. Focus group discussions were recorded, transcribed and analyzed. RESULTS: Five focus groups with 44 participants including hearing parents of deaf children, deaf parents and young deaf adults were held. Focus group participants supported the use of genetic tests to identify the etiology of hearing loss but were concerned that genetic information might influence reproductive decisions. Molecular newborn screening was advocated by some; however, others expressed concern about its effectiveness. CONCLUSION: Documenting the attitudes of parents and other consumers toward genetic technologies establishes the framework for discussions on the appropriateness of molecular newborn screening for hearing loss and informs specialists about potential areas of public education necessary prior to the implementation of such screening.     

A proposal for comprehensive newborn hearing screening to improve identification of deaf and hard-of-hearing children

Early intervention for newborns who are deaf or hard-of-hearing leads to improved language, communication, and social–emotional outcomes. Universal physiologic newborn hearing screening has been widely implemented across the United States with the goal of identifying newborns who are deaf or hard-of-hearing, thereby reducing time to diagnosis and intervention. The current physiologic newborn hearing screen is generally successful in accomplishing its goals but improvements could be made. In the past ten years, genetic testing has emerged as the most important etiological diagnostic test for evaluation of children with deafness and congenital cytomegalovirus has been recognized as a major cause of childhood deafness that may be treatable. A comprehensive newborn hearing screen that includes physiologic, genetic, and cytomegalovirus testing would have multiple benefits, including (1) identifying newborns with deafness missed by the current physiologic screen, (2) providing etiologic information, and (3) possibly decreasing the number of children lost to follow up. We present a framework for integrating limited genetic testing and cytomegalovirus screening into the current physiologic newborn hearing screening. We identify needed areas of research and include an overview of genome sequencing, which we believe will become available over the next decade as a complement to universal physiologic newborn hearing screening.     

Do parental perceptions and motivations towards genetic testing and prenatal diagnosis for deafness vary in different cultures?

Surveys of attitudes of individuals with deafness and their families towards genetic testing or prenatal diagnosis have mostly been carried out in the West. It is expected that the perceptions and attitudes would vary amongst persons of different cultures and economic background. There is little information on the prevailing attitudes for genetic testing and prenatal diagnosis for deafness in developing countries. Therefore, this study evaluates the motivations of Indian people with inherited hearing loss towards such testing. Twenty‐eight families with history of congenital hearing loss (23 hearing parents with child/family member with deafness, 4 couples with both partners having deafness and 1 parent and child with deafness) participated in a semi‐structured survey investigating their interest, attitudes, and intentions for using genetic and prenatal testing for deafness. Participants opinioned that proper management and care of individuals with deafness were handicapped by limited rehabilitation facilities with significant financial and social burden. Nineteen (68%) opted for genetic testing. Twenty‐six (93%) expressed high interest in prenatal diagnosis, while 19 (73%) would consider termination of an affected fetus. Three hearing couples, in whom the causative mutations were identified, opted for prenatal diagnosis. On testing, all the three fetuses were affected and the hearing parents elected to terminate the pregnancies. This study provides an insight into the contrasting perceptions towards hearing disability in India and its influence on the desirability of genetic testing and prenatal diagnosis. © 2012 Wiley Periodicals, Inc.     

Frequency of Usher syndrome in two pediatric populations: Implications for genetic screening of deaf and hard of hearing children

PurposeUsher syndrome is a major cause of genetic deafness and blindness. The hearing loss is usually congenital and the retinitis pigmentosa is progressive and first noticed in early childhood to the middle teenage years. Its frequency may be underestimated. Newly developed molecular technologies can detect the underlying gene mutation of this disorder early in life providing estimation of its prevalence in at risk pediatric populations and laying a foundation for its incorporation as an adjunct to newborn hearing screening programs.MethodsA total of 133 children from two deaf and hard of hearing pediatric populations were genotyped first for GJB2/6 and, if negative, then for Usher syndrome. Children were scored as positive if the test revealed ≥1 pathogenic mutations in any Usher gene.ResultsFifteen children carried pathogenic mutations in one of the Usher genes; the number of deaf and hard of hearing children carrying Usher syndrome mutations was 15/133 (11.3%). The population prevalence was estimated to be 1/6000.ConclusionUsher syndrome is more prevalent than has been reported before the genome project era. Early diagnosis of Usher syndrome has important positive implications for childhood safety, educational planning, genetic counseling, and treatment. The results demonstrate that DNA testing for Usher syndrome is feasible and may be a useful addition to newborn hearing screening programs.     

