
Prevalence of TECTA and GJB2 mutations in Asian children with nonsyndromic hearing loss: A meta-analysis
- Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Viet Nam
- School of Medicine, Vietnam National University, Ho Chi Minh City, Viet Nam
- School of Medicine, Viet Nam National University, Ho Chi Minh City, Viet Nam
Abstract
Introduction: The most common sensory disorder, hearing loss, may result from genetic causes. Various inheritance patterns exist, such as X-linked, autosomal dominant, autosomal recessive, and mitochondrial. However, the genetic underpinnings of racial distinctiveness and regional variation were incompletely understood. To fully evaluate the ethnic specificity of gap junction protein beta 2 (GJB2) and tectorin alpha (TECTA) mutations in this region, data from all GJB2 and TECTA gene studies on Asian children with hearing impairment were pooled and used in this research.
Methods: All nonsyndromic hearing loss studies on the prevalence of GJB2 or TECTA mutations published between 1990 and 2022 were retrieved from the PubMed database, evaluated for risk of bias, and meta-analyzed.
Results: Twelve studies were chosen, representing twelve prevalence estimates. The prevalence of GJB2 and TECTA mutations in Asian patients with nonsyndromic hearing loss was 13.36% (95% confidence interval [CI]: 7.74%?20.14%), varying significantly among trials (I2 = 96.74%; P < 0.001). The pooled prevalence of TECTA and GJB2 mutations was 3.6% (95% CI: 1.9%? 5.7%) and 24.06% (95% CI: 11.43%?31.35%), respectively.
Conclusions: There was an association between TECTA/GJB2 mutations and hearing impairment, but there were also regional and ethnic differences in mutation prevalence. Studies with larger sample sizes and genetic analyses based on long-read sequencing are needed to understand the mutations resulting in hearing loss.
Introduction
The ear loses its ability to change sound’s mechanical energy into electrical energy, leading to hearing loss. The cochlea’s hair cells maintain this role by converting oscillation into neuronal impulses and sending messages to the brain’s cortex via the VIII nerve1. Conductive hearing loss results from a disruption of sound transmission at the outer and/or middle ear. In contrast, sensorineural hearing loss (SNHI) occurs when the inner ear cannot communicate with the brain. Hearing loss can be genetic and/or acquired, depending on when it first appears2, 3. One in 1000 newborns has a hearing impairment, the most frequent sensory disorder. The most prevalent sensory disorder is believed to be of genetic origin, accounting for roughly 50% of all cases4.
Hearing loss is caused by gene mutations in 50% of cases. Environmental factors such as ototoxic medications, prematurity, and cranial trauma account for the remaining 50%. Approximately 70% of cases of inherited hearing loss are attributed to nonsyndromic hearing loss. Nonsyndromic genetic deafness has various inheritance patterns, such as autosomal recessive and dominant, X-linked, and mitochondrial2. Autosomal recessive inheritance, due to mutations in the gap junction protein beta 2 () gene, is more common (80%) than autosomal dominant (AD) inheritance (20%) in severe and congenital pre-lingual deafness5. AD nonsyndromic hearing loss (ADNSHL) is a condition with diverse genetic and clinical features. Tectorin alpha () mutations have been identified as contributing to ADNSHL in diverse populations, differing in their ages of onset and degrees of auditory impairment, rates of advancement, and extent of participation6, 7, 8. The association between deafness and mutations is the subject of an ongoing debate regarding the underlying mechanisms. Some studies have identified missense mutations in its zona pellucida domain as a potential biological factor contributing to ADSHNL.
These studies considered only parts of genetic figures related to ethnic particularity and regional differences. Due to the small sample sizes of case-control studies, detecting minor genetic associations in humans was difficult. To learn more about this variable, we need a meta-analysis of the association between ethnic specificity and mutations in and . In this study, all published studies on the and genes in Asian pediatric populations with hearing impairment were used in a combined meta-analysis. Based on the evaluation of the relationship between and mutations and hearing impairment and the genetic heterogeneity effect, a stratified meta-analysis was performed to determine whether and mutations causing hearing loss in Asian children are specific to that ethnic group.
