Gene-Polymorphism in Non - Syndromic Hearing Loss: A Systematic Review

Abstract

Hearing loss that happens alone, without other related physical or developmental issues, is known as non-syndromic hearing loss (NSHL). About 70% of instances of hereditary hearing impairment are of this kind, making it the most prevalent type of genetic hearing loss. There are three possible inheritance patterns for the condition: autosomal dominant, autosomal recessive, and X-linked. The most common type is autosomal recessive. Studies have shown a large number of genes implicated in the auditory system, and genetic variables are important in the development of NSHL. These comprise genes encoding elements of the central auditory circuits, auditory nerve, and cochlea. Hearing loss can result from a number of mutations or polymorphisms (differences in the DNA sequence) in various genes, ranging from mild to profound. Thus several studies showing different gene involved, a systematic review is needed. Two databases PubMed (medicine) and Google scholar, as the main literature source and performed literature searches using relatively mature search formula. Based on the inclusion and exclusion criteria, after screening 150 articles, 12 articles were selected and reviewd for the study. The results demonstrate that NSHL is largely caused by genetic alterations, with some polymorphisms being more common in particular populations. For instance, GJB2-related mutations are uncommon in sub-Saharan Africa, where other genetic variables probably prevail, but they are noticeably widespread in Asian and Caucasian populations.

Introduction

Hearing loss is not a diagnosis; rather, it is defined as a symptom of an underlying pathological change, whereas 80% of prelingual hearing loss has an underlying genetic cause. According to Koleilat et al. [5], the cause of prelingial hearing loss in developed countries is divided into 20% acquired or environmental causes and 80% genetic causes. In genetics, it can be as much as 30% syndromic and 70% non-syndromic. The syndromic genes can also be classified into recessive (80%), dominant (19%), mitochondrial, miRNA, and X-linked (> 1%).

Shadab et al. [10] has concluded that GJB2-related AR non-syndromic hearing loss is the most common genetic cause of severe to profound autosomal recessive non-syndromic hearing loss in Asian and white populations. In a contrast, biallelic GJB2 pathogenic mutations actually do not contribute to hereditary hearing loss in the sub-Saharan African population.

Lobanov et al. [6] did a study in which they concluded bialleic genetic alterations involving STRC are the most common cause of mild to moderate sensorineural hearing loss and the second most common cause of autosomal recessive hearing loss overall. They also concluded that biallelic contiguous gene deletions involving STRC and CATSPER 2 are associated with sensorineural hearing loss and decreased fertility in males.

Other genes involved in autosomal recessive non- syndromic hearing loss include BDPI which causes hearing loss that is progressive and postlingual, CDH 23 which is associated with phenotypic spectrum including autosomal recessive NSHL and AR SHL, EPS8L2 which cause hearing loss which is progressive and post lingual such as the LOXHDI. MY67A also causes progressive and postlingual hearing loss associated with the phenotypic spectrum, including AR and AD non-syndromic hearing loss. SLC26A4 causes pre- or post-lingual and progressive hearing loss. It is associated with a phenotypic spectrum including ARNSHL (non-syndromic enlarged vestibular aqueduct) and ARSHL (pendred syndrome).

When PDS and NSEVA are treated as part of the same conditions spectrum, the prevalence rates are quite high, as pathogenic modifications in SLC26A4 are the third most common cause of hearing loss. Other genes include TECTA, TMCI, TMPRSS3, USHIC, and WHRN.

Method

Literature Sources and Search Strategies

The two databases we used for this study’s primary literature sources were Google Scholar and PubMed (medical), and we conducted literature searches utilising a somewhat sophisticated search strategy. Our analysis period was the period from April 31, 2013, to April 31, 2024, when all literature searches were carried out.

Literature Screening

After identifying 150 papers in all, 12 articles were eventually included in the final study. Two audiology students used the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) concept to scan the literature based on the inclusion and exclusion criteria. The flowchart illustrating the procedure for the articles that were part of the review is shown in Fig. 1 (See Table 1).

Fig. 1.

PRISMA flowchart of the selection process of articles that were included in the review

Table 1.

The literature search’s summary on the relationship between NSHL and Gene polymorphisms

