Neonatal Screening; deafness gene; mutation; genetic counseling [Abstract] Since 2012, the Neonatal Screening Program has been implemented in Beijing. The genetic screening program has been implemented since 2012. It can detect patients with hereditary deafness, effectively ensure and advance the diagnosis of hereditary deafness, and reduce the occurrence of deafness by avoiding the triggering factors. We will also identify a large number of deafness carriers and use the genetic counseling clinic as a position to provide guidance to carriers and family members on marriage and childbirth. The implementation of the combined newborn hearing and deafness genetic screening will definitely contribute to the reduction of deafness in China. [Abstract] Government-funded universal newborn genetic analyses of deafness predisposing genes in Beijing began in 2012, which has led to earlier It is more effective since the etiologies of the hearing deficits are known. identification of deafness gene for individuals can help them by avoiding situations that might lead to damage the function of hearing organs, and The combination of genetic and audiological screening can play an important role in deafness detections of Genetic screening provides useful and targeted information to aid in genetic counseling. ”Newborn screening” is a technical term used to describe testing that begins within hours or days of birth and whose results can be used to indicate and prevent serious illness, including death. In the 1990s, the United States passed legislation to implement universal newborn hearing screening (UNHS) nationwide and to develop an early hearing detection and intervention (EHDI) program to address hearing disabilities and the speech disorders they cause. intervention, EHDI), and our government also affirmed guidance and regulation of UNHS in 2000 in the form of the Maternal and Child Health Law of the People’s Republic of China, which is now widely implemented nationwide. In addition, screening for metabolic diseases, common deafness genes and other genetic disorders using neonatal pedal blood films is commonly used worldwide. Since 2012, the Beijing Newborn Deafness Genetic Screening Program has been implemented. Genetic screening can identify patients with hereditary deafness, effectively ensure and advance the time of diagnosis of hereditary deafness, and slow down and reduce the occurrence of deafness by avoiding predisposing factors; it can identify carriers of drug-sensitive deafness genes and prevent deafness by using medication warnings; scientifically develop hearing follow-up plans to avoid hearing loss during speech development We can identify a large number of deafness gene carriers and use the genetic counseling clinic as a position to provide guidance to carriers and family members on marriage and childbirth. The implementation of the combined newborn hearing and deafness genetic screening will definitely make a positive contribution to the reduction of deafness disability in China. 1. Study on genetic screening of newborn deafness and genetic outpatient consultation in Beijing Hospital Research on genetic deafness in Beijing Hospital started in the 1990s and gradually carried out genetic etiological diagnosis in the deaf population [1,2]. Since the operation of the newborn deafness genetic screening laboratory and the opening of a special deafness genetic counseling clinic in 2012, the significance of genetic screening combined with hearing screening results combined with genetic counseling has been practiced and demonstrated in microarray screening for common hotspot mutations and interpreting reports, giving counseling and advice [3,4]. 1.1 Study sample. The study sample was subject to the following conditions: a total of 49396 heel blood slices of newborns randomly distributed by the Beijing Municipal Health and Family Planning Commission to the genetic screening laboratory of Beijing Hospital for genetic locus distribution analysis from March 2012 to May 2015. Newborns carrying mutations in deafness genetic screening and who came to the genetic clinic for consultation were selected for further follow-up, and a total of 1212 cases were screened for hearing follow-up and genetic consultation significance study. Male: female was 580 cases: 632 cases, and the follow-up period was 4 to 36 months. 1.2 Study method. The crystal core 9 genetic deafness gene test microarray kit (Boao Biological Co., Ltd.) was selected to screen for 9 hotspot mutations in 4 genes commonly found in the national population, including GJB2 gene (35delG, 176dell6, 235delC, 299delAT), GJB3 gene (538CT), SLC26A4 gene (IVS7-2AG, 2168AG), and the mitochondrial DNA 12SrRNA gene (1555AG, 1494CT). All positive results were verified by sequencing. Audiological evaluation included analysis of hearing screening results, hearing diagnosis and long-term follow-up of hearing. Diagnostic audiometry included brainstem auditory evoked potentials (ABR), distortion product otoacoustic emissions (DPOAE), multifrequency steady-state evoked potentials (ASSR)/frequency-specific ABR (fsCABR) and 1000 Hz tympanic chamber acoustic conductance to rule out abnormal middle ear functional status. The timing of audiological diagnosis is as follows: (1) schedule audiological evaluation and diagnosis at 3 months of age, when the deafness genetic screen is clear that two mutation loci are carried simultaneously (including compound heterozygotes carrying mutations at two loci on the same gene; also including newborn individuals carrying one mutation on each of two different genes) and mutation carriers who fail the audiological screen; (2) recommend audiological evaluation and diagnosis at 8 to 10 months of age. Newborns with a single disease-causing mutation that is suggested by deafness genetic screening and who pass the hearing screening. The first hearing follow-up is required once/year for normal newborns, and parents are advised to pay close attention to their hearing and speech development and to seek medical consultation if there is any abnormality. Genetic counseling provides the greatest convenience to those who have not passed the genetic screening for newborn deafness, as reflected by the opening of a special genetic counseling unit and the opening of a convenient extra number to ensure access to the target group. The study will follow the principles of “respect, privacy and individualization” to predict the likelihood of deafness and the risk of deafness in family members, and to provide methods of prevention. 