Hearing loss is the most prevalent neurosensory disorder in humans, with significant implications for language, social and cognitive development if not diagnosed and treated early. The present systematic review and meta-analysis aimed to determine the rate of hearing screening pass and genetic screening failure [universal newborn hearing screening (UNHS) pass/genetic failure] and to investigate the advantages of combining newborn hearing and genetic screening for newborn hearing impairment. The PubMed, Embase and Cochrane databases were searched from inception to September 2023 to identify studies reporting the combination of neonatal hearing screening with genetic screening. Duplicate literature, unpublished literature, studies with incomplete data, animal experiments, literature reviews and systematic studies were excluded. All the data were processed by STATA15.1 statistical software. A total of nine cross-sectional studies were included in this meta-analysis. The sample sizes ranged from 1,716 to 180,469, and there were a total of 377,688 participants. The pooled results revealed that the prevalence of passing the UNHS while failing genetic screening was 0.31% (95% CI, 0.22-0.41%). The prevalence of UNHS pass and gap junction protein beta 2 and solute carrier family 26 member 4 variant screen failure was 0.01% (95% CI, 0.00-0.02%) and 0.00% (95% CI, 0.00%), respectively, while the prevalence of mitochondrially encoded 12S RRNA variant screening failure and UNHS pass was 0.21% (95% CI, 0.18-0.26%). Combined screening has a significant advantage over pure hearing screening, especially in terms of identifying newborns with mitochondrial gene mutations that render them sensitive to certain medications. In clinical practice, decision-makers can consider practical circumstances and leverage the benefits of combined newborn hearing and genetic screening for early diagnosis, early counseling, and early intervention in patients with hearing loss.

Concurrent screening has been proven to provide a comprehensive approach for management of congenital deafness and prevention of ototoxicity. The SLC26A4 gene is associated with late-onset hearing loss and is of great clinical concern. For much earlier detection of newborns with deafness-causing mutations in the SLC26A4 gene, the Beijing Municipal Government launched a chip for optimized genetic screening of 15 variants of 4 genes causing deafness based on a chip to screen for 9 variants of 4 genes, and 6 variants of the SLC26A4 gene have now been added. To ascertain the advantage of a screening chip including 15 variants of 4 genes, the trends in concurrent hearing and genetic screening were analyzed in 2019 and 2020. Subjects were 76,460 newborns who underwent concurrent hearing and genetic screening at 24 maternal and child care centers in Beijing from January 2019 to December 2020. Hearing screening was conducted using transiently evoked otoacoustic emissions (TEOAEs), distortion product otoacoustic emissions (DPOAE), or the automated auditory brainstem response (AABR). Dried blood spots were collected for genetic testing and 15 variants of 4 genes, namely GJB2, SLC26A4, mtDNA 12S rRNA, and GJB3, were screened for using a DNA microarray platform. The initial referral rate for hearing screening decreased from 3.60% (1,502/41,690) in 2019 to 3.23% (1,124/34,770) in 2020, and the total referral rate for hearing screening dropped form 0.57% (236/41,690) in 2019 to 0.54% (187/34,770) in 2020, indicating the reduced false positive rate of newborn hearing screening and policies to prevent hearing loss conducted by the Beijing Municipal Government have had a significant effect. Positivity according to genetic screening was similar in 2019 (4.970%, 2,072/41,690) and 2020 (4.863%,1,691/34,770), and the most frequent mutant alleles were c.235 del C in the GJB2 gene, followed by c.919-2 A > G in the SLC26A4 gene, and c.299 del AT in the GJB2 gene. In this cohort study, 71.43% (5/7) of newborns with 2 variants of the SLC26A4 gene were screened for newly added mutations, and 28.57% (2/7) of newborns with 2 variants of the SLC26A4 gene passed hearing screening, suggesting that a screening chip including 15 variants of 4 genes was superior at early detection of hearing loss, and especially in early identification of newborns with deafness-causing mutations in the SLC26A4 gene. These findings have clinical significance.