听力筛查联合遗传性耳聋基因检测在新生儿筛查中的应用

目的 探讨听力筛查联合遗传性耳聋基因检测在新生儿筛查中的应用。方法 选取2018年12月~2019年7月我院接受产检的产妇509例,对所有产妇进行遗传性耳聋基因检测,并在产妇完成分娩后48 h对新生儿作常规听力筛查,确诊新生儿是否存在听力障碍。结果 509例产妇经遗传性耳聋基因检测显示阳性16例,阳性率3.14%;听力筛查不通过同时伴有耳聋基因突变新生儿共5例,听力学诊断结合随访确诊3例新生儿存在听力障碍,包含1例GJB2 299-300delAT突变,1例GJB2 235delC突变、1例SLC26A4 919-2A＞G突变。结论 在新生儿常规听力筛查的同时提供遗传性耳聋基因检测,能够有效弥补听力筛查的不足,可用作听力筛查工作的有效补充,有助于筛查出迟发型及潜在性耳聋患儿,提升听力障碍的检出率。     

Study of the etiology of deafness in an institutionalized population in Colombia.

To identify causative factors we screened 1,715 deaf individuals from 16 schools for the deaf in Colombia. We found evidence of environmental causation in 579 (33.8%) cases, genetic in 608 (35.4%), and in 528 (30.8%) we were unable to identify the etiology. The degree of hearing loss was severe to profound in 1,238 (72.2%), although in 987 (57.5%) of the deaf population studied the hearing impairment was not noticed until 2 to 5 years of age. The frequent association of deafness with other anomalies underscores the importance of a careful clinical and ophthalmologic evaluation in individuals with hearing loss. Our observations also emphasize the need for programs directed towards the prevention of hearing loss, including primary prevention as well as early diagnosis, investigation of possible genetic causes, and rehabilitation of deaf individuals.     

Study of the etiology of deafness in an institutionalized population in colombia

To identify causative factors we screened 1,715 deaf individuals from 16 schools for the deaf in Colombia. We found evidence of environmental causation in 579 (33.8%) cases, genetic in 608 (35.4%), and in 528 (30.8%) we were unable to identify the etiology. The degree of hearing loss was severe to profound in 1,238 (72.2%), although in 987 (57.5%) of the deaf population studied the hearing impairment was not noticed until 2 to 5 years of age. The frequent association of deafness with other anomalies underscores the importance of a careful clinical and ophthalmologic evaluation in individuals with hearing loss. Our observations also emphasize the need for programs directed towards the prevention of hearing loss, including primary prevention as well as early diagnosis, investigation of possible genetic causes, and rehabilitation of deaf individuals.     

Importance of congenital cytomegalovirus infections as a cause for pre-lingual hearing loss.

BACKGROUND: No large population based studies of newborn hearing screening have reported the population frequency of more than one specific form of deafness. OBJECTIVES: To combine available data on the overall incidence of pre-lingual deafness with estimates for specific causes to gain insight into age-related changes in the prevalence of the major causes of pre-lingual deafness. STUDY DESIGN: The incidence of deafness in England was adjusted for the exclusion of unilateral losses to obtain an overall estimate of 1.86 per 1000 births in the United States. Longitudinal data were used to estimate that the prevalence rises to 2.70 per 1000 at age 4. The genetic component was estimated sentinel phenotype analysis, and studies of single entities were integrated to estimate the prevalence of specific causes. RESULTS AND CONCLUSIONS: Congenital CMV infections and connexin mutations are the two major causes of deafness at birth, while causes for enlarged vestibular aqueduct along with congenital CMV infection are the major causes of pre-lingual hearing loss that is not expressed at birth. By molecular screening tests on newborn blood spots for four known causes, 60% of the infants who develop late onset pre-lingual hearing loss could be identified at birth.     

Performance of cochlear implant recipients with GJB2-related deafness

Congenital profound hearing loss affects 0.05-0.1% of children and has many causes, some of which are associated with cognitive delay. For prelingually-deafened cochlear implant recipients, the etiology of deafness is usually unknown. Mutations in GJB2 have been established as the most common cause of heritable deafness in the United States. In this report, we identify cochlear implant recipients with GJB2-related deafness and examine the performance of these individuals. Cochlear implant recipients received a battery of perceptive, cognitive, and reading tests. Neither subjects nor examiners knew the etiology of deafness in these individuals. The implant recipients were then examined for mutations in GJB2 using an allele-specific polymerase chain reaction assay, single-strand conformation polymorphism analysis, and direct sequencing. GJB2 mutations were the leading cause of congenital deafness among the cochlear implant recipients screened. Cochlear implant recipients with GJB2-related deafness read within one standard deviation of hearing controls better than other congenitally deaf cochlear implant recipients and non-cochlear implant recipients. Individuals with congenital deafness should be offered GJB2 screening. Positive results establish an etiologic diagnosis and provide prognostic, genetic, and therapeutic information. Effective rehabilitation for profoundly deaf individuals with GJB2-related deafness is possible through cochlear implantation.     