Methods
Eligibility requirements
All nonsyndromic hearing loss studies published since 1990 were considered for inclusion if the prevalence of or mutations was reported or could be calculated from the available data. Studies that presented assumptions based on specific subgroups of the overall population were excluded (., women or related family). Notably, certain populations, such as the Han Chinese population or those participating in the hospital-based studies, were not excluded since they were considered to reflect the broader population within a given geographic region.
Search strategy
Using a search methodology that combined appropriate key phrases and subject-specific terms within the respective databases, PubMed was searched through November 6, 2022. The search strategy incorporated (235delC and V37I) or -related terms with study design-related terms, such as epidemiology, cohort, cross-sectional, and observational study.
The titles of the identified articles were examined, and those that were irrelevant to this study were eliminated. After checking the abstracts, the full texts of the remained articles were examined to identify pertinent investigations that satisfied the established inclusion criteria.
Additional pertinent articles were identified by reviewing the reference lists of full-text articles.
Risk of bias assessment
The potential bias in the included studies was assessed using the Agency for Healthcare Research and Quality (AHRQ) checklist, which is intended specifically for cross-sectional or prevalence studies9. This evaluation was conducted independently. The methodology checklist developed by the AHRQ comprises eleven parts. A score of “1” is assigned to each item if the response is affirmative, while a score of “0” is assigned for an unclear or negative response. Research investigations are classified into three categories of bias risk based on their quality scores: 0–3, high; 4–7, moderate; 8–11, low. The AHRQ methodology checklist findings were subjected to cross-validation, and any discrepancies were resolved through team deliberation.
Data extraction
The data extraction from each article was standardized using a data collection form. The extracted data included information on the sampled population, prevalence rate, period of the estimated prevalence (such as a point or a year), and any reported rates stratified by specific or variants, age, sex, or location. The form also contained sections to gather relevant information to assess potential bias.
Analysis
The average carrier frequency of the 235delC and p.V37I mutations of the and genes was determined in each study. According to the distribution of carriers, the included populations were divided into two categories: patients with nonsyndromic hearing loss with or gene mutations.
The investigations were subjected to preliminary descriptive statistics. The diversity among assumptions was evaluated using the statistic, which represents the proportion of variation across studies that was not due to sampling error. An >75% indicates considerable heterogeneity. A model with random effects was used to conduct a meta-analysis. A pooled prevalence with a 95% confidence interval (CI) was calculated. The statistical analyses were performed using STATA software (version 14).

A flowchart showing how articles were included and excluded from the study.
Characteristics of the included studies
ID |
References |
Survey period |
Sample size (n) |
Country |
Sex (F/M) |
Mean age (± SD/range) |
---|---|---|---|---|---|---|
1 |
Identification of novel variants in Iranian consanguineous pedigrees with nonsyndromic hearing loss by next-generation sequencing |
2020 |
44 |
Iran |
NA |
39.6 (7–60) |
2 |
The prevalence and clinical characteristics of TECTA-associated autosomal dominant hearing loss |
2000–2017 |
812 |
Japan |
NA |
37.1 (0–86) |
3 |
Mutation analysis of common GJB2, SCL26A4 and 12S rRNA genes among 380 deafness patients in northern China |
NA |
380 |
China |
199/181 |
9.9 (0.5–38) |
4 |
Targeted next-generation sequencing successfully detects causative genes in Chinese patients with hereditary hearing loss |
NA |
116 |
China |
56/60 |
0–70 |
5 |
The prevalence of the 235delC GJB2 mutation in a Chinese deaf population |
NA |
3004 |
China |
1298/1706 |
13.8 (±4.5) |
6 |
TECTA mutations in Japanese with mid-frequency hearing loss affected by zona pellucida domain protein secretion |
