Newborn hearing concurrent gene screening can improve care for hearing loss: A study on 14,913 Chinese newborns

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Abstract

Objective

Newborn hearing screening has been widely adopted and made an achievement to some degree. Current screening protocols rely solely on detecting existing auditory disorders at the time of screening and are unable to identify individuals susceptible to auditory disorders in later life. Even if the hearing loss newborn is referred, most cases could not be diagnosed until 6–12 months old with no etiology being elucidated. This study reports the first effort to combine traditional hearing screening with genetic screening to improve the efficacy of newborn hearing screening.

Methods

This study was undertaken in 12 regional hospitals located in 11 provinces of China. 14,913 newborn babies received hearing concurrent genetic screening. The hearing screening was performed with OAE or AABR. Blood sample was collected with a universal newborn genetic screening card. And three common gene, mtDNA 12S rRNA, GJB2 and SLC26A4 were screened with standard protocol.

Results

Among all the 14,913 newborns, 86.1% (12,837/14,913) individuals passed the first-step hearing screening, 7.8% (1168/14,913) babies passed only one side, and the other 6.1% (908/14,913) were bilaterally referred. Gene screening found 306 individuals had one or two mutant alleles, the carrier rate is 2.05% (306/14,913) among the entire newborn population. The risk for hearing loss was 100% (7/7) for those newborns carrying causative GJB2 or SLC26A4 mutations (homozygotes or compound heterozygotes), 14.4% (23/160) for GJB2 heterozygote carriers, 12.3% (15/122) for SLC26A2 heterozygous carriers, and the total prevalence of referral hearing screening was approximately 14.7% (45/306). However, 85.3% (261/306) newborns passed hearing screening among these carriers including 18 newborns with 12S rRNA mt.1555A>G pathogenic mutation, who would suffer from sudden hearing loss once applying aminoglycoside drugs.

Conclusion

The cohort studies provided the essential population parameters for developing effective programs for hearing care of newborns in China. Hearing concurrent gene screening in newborns may confirm the abnormal results from hearing screening tests, help to find the etiologic of the hearing loss, and better recognize infants at risk for late-onset hearing loss occurring prior to speech and language development. In conclusion, a survey on 14,913 Chinese newborns proved that concurrent genetic screening could improve newborn hearing screening for hearing defects.

Introduction

With the implementation of universal newborn hearing screening, retrospective evaluation of the audiological/physiological screening programs for newborns and prelingual children reveals that the causative factors and incidence of hearing loss in children have evolved considerably over the ages and are ethnic-specific. In England, the reported incidence of hearing loss (defined as moderate to profound bilateral hearing loss, typically a pure tone average of 50 dB hearing level or worse) is 1.33 per 1000 newborns [1], [2], while the figure, when also including mild to moderate bilateral hearing loss in addition to unilateral hearing loss, is 1.86 per 1000 newborns in United States of America [3]. The prevalence of permanent sensorineural hearing loss continues to increase during childhood and reaches a rate of about 2.7 per 1000 children before the age of five years and 3.5 per 1000 during adolescence [2], [4], [5]. Therefore, the existing universal audiological screening programs have limitations in identifying some forms of hearing loss [6], [7], [8] such as cytomegalovirus-induced hearing loss [9], nonsyndromic hearing impairment of autosomal dominant inheritance [10], enlarged vestibular aqueduct syndrome (EVA) [11], [12], mtDNA 12S rRNA 1555A>G induced cases, where evidence of hearing impairment is only gradually salient after birth, i.e., a delayed onset of hearing disorder [13], [14], [15]. An additional limitation in most existing newborn hearing screen programs is a lack of focus on etiology, especially on screening for the known genetic causes of hearing loss. All of these challenges urged the introduction of genetic testing in the newborns as a critical complement to the traditional audiological screening as suggested by Morton and Nance [5].