UNASSIGNED: To understand the knowledge, attitude, willingness, and ability of healthcare professionals working in newborn screening (NBS) centers regarding newborn genetic screening (nGS).
UNASSIGNED: The questionnaire consisted of four sections with 27 questions and the data were collected by the WJX platform. All participants accessed the questionnaire by scanning a specific QR code with their mobile phones. Two researchers independently completed the summary and analysis.
UNASSIGNED: A total of 258 valid questionnaires were collected from 43 NBS centers in six provinces of southeast China. In total, 209 (81.01%) participants were interested in nGS, and almost all participants (97.67%) thought that nGS was necessary in China. About 89.53% of participants thought that it could be used to effectively expand the diseases that could be screened, but 72.87% also worried about the inability to provide genetic counseling. About 55.34% suggested that nGS and tandem mass spectrometry (TMS) screening could be applied in a unite screening mode. The higher the institution and personal education levels, the higher the interest healthcare professionals displayed toward nGS. However, they also showed greater concern about the inability to provide genetic counseling and ethical issues. If a center had engaged in TMS screening, its staff would have been more likely to believe that nGS had great advantages. In addition, most participants had ethical concerns, such as \"the psychological burden caused by carrying information regarding adult morbidity risk.\"
UNASSIGNED: Most participants were interested and considered nGS necessary. The inability to provide genetic counseling may be the primary impediment to clinical practice. Three important influencing factors were level of education, institution level, and engagement in TMS screening.

Newborn screening (NBS) has been implemented for neonatal inborn disorders using various technology platforms, but false-positive and false-negative results are still common. In addition, target diseases of NBS are limited by suitable biomarkers. Here we sought to assess the feasibility of further improving the screening using next-generation sequencing technology.
We designed a newborn genetic sequencing (NBGS) panel based on multiplex PCR and next generation sequencing to analyze 134 genes of 74 inborn disorders, that were validated in 287 samples with previously known mutations. A retrospective cohort of 4986 newborns was analyzed and compared with the biochemical results to evaluate the performance of this panel.
The accuracy of the panel was 99.65% with all samples, and 154 mutations from 287 samples were 100% detected. In 4986 newborns, a total of 113 newborns were detected with biallelic or hemizygous mutations, of which 36 newborns were positive for the same disorder by both NBGS and conventional NBS (C-NBS) and 77 individuals were NBGS positive/C-NBS negative. Importantly, 4 of the 77 newborns were diagnosed currently including 1 newborn with methylmalonic acidemia, 1 newborn with primary systemic carnitine deficiency and 2 newborns with Wilson\'s disease. A total of 1326 newborns were found to be carriers with an overall carrier rate of 26.6%.
Analysis based on next generation sequencing could effectively identify neonates affected with more congenital disorders. Combined with C-NBS, this approach may improve the early and accurate identification of neonates with inborn disorders. Our study lays the foundation for prospective studies and for implementing NGS-based analysis in NBS.

Concurrent hearing and genetic screening of newborns is expected to play important roles not only in early detection and diagnosis of congenital deafness, which triggers intervention, but also in predicting late-onset and progressive hearing loss and identifying individuals who are at risk of drug-induced HL. Concurrent hearing and genetic screening in the whole newborn population in Beijing was launched in January 2012. This study included 180,469 infants born in Beijing between April 2013 and March 2014, with last follow-up on February 24, 2018. Hearing screening was performed using transiently evoked otoacoustic emission (TEOAE) and automated auditory brainstem response (AABR). For genetic testing, dried blood spots were collected and nine variants in four genes, GJB2, SLC26A4, mtDNA 12S rRNA, and GJB3, were screened using a DNA microarray platform. Of the 180,469 infants, 1,915 (1.061%) were referred bilaterally or unilaterally for hearing screening; 8,136 (4.508%) were positive for genetic screening (heterozygote, homozygote, or compound heterozygote and mtDNA homoplasmy or heteroplasmy), among whom 7,896 (4.375%) passed hearing screening. Forty (0.022%) infants carried two variants in GJB2 or SLC26A4 (homozygote or compound heterozygote) and 10 of those infants passed newborn hearing screening. In total, 409 (0.227%) infants carried the mtDNA 12S rRNA variant (m.1555A>G or m.1494C>T), and 405 of them passed newborn hearing screening. In this cohort study, 25% of infants with pathogenic combinations of GJB2 or SLC26A4 variants and 99% of infants with an m.1555A>G or m.1494C>T variant passed routine newborn hearing screening, indicating that concurrent screening provides a more comprehensive approach for management of congenital deafness and prevention of ototoxicity.