Author	Title	Population	Sample size	Technique used	Conclusion
Pandey et al. [8]	Mutations in OTOF, CLDN14, SLC26A4 genes as major causes of hearing impairement in Dhadkai Village, Jammu and Kashmir, India	Jammu and Kashmir, India	72 cases of hearing impaired	1. Genome-widescan &linkage analysis 2. Mutation analysis	The KSHO1 family’s major deafness locus maps to chromosomes 2p24–p22. No Cx26 mutation was detected in proband Using haplotyping analysis, all of the afflicted siblings had the co segregating marker D2S165. The alleles shared by siblings included D2S165 &D2S367
Vona et al. [11]	Hereditory hearing loss SNP-microarray pilot study		99 consecutively recruted patients with suspected hereditory hearing loss and 9 unaffected family member	1. Genomic DNA extracted from whole blood 2. Diagnostic GJB2 screening 3. Illumina infinium HD assay	A large number of clinically significant mutations are located outside the SNP microarray resolution. SNP-micro array involve inability to detect balanced translocations, copy neutral alterations and inversus
Castiglione et al. [1]	Sudden sensorineural hearing loss and polymorphisms in iron homeostasis genes: New insights from a case-control study		200 patients with idiopathic Sudden sensorineural hearing loss	DNA analysis	ISSNHL was significantly correlated with the FPNI 8 C gene polymorphism, as patients with this polymorphism showed a higher chance of getting this disease as an adult. The highest concentration of ferritin is found at the stria vascular level, where the distribution of DMTI is superficial.
Kitano et al. [4]	POU4F3 mutation screening in Japaneese hearing loss patients: Massively parallel DNA sequencing- based analysis identified novel variants associated with autosomal dominant hearing loss	Japan	0–79 years (2.549 probands) Autosomal dominant: 602 Autosomal Recessive: 1,577 Unknown inheritance: 370	1. Emulsion PCR and sequencing 2. MPS performed with Ion Torrent Personal Genome Machine variant detection using ANNOVAR software	Total of 12 possible disease causing variants Among 12,8 were located in POU-specific domain (aminoacids 179–256) or Homeobox domain (amino acids 272–332) Other 4 variants p.His25fs & p.IIIeII23fs A non sense variant p.GInI437er
Xiong et al. [14]	Effect of GJB2 235del C & 30–35 del G genetic polymorphisms on risk of congenital deafness in a chinese population	China	118 patients with congenital hearing loss and 242 healthy individuals	1. DNA extraction 2. PCR	GG, GC & CC genotypes of GJB2 235delC significantly differed between patients ad control subjects whereas those of GG, GA &AA genotypes of GJB2 30–35 delG Distrbution of GJB235 del C genotypes was consistent GJB2 235 delC GC & CC genotype significantly associated with a higher risk of congenital deafness compared to GG genotype Individuals with GC + CC genotypes were found to be exposed to a greatly increased risk of congenital deafness compared to GG genotype No significant association between GJB2 30-35del G polymorphism and risk of disease
Parzefall et al. [9]	The role of alternative GJB2 transcription in screening of neonatal SNHL in Austria	Austria	30 normal hearing 11 hearing impaired with familial history 9 NSHL lacking in mutation in GJB2 hetrozygous C.35delG mutations 6 pathogenic hetrozygous GJB2 mutations	PCR &sequencing	Single alterations c-2410T > C (rs7994748)in a newly identified exon Ela of GJB2 in a region previously consideration to be intronic Weak association of alteration with commo 35del G mutation
Cui Qingjia et al. [2]	The sequencing analyze of 915 newborn with GJB2 hetrozygous mutation I Beijing	China	915 newborn	PCR & Sequencing	400 newborn detected to carry atleast one mutation allelle in GJB2 3 had pathogeic mutations (c.94 C > T,c.380G > T, c.3477 > G 14 had unidentified variant
Woo et al. [12]	Identification of CDH 23 mutations in Korean families with hearing loss by whole-exome sequencing	Korea	16 affected individuals from 13 families with recessive NSHL	Whole exome sequencing In silico analysis	Hetrozygous mutations in CDH23 from 2 families SR-106 &SR 209 Average number of observed variants per sample was 59,589
Zhu et al. [15]	Mutations in the mitochondrial 12srRNA gene in elderly chinese people	China	662 elderly Chinese individual 211 normal hearing 51 age related hearing loss	Mutational screening of mitochondrial 12srRNA gene	Total of 4 mutations located within the highly conserved region of 12srRNA gene 1. A1555G: 1 subjects, 2. A827G-29 subjects 3. T1005C-25 subjects 4. T1095C-3 subjects
Wolber et al. [13]	Epigenome-Wide DNA Methylation in Hearing Ability: New Mechanisms for an Old Problem	UK	115 subjects aged between 47 and 83 years	Epigenome-wide association scan (EWAS) using the Illumina 27k array toidentify associations between DNA	The study revealed significant correlations between DNA methylation levels in promoter regions of genes like TCF25, FGFR1, and POLE and hearing ability.
Hoffmann et al. [3]	A Large Genome-Wide Association Study of Age-Related Hearing Impairment Using Electronic Health Records	Northern California	6,527 subjects with age related hearing loss	genome-wide association study method allows researchers to scan the entire genome for single nucleotide polymorphisms	The research identified two novel genome-wide significant SNPs, rs4932196 and rs58389158, which are associated with Age related hearing loss
Nakanishi et al. [7]	Genetic Hearing Loss Associated With Autoinflammation		Review study	This included the use of staining techniques to label F-actin and nuclei, allowing for detailed observation of cellular structures within the cochlea	1. This included the use of staining techniques to label F-actin and nuclei, allowing for detailed observation of cellular structures within the cochlea 2. The activation of the NLRP3 inflammasome in macrophage/monocyte-like cells within the cochlea leads to the secretion of IL-1β, which is associated with inflammatory responses that can contribute to hearing impairment

This study systematically reviewed genetic polymorphisms linked to non-syndromic hearing loss (NSHL), revealing complex interrelations among various genes across diverse populations. The findings show that genetic mutations are a major contributor to NSHL, with certain polymorphisms being more prevalent in specific demographics. For example, GJB2-related mutations are notably common in Asian and Caucasian populations but are rare in sub-Saharan Africa, where other genetic factors likely predominate. This regional variability aligns with findings by Koleilat et al. [5] and Shadab et al. [10], underscoring the need for region-specific genetic screening and interventions.

Additionally, the review highlights mutations in genes such as SLC26A4, which not only correlate with hearing loss but also exhibit a broad phenotypic spectrum, including Pendred syndrome. This dual-role characteristic underlines the potential for multifaceted health impacts in affected individuals. The study also pointed out that techniques like PCR, sequencing, and SNP-microarrays are indispensable for detecting significant mutations, although limitations remain in identifying translocations and structural changes.

Conclusion

In conclusion, genetic mutations significantly influence the development of NSHL, with distinct patterns across populations. This review affirms that targeted genetic screening can improve diagnostic accuracy and personalized treatment strategies. Future research should explore advanced genomic techniques to uncover complex mutations and examine gene-environment interactions in NSHL. Enhanced screening and awareness of genetic predispositions may enable earlier intervention and improved management of hearing loss, ultimately benefiting patient outcomes and quality of life.

Declarations

Conflict of interest

The authors have no conflicts of interests to declare.