In China, there are about 0.8 million children of <7 years whose hearing is disabled, and this number continues to grow with an increase of more than 30,000 deaf children annually. Previous epidemiological studies indicate that among the hearing impaired Chinese children, at least 36% cases were resulted from GJB2, SLC26A4 or mtDNA 12S rRNA mutations (mtDNA 12S rRNA, 3.96% [16]; SLC26A4, 13.73% [17]; GJB2, 18.31% [17]). GJB2 is the most common gene related to hearing loss. Most cases resulting from GJB2 mutations were of profound hearing loss, however, mild and progressive hearing loss was found to be associated with a substantial number of cases with GJB2 mutations [7], [18]. Mutations in SLC26A4 are associated with enlarged vestibular aqueduct syndrome (EVA), hearing loss will be found at birth or in early childhood. Individuals with mtDNA 12S rRNA mutation are aminoglycoside-sensitive, and inadvertent exposure to this drug may cause late-onset hearing loss although the individuals passed the initial newborn hearing screen [19], [20]. Therefore, for early disclosure of genetic causes leading to late-onset or aminoglycoside-sensitive hearing loss and identification of carriers with pathogenic mutation, integration of genetic tests into the current hearing screening programs is essential for maintaining hearing health of Chinese children who are most vulnerable to both genetic and environmental risk exposures. In this report, we first thoroughly analyzed the universal newborn hearing and the newly developed genetic screening conducted in 11 provinces of China and then, we proposed several strategies for improving the concurrent audiological and genetic testing based on the practical evidence from the largest population in the world.

Section snippets

Study design and subject recruitment

This study was a multi-centre and large-scale genetic epidemiological study, conducted from May 2007 to May 2009. Newborn infants were recruited from 11 provincial jurisdictions, including Beijing, Gansu, Fujian, Guangdong, Hubei, Liaoning, Henan, Chongqing, Guangxi, Xinjiang and Yunnan, as shown in Fig. 1. A total of 12 regional maternal and children's health or general hospitals were organized into a nation-wide consortium for newborn hearing and genetic screening, named as Newborn Gene

Demographic characteristics and risk exposures for the large-scale cohort

A total of 14,913 newborns received audiological and genetic tests. The demographic characteristics and risk exposures for this cohort are given in Table 1. In this cohort of newborns, there were more males than females, with a gender ratio of 1.24:1.00. The majority of these newborns were Hans (87.53%) and Zhuang (6.71%), and the others were from 28 ethnical minorities, and taking up 5.75% of the sample size. A list of environmental risk factors were identified, with hyperbilirubinemia (883

Discussion

This study is the first largest nation-wide clinical-genetic survey so far conducted in China. In the newborn hearing screening, genetic tests of three common hearing loss genes were efficiently integrated. This large-scale study indicated that the conventional newborn hearing screening program for newborns could be improved greatly by adding the genetic component. First, genetic tests could immediately confirm hearing impaired babies referred by conventional hearing screening test and

Contributors

QJ Wang contributed to the concept, design and preparing manuscript of the study. YL Zhao, SQ Rao, YF Guo, L Lan, Y He, QY Zheng and the NGCHS Study Team involved in the acquisition of data. QJ Wang, YL Zhao, SQ Rao, WY Yang, RJ Ruben, DY Han and Y Shen contributed to the analysis and interpretation of data. All authors critically reviewed the report and approved the final version of the report for submission.

Conflicts of interest

We declare that we have no conflicts of interest.

Acknowledgements

The authors thank AI YOU HUA-XIA Charity Foundation and Audiological Development Foundation of China for their support in the program, Cindy Benedict-Alderfer for her helpful comments on the manuscript. This study was supported partially by the grant (No. 2006AA028Z181 to Dr. Wang) from the Chinese National High Tech Development Project; by a grant from a National Natural Science Foundation of China, Key Project (No. 30830104 to Dr. Wang); by grants from the National Natural Science Foundation

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