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and a leading genetic cause of infant death worldwide. However, there is no routine screening program for SMA in the UK. Lack of treatments and the inability of screening tests to accurately predict disease severity are among the key reasons implementation of screening has faltered in the UK. With the recent release of the first therapy for SMA (Nusinersen), calls are being made for a reconsideration of this stance; however, very little is known about the views of the general public.
An online survey was administered to 232 individuals with no prior relationship with SMA to assess their attitudes toward a newborn screening program for it. Results are compared with previously gathered data on the views of SMA-affected families toward screening.
Eighty-four percent of participants were in favor of newborn screening. Key reasons for support were a belief that it would lead to better healthcare and life expectancy for affected infants and facilitate informed decision-making for future pregnancies. Key reasons for nonsupport were a belief in the potential for significant negative impact on the family unit in terms of bonding and stress.
Public acceptability is a key component in the evaluation of any potential screening program in the UK. This study demonstrates that newborn screening for SMA is viewed largely positively by people unfamiliar with the condition. The importance of early identification overrode all other social and ethical concerns about screening for the majority of participants.

Spinal muscular atrophy (SMA) is one of the leading genetic causes of infant death worldwide. However, due to a lack of treatments, SMA has historically fallen short of Wilson-Jungner criteria. While studies have explored the acceptability of expanded newborn screening to the general public, the views of affected families have been largely overlooked. This is in spite of the potential for direct impacts on them and their unique positioning to consider the value of early diagnosis. We have previously reported data on attitudes toward pre-conception and prenatal genetic screening for SMA among affected families (adults with SMA [n = 82] and family members [n = 255]). Here, using qualitative interview [n = 36] and survey data [n = 337], we report the views of this same cohort toward newborn screening. The majority (70%) of participants were in favor, however, all subgroups (except adults with type II) preferred pre-conception and/or prenatal screening to newborn screening. Key reasons for newborn screening support were: (1) the potential for improved support; (2) the possibility of enrolling pre-symptomatic children on clinical trials. Key reasons for non-support were: (1) concerns about impact on the early experiences of the family; (2) inability to treat. Importantly, participants did not view the potential for inaccurate typing as a significant obstacle to the launch of a population-wide screening program. This study underscores the need to include families affected by genetic diseases within consultations on screening. This is particularly important for conditions such as SMA which challenge traditional screening criteria, and for which new therapeutics are emerging.

OBJECTIVE: Previous epidemiological studies indicate that GJB2, SLC26A4 or mtDNA 12S rRNA mutations were chiefly responsible for the hearing loss in children. A cost-effective method for screening deafness-associated mutations at early age is needed. This study aimed to develop a simple kit for screening of high risk deafness-associated mutations in newborns using tetra-primer amplification refractory mutation system PCR.
METHODS: The screening kit was designed to detect high risk deafness-associated mutations (GJB2 c.235delC, SLC26A4 c.919-2A>G, mtDNA 12S rRNA mt.1555A>G and mt.1494C>T). The kit was able to amplify both wild-type and mutant alleles with a control fragment. The proposed method was conducted to genotype the above four deafness gene mutations in four PCR reactions. Each mutation was genotyped by a set of four primers, two allele-specific inner primers, and two common outer primers. A mismatch at the penultimate or antepenult nucleotide of the 3\' terminus was introduced in order to maximize specificity. The 16 primers were used for the amplification of genomic DNA as a template. Amplified fragments were separated by electrophoresis. We designed and validated the kit with wild and mutant type DNA samples that had been previously been confirmed by Sanger sequencing. Then 1181 newborns were enrolled, and those samples with mutations were further validated with sequencing too.
RESULTS: Among 1181 newborns, 29 individuals had one or two mutant alleles, with the carrier rate being 2.46% (29/1181). For GJB2 c.235delC mutation, one case was homozygote and 12 cases were heterozygote carriers. For SLC26A4 c.919-2A>G mutation, 12 cases were heterozygotes carriers, and no homozygotes were found; for mtDNA 12S rRNA mt.1555A>G mutation, one case was identified; three cases of mtDNA 12S rRNA mt.1494C>T mutation were detected. All mutations were detected with high specificity. Mutation samples were confirmed via Sanger sequencing. No false positive was found.
CONCLUSIONS: A user-friendly screening kit for deafness-associated mutations was successfully developed. It provided rapid, reproducible, and cost-effective detection of deafness gene mutation without special equipment. The kit allowed the detection of the four high risk deafness-associated mutations with only 4 single tube PCR reactions. In the future, the kit could be applied to large population-based epidemiological studies for newborn hearing defects screening.