Evaluation of newborn screening bloodspot-based genetic testing as second tier screen for bedside newborn hearing screening

PurposeBedside newborn hearing screening is highly successful in identifying deaf or hard-of-hearing infants. However, newborn hearing screening protocols have high loss to follow-up rates. We propose that bloodspot-based genetic testing for GJB2 alleles can provide a means for rapid confirmation in a subset of infants who fail bedside newborn hearing screening.MethodsWe performed a case-control study comparing the prevalence of common GJB2 mutations from deidentified bloodspots designated as “refer” by newborn hearing screening and contemporaneously selected randomly chosen controls designated as “pass.” Between March 2006 and December 2007, 2354 spots were analyzed for common alleles, c.35delG, c.167delT, c.235delC, and p.V37I in GJB2 with a subset reanalyzed by conventional Sanger sequencing to search for additional alleles.ResultsThe prevalence of biallelic GJB2 mutations in bloodspots from infants who referred by newborn hearing screening is approximately 1 in 50 (23/1177). In contrast, one bloodspot from an infant who passed newborn hearing screening was identified to harbor biallelic GJB2 mutations.ConclusionsThese findings show that when a newborn refers by newborn hearing screening, there is a significant chance that GJB2-related hearing loss is present. Bloodspot-based genetic testing for common GJB2 alleles should be considered as second tier testing for bedside newborn hearing screening.     

Performance of cochlear implant recipients with GJB2‐related deafness

Congenital profound hearing loss affects 0.05–0.1% of children and has many causes, some of which are associated with cognitive delay. For prelingually‐deafened cochlear implant recipients, the etiology of deafness is usually unknown. Mutations in GJB2 have been established as the most common cause of heritable deafness in the United States. In this report, we identify cochlear implant recipients with GJB2‐related deafness and examine the performance of these individuals. Cochlear implant recipients received a battery of perceptive, cognitive, and reading tests. Neither subjects nor examiners knew the etiology of deafness in these individuals. The implant recipients were then examined for mutations in GJB2 using an allele‐specific polymerase chain reaction assay, single‐strand conformation polymorphism analysis, and direct sequencing. GJB2 mutations were the leading cause of congenital deafness among the cochlear implant recipients screened. Cochlear implant recipients with GJB2‐related deafness read within one standard deviation of hearing controls better than other congenitally deaf cochlear implant recipients and non‐cochlear implant recipients. Individuals with congenital deafness should be offered GJB2 screening. Positive results establish an etiologic diagnosis and provide prognostic, genetic, and therapeutic information. Effective rehabilitation for profoundly deaf individuals with GJB2‐related deafness is possible through cochlear implantation. © 2002 Wiley‐Liss, Inc.     

聋人婚前耳聋基因检测及婚配生育情况调查分析

目的了解婚前聋人基因检测及婚配生育情况,为预防耳聋提供依据。方法对自愿接受基因检测的情侣耳聋基因突变进行检测。结果聋人婚配模式是15对聋人与聋人婚配的9对占60％;聋人与健听人婚配占26．67％;聋人与重听人结婚的占13．33％。其中9对聋与聋在婚前进行遗传咨询占60．O％,接受致聋基因检测的仅有3对占20．0％。生育正常12例后代,1例听力正常的女孩为GJB2235delc杂合突变携带者,1例男婴,重度耳聋为SLC26A4IVS7—2A〉G杂合突变。结论婚前进行常见耳聋基因检测,是对耳聋预防与出生缺陷干预的有效措施。     

A sensitive and specific diagnostic test for hearing loss using a microdroplet PCR‐based approach and next generation sequencing