NA |
139 |
Japan |
NA |
NA |
7 |
Prevalence of p.V37I variant of GJB2 in mild or moderate hearing loss in a pediatric population and the interpretation of its pathogenicity |
2010–2012 |
380 |
Korea |
NA |
NA |
8 |
High prevalence of V37I genetic variant in the connexin-26 (GJB2) gene among nonsyndromic hearing-impaired and control Thai individuals |
2000–2002 |
166 |
Thailand |
89/77 |
NA |
9 |
GJB2 (connexin 26) mutations and childhood deafness in Thailand |
NA |
17 |
Thailand |
10/7 |
NA |
10 |
Genetic etiology study of the nonsyndromic deafness in Chinese Hans by targeted next-generation sequencing |
NA |
190 |
China |
53/84 |
14 (0–50) |
11 |
First molecular screening of deafness in the Altai Republic population |
NA |
76 |
Altai Republic |
39/37 |
30.2 (3–80) |
12 |
The p.V37I exclusive genotype of GJB2: A genetic risk-indicator of postnatal permanent childhood hearing impairment |
2009–2010 |
45 |
China |
NA |
7 (3.9–10.1) |
The risk of bias in the included studies
ID |
Author |
Publication year |
Gene |
Gene subgroup |
Sample (n) |
No. of cases (n) |
Quality rating | ||
---|---|---|---|---|---|---|---|---|---|
1 |
Fatemeh Bitarafan |
2020 |
TECTA |
44 |
26 |
Moderate | |||
2 |
Rika Yasukawa |
2019 |
TECTA |
812 |
76 |
Moderate | |||
3 |
Jing Pan |
2017 |
GJB2 |
235delC |
380 |
9 |
Moderate | ||
4 |
Siqi Chen |
2016 |
TECTA |
116 |
9 |
Moderate | |||
GJB2 |
116 |
37 |
Moderate | ||||||
5 |
Pu Dai |
2007 |
GJB2 |
235delC |
3004 |
488 |
Moderate | ||
6 |
Hideaki Moteki |
2012 |
TECTA |
139 |
4 |
High | |||
7 |
So Young Kim |
2013 |
GJB2 |
p.V37I |
380 |
4 |
Low | ||
8 |
Duangrurdee Wattanasirichaigoon |
2004 |
GJB2 |
p.V37I |
166 |
56 |
Moderate | ||
9 |
T Kudo |
2001 |
GJB2 |
17 |
4 |
High | |||
10 |
Tao Yang |
2013 |
GJB2 |
190 |
36 |
High | |||
11 |
Olga Posukh |
2005 |
GJB2 |
76 |
18 |
High | |||
12 |
Lei Li |
2012 |
GJB2 |
p.V37I |
45 |
9 |
Moderate |

The prevalence of GJB2/TECTA mutations in Asian individuals with nonsyndromic hearing loss (event: the number of cases with GJB2 or TECTA mutations; weight: the prevalence in each study).

The frequency of GJB2/TECTA mutations in Asian individuals with nonsyndromic hearing loss.

The pooled frequency of specific variants carried by individuals with nonsyndromic hearing loss.
Results
Search results
The PubMed database search identified 112 publications, of which 69 were chosen for full-text review. Their reference lists led to the identification of 12 additional studies. The screening procedure is illustrated in Figure 1.
After a full-text evaluation, 23 articles were excluded. Therefore, 12 studies were selected for review (
Risk of bias
Prevalence rates were often presented in an article or calculatable from the provided data. Iran had the highest prevalence of mutations (Fatemeh Bitarafan, 2020)10, while Japan had the lowest prevalence (Hideaki Moteki, 2012)15. Thailand had the highest prevalence of mutations (Duangrurdee Wattanasirichaigoon, 2002)17, while Korea had the lowest prevalence (So Young Kim, 2013)16.
Meta-analysis
This study investigated the prevalence of / mutations in individuals with nonsyndromic hearing loss in Asia. Its findings indicate that the frequency of / mutations in Asian individuals with nonsyndromic hearing loss was 13.36% (95% CI: 7.74%–20.14%). The included studies showed significant heterogeneity, with an of 96.74% ( < 0.001; Figure 2, Figure 3). An asymmetric funnel plot suggested the possibility of publication bias.
A funnel plot was used to determine whether there was any publication bias in the included articles. Based on the study distribution (Figure 3), the funnel plot is almost the same on both sides. The meta-analysis conducted did not show any notable indication of publication bias based on the included studies.
Four studies examined the number of people with nonsyndromic hearing loss with a mutation. The combined occurrence rate of mutations was 3.6% (95% CI: 1.9%–5.8%). The studies exhibited moderate heterogeneity ( = 37.87%, = 0.18).
Four studies reported the occurrence of mutations in individuals with nonsyndromic hearing loss. The combined prevalence of mutations was 24.06% (95% CI: 11.43–31.36). The studies exhibited moderate heterogeneity ( = 53.6%, = 0.09).
Two studies reported the prevalence of the gene variant 235delC in individuals with nonsyndromic hearing loss. Its pooled frequency was 16.6% (95% CI: 15.4%–17.9%).