1.3 Study results. A total of 2262 (4.58%) of the 49396 newborn blood film samples were screened for carrying at least one pathogenic mutation in the screened deafness gene. These included 2206 cases carrying a single autosomal single locus, namely GJB235delG in 9 cases, 176del16 in 58 cases, 235delC in 900 cases, 299delAT in 218 cases, GJB3538CT in 175 cases, SLC26A42168AG in 125 cases, and SLC26A4IVS7-2AG in 603 cases. There were 110 cases of 1555AG and 8 cases of 1494CT in mitochondrial DNA 12SrRNA gene; in addition, 10 cases of pure mutations and 5 cases of compound heterozygous mutations in GJB2 gene; 1 case of pure mutation in GJB3 gene; 1 case of pure mutation in SLC26A4 IVS7-2AG were found. There were 39 cases carrying two different mutation loci at the same time. In an individual study of the deafness gene carriage rate in the neonatal population (repeated counts of samples carrying multiple loci), GJB2 mutation carriage was the highest at 2.50% (1236/49396), followed by SLC26A4 (carriage rate 1.52%; 752/49396), GJB3 (carriage rate 0.37%, 185/49396) and mitochondrial drug deafness gene carriers (0.26%, 128/49396). A total of 492 newborns were confirmed to have normal hearing after completion of the objective hearing examination and were included in the long-term follow-up work of the genetic clinic. Among the 17 newborns with the disease-causing genotype, 10 pure and 5 compound heterozygotes showed “failed” hearing screening; 2 pure heterozygotes (1 pure GJB2 235del C and 1 pure GJB3 538CT) showed “binaural passed” hearing screening. Sixteen children with the causative genotype were diagnosed with varying degrees of bilateral hearing loss after objective hearing examinations, and one case of GJB3 pure congeners was within normal hearing range, with continued hearing follow-up. 39 newborns with two different genetic mutations at the same time “passed” the hearing screening. All 39 newborns with two different genetic mutations “passed” the hearing screening, and 14 cases have completed the hearing assessment at 8-10 months of age with no significant abnormalities. Eight additional cases carrying a single deafness gene at one locus failed hearing screening and showed varying degrees of hearing loss after objective hearing assessment at 3 months of age. In this study, a large sample of newborns was screened for universal deafness genes, and the rate of carriage of hotspot mutations in common deafness genes was found to be 4.58% in the national population. Data support for genetic counseling for deafness. A special genetic counseling clinic has been established at Concordia Hospital to provide a green channel for consultation through a user-friendly approach, and medical records have been created to ensure timely and efficient follow-ups, follow-ups and hearing follow-ups. Genetic counseling includes the interpretation of reports, assessment of the reproductive risk of family members, arrangement of hearing follow-up, early warning and avoidance of deafness, such as issuance of drug warning cards to mitochondrial mutation carriers and their maternal family members, and guidance to parents of newborns at risk for enlarged vestibular aqueducts to avoid predisposing factors for hearing loss. 2. Implications of deafness susceptibility genes and genetic counseling in the neonatal population Hearing loss is the most common sensory disorder in infancy and childhood, and genetic and multiple environmental factors may be causative, with genetic factors being up to 60% [5]. The most common causative genes in the national population are GJB2, SLC26 A4, GJB3 gene and mitochondrial DNA 12SrRNA gene [6]. Previously, it was thought that GJB2 caused deafness mostly as a congenital, ectopic at birth, binaurally symmetrical, severe prespeech deafness that could be clearly identified by hearing screening [7]. The literature states that GJB2 deaf patients can be born without a deaf phenotype in 3.8%, or 8.9% or even higher [7-9]. The clinical phenotype of children with enlarged vestibular aqueducts is often a delayed fluctuating hearing loss, and it has been shown that only 28.6% of children with this inner ear malformation diagnosed molecularly present with binaural “failures” and 28.6% with monaural “failures” in neonatal hearing screening, with nearly half presenting with “failures”. “Pass” in both ears, and nearly half of them “pass” in both ears [10]. With hearing screening alone, the final diagnosis of hearing loss for the GJB2 pathogenic genotype is often made between 12 months of age and 5 years of age [7]; children with enlarged vestibular aqueducts who pass hearing screening often present with delayed or poor speech development, and hearing loss is diagnosed at 31.5 ± 17.9 months of age, which is not different from the population of deaf children who do not receive newborn hearing screening [10], which would severely affect the speech development of the affected children. It also explains to some extent the continued increase in deafness prevalence even after hearing screening. Genetic screening can advance the time of diagnosis to 1 to 2 months, which is a reliable guarantee of normal language learning. Genetic screening helps parents to understand the cause of the disease, to strictly follow professional recommendations for hearing follow-up and rehabilitation, and to prevent or reduce or delay the onset of deafness. In children with enlarged vestibular aqueducts, hearing loss can be prevented by preventing colds, fevers, minor cranial trauma, pneumatic trauma or other increases in intracranial pressure, and by providing medication warnings to drug-deaf gene carriers and their maternal family members to avoid “one shot deafness”. It also provides genetic information to newborns and family members, and advises them on appropriate marriage and eugenics. Genetic screening is useful for assessing the effectiveness of interventions and selecting