Implementing DNA diagnostics in clinical practice for extremely heterogeneous diseases such as hearing loss is challenging, especially when attempting to reach high sensitivity and specificity in a cost‐effective fashion. Next generation sequencing has enabled the development of such a test, but the most commonly used genomic target enrichment methods such as hybridization‐based capture suffer from restrictions. In this study, we have adopted a new flexible approach using microdroplet PCR‐based technology for target enrichment, in combination with massive parallel sequencing to develop a DNA diagnostic test for autosomal recessive hereditary hearing loss. This approach enabled us to identify the genetic basis of hearing loss in 9 of 24 patients, a success rate of 37.5%. Our method also proved to have high sensitivity and specificity. Currently, routine molecular genetic diagnostic testing for deafness is in most cases only performed for the GJB2 gene and a positive result is typically only obtained in 10–20% of deaf children. Individuals with mutations in GJB2 had already been excluded in our selected set of 24 patients. Therefore, we anticipate that our deafness test may lead to a genetic diagnosis in roughly 50% of unscreened autosomal recessive deafness cases. We propose that this diagnostic testing approach represents a significant improvement in clinical practice as a standard diagnostic tool for children with hearing loss. © 2012 Wiley Periodicals, Inc.     

Newborn genetic screening for hearing impairment: a population-based longitudinal study

PurposeThe feasibility of genetic screening for deafness-causing mutations in newborns has been reported in several studies. The aim of this study was to investigate the long-term results in those who screened positive for deafness mutations; these results are crucial to determine the cost-effectiveness to justify population-wide genetic screening.MethodsWe performed simultaneous hearing screening and genetic screening targeting four common deafness mutations (p.V37I and c.235delC of GJB2, c.919-2A>G of SLC26A4, and the mitochondrial m.1555A>G) in 5173 newborns at a tertiary hospital between 2009 and 2015. Serial audiometric results up to 6 years old were then analyzed in children with conclusive genotypes.ResultsNewborn genetic screening identified 82 (1.6%) babies with conclusive genotypes, comprising 62 (1.2%) with GJB2 p.V37I/p.V37I, 16 (0.3%) with GJB2 p.V37I/c.235delC, and 4 (0.1%) with m.1555A>G. Of these, 46 (56.1%) passed hearing screening at birth. Long-term follow-up demonstrated progressive hearing loss in children with the GJB2 p.V37I/p.V37I and p.V37I/c.235delC genotypes; this hearing loss deteriorated by approximately 1 decibel hearing level (dBHL) per year.ConclusionsWe delineated the longitudinal auditory features of the highly prevalent GJB2 p.V37I mutation on a general population basis and confirmed the utility of newborn genetic screening in identifying infants with late-onset or progressive hearing impairment undetectable by newborn hearing screening.     

Infant hearing loss and connexin testing in a diverse population

PurposePrevious studies of connexin-related hearing loss have typically reported on mixed age groups or adults. To further address epidemiology and natural history of connexin-related hearing loss, we conducted a longitudinal study in an ethnically diverse cohort of infants and toddlers under 3 years of age. Our study compares infants with and without connexin-related hearing loss to examine differences in the prevalence of connexin and non-connexin-related hearing loss by ethnic origin, detection by newborn hearing screening, phenotype, neonatal risk factors, and family history. This is the first study to differentiate infants with and without connexin-related hearing loss.MethodsWe enrolled 95 infants with hearing loss from whom both exons of Cx26 were sequenced and the Cx30 deletion was assayed. Demographic, family history, newborn hearing screening data, perinatal, and audiologic records were analyzed.ResultsGenetic testing identified biallelic Cx26/30 hearing loss-associated variants in 24.7% of infants with a significantly lower prevalence in Hispanic infants (9.1%). Eighty-two infants underwent newborn hearing screening; 12 infants passed, 3 had connexin-related hearing loss. No differences in newborn hearing screening pass rate, neonatal complications, or hearing loss severity were detected between infants with and without connexin-related hearing loss. Family history correlates with connexin-related hearing loss.ConclusionsConnexin-related hearing loss occurs in one quarter of infants in an ethnically diverse hearing loss population but with a lower prevalence in Hispanic infants. Not all infants with connexin-related hearing loss fail newborn hearing screening. Family history correlates significantly with connexin-related hearing loss. Genetic testing should not be deferred because of newborn complications. These results will have an impact on genetic testing for infant hearing loss.     