Three studies explored the number of people with nonsyndromic hearing loss with the gene variant p.V37I. Its pooled frequency was 14.7% (95% CI: 0%–48.6%).
Discussion
The commonly observed inherited etiology of SNHI is attributed to recessive variants in the gene. The prevalence of mutations varies significantly among different ethnic communities. For example, Europeans carry c.35delG (p.Gly12ValfsTer2) and c.101T>C (p.Met34Thr) mutations22, 23, 24, while East Asians carry c.235delC (p.Leu79CysfsTer3) and c.109G>A (p.Val37Ile) mutations14, 25, 26, 27. Additionally, Ghanaians carry the c.427C>T (p.Arg143Trp) mutation28. Three plausible mechanisms that could account for these inconclusive results exist. SNHI could also be caused by pathogenic mutations in other genes known to cause deafness. In such cases, patients who do not present with the confirmatory symptoms for SNHI may still carry mono-allelic variants as incidental carriers. Furthermore, mutation frequencies fluctuate widely between countries.
One study on ADNSHL communities in Japan found a prevalence of mutations of 2.9% (4/139), with an incidence of 7.7% (4/52) in those with moderate hearing loss15. These findings indicate that the frequency of mutations in the Japanese is relatively low compared to Iranians, whose prevalence was >50%10. The prevalence of mutations can vary widely even within the same country. In 2017, Jing Pan reported a prevalence of 2.4% for mutations in Northern China, while Pu Dai reported a prevalence of 16.2% in Chinese patients29, 30. Despite having a pooled prevalence of 3.6% (95% CI: 1.9%–5.7%) for mutations and 24.06% (95% CI: 11.43%–31.35%) for mutations, this comparison indicates geographical differences in mutation frequency, emphasizing the need for further research on regional risk factors such as lifestyles, education, and life qualities.
The prevalence of each mutation shows variation across different ethnic groups and countries. The 35delG mutation has been observed in up to 85% of Caucasians31. In contrast, the 235delC mutation has been identified most frequently in the Chinese32 (20.3%), Koreans33 (6.9%), and Japanese34 (49.8%). The c.167delT mutation has been found in 4.03% of Ashkenazi Jews35 and 2% of Argentianians36. These results indicate ethnic differences in mutation prevalence, emphasizing the need for further studies with larger sample sizes and genetic analyses based on long-read sequencing to better understand mutations associated with hearing impairment.
This study’s main limitation was the heterogeneity of its included studies. The population of individuals suspected of hearing loss varied across studies, and most were not precisely defined. Several studies focused exclusively on children, while most did not provide any particular age range. The allele frequencies in various countries may be influenced by particular population samples, resulting in sampling bias. In addition, the ethnic or racial origin of part of the study population was not specified, and the scope of this analysis was limited to the geographic aspect and did not encompass ethnicity. Another limitation of this study was that its data was only extracted from the Pubmed database. Therefore, some studies indexed in Embase, Web of Science, or Scopus were not included.
Conclusions
Our results showed an association between / mutations and hearing impairment, but there were also regional and ethnic differences in mutation prevalence. However, studies with larger sample sizes and genetic analyses based on long-read sequencing are needed to better understand the changes resulting in hearing loss.
Abbreviations
AD: autosomal dominant; AHRQ: Agency for Healthcare Research and Quality; GJB2: gap junction protein beta 2; SNHL: sensorineural hearing loss; TECTA: tectorin alpha
Acknowledgments
We sincerely thank PhD. MD Quang Minh Le Tran (Director of Ear Nose Throat Hospital Hochiminh City) for the permission to perform the research.
Author’s contributions
Minh Xuan Ngo and Chung Thuy Tran Phan conceived of the presented idea, developed the theory and supervised the findings of this study. Phuong Hoang Vu, Anh Thu Ha Nguyen and Thanh Vu Nguyen worked out the technical details, and performed the numerical calculations for the suggested experiment, verified the numerical results of the study. Phuong Hoang Vu and Quang An Lan interpreted the results and worked on the manuscript. All authors read and approved the final version of manuscript.
Funding
This study is supported by a grant from Vietnam National University Ho Chi Minh City (VNU-HCM) with grant number GENE2020-44-01.
Availability of data and materials
Data and materials used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.