appropriate interventions. Severe or profound sensorineural deafness is one of the indications for cochlear implantation (CI), and most of the patients who undergo CI in China have infantile onset, and genetic deafness is not uncommon. It has been reported that GJB2 mutation is one of the main causative factors of deafness in the population receiving CI; patients with GJB2 mutation deafness under 7 years of age have satisfactory auditory and speech rehabilitation after cochlear implantation [11]. Patients with SLC26A4 deafness have better hearing rehabilitation outcomes at 12 and 24 months postoperatively than patients with no abnormalities in common deafness genetic screening. It is suggested that people with SLC26A4 deafness may benefit from cochlear implantation [12]. Cochlear implantation for mitochondrial genetic mutation deafness, which is predominant in female patients, has been performed since 1995 for this type of maternally inherited deafness with satisfactory postoperative results [13]. Genetic screening of newborns must be combined with hearing screening and diagnostic results to give an effective counseling and early warning to the child and parents, and combined hearing and genetic screening improves the deafness prevention and control system and has important social significance [14]. 3. A little reflection on genetic screening and genetic counseling for newborn deafness 3.1 Continue to take advantage of the government-led approach. Although newborn screening has been implemented throughout the world, the level of implementation varies widely by region. In developed countries, such as Canada, the government does not have a lead role in newborn screening programs, and the actual implementation of screening is the responsibility of the provincial and territorial health care agencies. There are significant differences in new screening processes, medical choices, recommendations, and interventions across administrative regions. The ability of China to complete such a large and efficient program in a short period of time and to be rated as a “noteworthy success” in the 2015 literature assessing the status of newborn screening around the world [15] is inextricably linked to government leadership. 3.2 Current issues for consideration and urgent solutions. 3.2.1 The lack of uniform guidelines and norms for the preservation and use of residual screening samples after testing is not conducive to further research on the existing basis. The same problem is faced in developed countries. In the United States, about half of the remaining test samples from newborn screening programs will be uniformly disposed of and destroyed after 2 years, while the remaining programs choose to keep the samples for 18 years or longer [16]. Lawsuits have been filed in Texas, Minnesota, and Indiana over the preservation and use of newborn screening samples [17]. At the same time, many scholars of new screening programs in the United States and Canada have conducted lengthy studies to improve newborn screening programs and resolve disagreements and conflicting factors, and in Michigan, a biobank based on surplus newborn screening samples has been established [18], and the National Institutes of Health (NIH) The Newborn Screening Transla-tional Research Network (NBSTRN) has been funded by the National Institutes of Health (NIH) to serve as a platform for continuing education in the field and as an application pathway for residual samples from prospective studies [19]. This will be informative for our country. 3.2.2 Screening platforms and target genes should be continuously updated and improved. The tremendous superiority of next-generation sequencing has led to its rapid application to clinical practice, and as new target genes are clarified, localized, and turned into alternative screening genes, they will certainly provide clues to reveal more complex genetic deafness or syndromic deafness. Relying on the current platform and mature operation model, China will be at the forefront of the development of deafness genetic research and clinical genetic diagnosis technology based on NGS technology in the next 10 years. 3.3.3 Better achieve genetic counseling and improve the counseling ability to be competent in counseling. The goal of genetic counseling is to use the results of genetic testing to maximize the benefit to the patient. In the United States and Canada, genetic counseling is provided by dedicated genetic counselors and requires a license to practice from the American Board of Genetic Counseling. There is currently no dedicated and mature genetic counselor access system in China, and clinical genetic counseling clinics are provided by physicians with a background in genetic medicine, with the focus of the clinics being on providing genetic testing and insufficient counseling. Psychological guidance and emotional comfort are often unsatisfactory. This study found that parents of newborns have a high level of trust in the deafness genetic counseling clinic, and in addition to a desire to know more about the cause of their baby’s deafness, there is an urgent desire for genetic testing to guide treatment and help family members and fertility planning. At the same time, a few parents have concerns about the psychological and emotional aspects of genetic testing, including the belief that the results of genetic testing are impossible and unscientific, emotional unacceptability, “guilt”, negative impact on the newborn or the family, and the impact on the newborn’s future health insurance, etc. More effective communication and support are needed during the consultation process. Happily, in recent years, scholars in China have also been working to expand and improve in this area. In addition to special training courses, China’s first online genetic counseling and genetic education website, China Genetic Counseling Network, has been developed to provide a dedicated platform for communication and learning. With the improvement of the project implementation, the combined newborn hearing and genetic screening system in combination with the increasing capacity of genetic counseling will truly achieve the goal of significantly reducing the incidence of deafness in China.