33911例新生儿听力联合耳聋基因筛查及随访结果的分析

目的通过分析新生儿听力联合耳聋基因筛查的结果,以及对阳性病例的随访和管理,提高遗传性耳聋的检出率。方法收集33911例新生儿听力联合耳聋基因筛查的结果,应用Sanger测序对听力未通过或基因筛查提示阳性的患儿进行验证。结果听力初筛通过率为93.32%,复筛为87.01%。耳聋基因筛查阳性率为4.18%。GJB2、SLC26A4、GJB3和12SrRNA基因变异的检出率分别为1.98%、1.58%、0.37%和0.25%。共检出126例迟发性耳聋,84例药物性耳聋,4例GJB2纯合/复合杂合变异,5例SLC26A4纯合/复合杂合变异。联合筛查发现GJB2、SLC26A4、GJB3和12SrRNA单杂合变异者听力初筛和复筛未通过的比例分别为6.75%和2.61%、3.3%和1.2%、0.72%和0.14%、0.36%和0%。纯合/单基因复合杂合变异、单基因杂合变异、多基因复合杂合以及GJB3纯合变异组听力筛查未通过率明显高于阴性组,差异具有统计学意义。结论基因检测是对新生儿听力筛查很好的补充。对阳性患儿的追踪管理能够有效提高耳聋的诊断率,但基因筛查不能等同于诊断,应综合分析基因检测、听力筛查和影像学的结果,Sanger/二代测序可作为重要的补充检查手段。     

Fitness Among Individuals with Early Childhood Deafness: Studies in Alumni Families from Gallaudet University

The genetic fitness of an individual is influenced by their phenotype, genotype and family and social structure of the population in which they live. It is likely that the fitness of deaf individuals was quite low in the Western European population during the Middle Ages. The establishment of residential schools for deaf individuals nearly 400 years ago resulted in relaxed genetic selection against deaf individuals which contributed to the improved fitness of deaf individuals in recent times. As part of a study of deaf probands from Gallaudet University, we collected pedigree data, including the mating type and the number and hearing status of the children of 686 deaf adults and 602 of their hearing siblings. Most of these individuals had an onset of severe to profound hearing loss by early childhood. Marital rates of deaf adults were similar to their hearing siblings (0.83 vs. 0.85). Among married individuals, the fertility of deaf individuals is lower than their hearing siblings (2.06 vs. 2.26, p = 0.005). The fitness of deaf individuals was reduced (p = 0.002). Analysis of fertility rates after stratification by mating type reveals that matings between two deaf individuals produced more children (2.11) than matings of a deaf and hearing individual (1.85), suggesting that fertility among deaf individuals is influenced by multiple factors.     

Estimated number of loci for autosomal recessive severe nerve deafness within the Israeli Jewish population,with implications for genetic counseling

Deafness occurs in about 1 per thousand live births, and at least 50% of congenital deafness is hereditary. The aim of this study was to examine the number of loci for recessively in herited severe nerve deafness of early onset within the Israeli population and to compare the results to those obtained in other populations. The Jewish population in Israel originates from many countries and may be divided into Sephardi, Eastern and Ashkenazi Jews, and the matings will be intraethnic or interethnic. Data were obtained on 133 deaf couples who lived in the Tel Aviv area, through the files of the Helen Keller Center. Causes of deafness in the spouses were studied and data on their children were obtained. Among 111 couples who had recessive or possibly recessive deafness and had at least 1 child, there were 12 with only deaf children and 5 with both deaf and hearing children. The number of loci for recessive deafness in the whole group was estimated at 8–9. Intraethnic and interethnic matings gave an estimate of 6.7 and 22.0 loci, respectively, which indicates that within populations fewer loci exist with recessive mutations for deafness than between populations. it could be shown that the sharing of loci between spouses decreased with increasing geographical distance of their origin. The results provide data for genetic counseling in Israel for deaf couples who have no children or have one hearing or one deaf child.     

遗传性非综合征型耳聋的临床实践指南

遗传因素是非综合征型聋常见的致病原因。随着分子检测技术的发展和日臻成熟,基因诊断和遗传咨询越来越多地影响着耳聋的临床实践。新生儿听力筛查的普及有助于耳聋的早期发现,耳聋基因筛査和诊断的普及有助于明确其病因,临床基因诊断和遗传咨询则有助于耳聋的早期干预。至今发现的非综合征型聋的致病基因有110个,鉴定其致病基因在临床上仍存在很多挑战。临床遗传咨询和产前诊断的开展,对耳聋基因检测和数据解读提出了更高的要求。本指南阐述了非综合征型耳聋的人群发病率、致病基因谱、遗传方式、疾病发展过程、临床表现、基因型-表型对应关系、基因诊断、治疗和干预,以及耳聋预防和再发风险评估等关键问题,为遗传咨询师、临床耳科医师及基因检测专业人员提供指导。