Breakthrough in Understanding Nonsyndromic Hearing Loss Genetics

Researchers at Duke-NUS Medical School in Singapore have published a landmark study revealing the genomic biomarkers and mutational landscape of nonsyndromic hearing loss (NSHL) in the local population. Nonsyndromic hearing loss refers to hearing impairment that occurs without other associated symptoms or medical conditions, making it one of the most common sensory disorders worldwide. This research, detailed in the journal Biomolecules, analyzed whole-exome sequencing data from 115 patients, achieving a molecular diagnosis rate of 57%—notably higher than the typical 30-45% seen in similar global studies.

The study's lead authors, Che Kang Lim and Vanessa Yee Jueen Tan from Duke-NUS and Singapore General Hospital's Department of Otorhinolaryngology—Head & Neck Surgery, highlight how these findings fill a critical gap in knowledge for Singapore's multi-ethnic population, predominantly Chinese (88.7% of the cohort), but also including Malay, Indian, and others. This diversity underscores the need for population-specific genetic insights, as East Asian founder variants differ from those in European or other cohorts.

The Scope and Methods of the Duke-NUS Investigation

Duke-NUS Medical School, a premier graduate-level institution established in 2005 as a collaboration between Duke University and the National University of Singapore, continues to lead in precision medicine research. The study employed rigorous whole-exome sequencing (WES) using the Agilent SureSelectXT Human All Exon V6 kit on Illumina NovaSeq 6000 platforms. DNA from peripheral blood was processed, aligned to the GRCh38/hg38 reference genome, and variants called via GATK HaplotypeCaller. Bioinformatics filtering targeted over 150 known NSHL genes from OMIM, prioritizing minor allele frequency (MAF) ≤1% in gnomAD and pathogenicity per ACMG-AMP guidelines.

Validation through Sanger sequencing confirmed findings. The cohort comprised patients aged 16 to 81 with confirmed sensorineural hearing loss (SNHL), excluding syndromic cases, ototoxic drugs, or noise exposure as primary causes. Clinical data included audiograms showing bilateral involvement in 88.7%, down-sloping configuration in 62.6%, and moderate-to-severe or worse loss in 51.3%.

This methodological rigor exemplifies Duke-NUS's commitment to translational research, bridging laboratory discoveries to clinical practice in Singapore's healthcare system.

Key Genetic Discoveries: Dominant Genes and Variants

The mutational landscape revealed GJB2 (connexin 26 gene) as the most prevalent, accounting for 27.8% of cases (32/115 patients). Common variants included the East Asian founder p.V37I (homozygous in mild-moderate loss) and truncating p.L79Cfs*3 linked to severe-profound impairment. SLC26A4 (pendrin gene), associated with enlarged vestibular aqueduct (EVA), was found in 20% of diagnosed cases (13/66), often with inner ear malformations.

Other significant genes encompassed OTOF (otoferlin, involved in synaptic transmission), STRC (stereocilin, outer hair cell links), and TMPRSS3 (transmembrane protease). Autosomal recessive inheritance dominated at 86%, with 12% autosomal dominant and 2% X-linked (e.g., SMPX). Less common but notable were ACTG1, MYO6, MYH14, and TMC1, reflecting broad heterogeneity.

• GJB2: Mild-moderate phenotypes, early intervention potential.
• SLC26A4: Severe-profound, often with imaging anomalies like EVA.
• OTOF: Pre- or perilingual onset, candidate for emerging gene therapies.

Novel Variants Expanding the NSHL Spectrum

A standout contribution is the identification of novel and rare damaging variants. Three novel mutations were pinpointed: MYO6 c.554-2A>G (splice site acceptor), TNC p.N750Y (missense in tenascin-C), and CDH23 p.N2063K (cadherin 23, Usher syndrome overlap). Fourteen very rare variants with high pathogenic potential were also uncovered, many autosomal dominant, such as in CEACAM16, COL11A2, DIAPH1, and TJP2.

These discoveries, absent from major databases like ClinVar or gnomAD, expand the known spectrum of NSHL mutations. In silico predictions (SIFT, PolyPhen-2, CADD scores >20) and evolutionary conservation supported their deleteriousness. Such findings are crucial for Singapore, where consanguinity is low, yet de novo or rare recessive variants prevail.

Genotype-Phenotype Correlations in Singaporeans

Genotype-phenotype analysis provided actionable insights. GJB2 variants correlated with milder loss, allowing potential for hearing aid optimization over cochlear implants. Conversely, SLC26A4 mutations aligned with profound deafness and structural anomalies, warranting MRI/CT scans and early surgical consideration.

OTOF cases showed congenital or early-onset severe loss, positioning them for trials like DB-OTO gene therapy. Inheritance patterns influenced family screening: recessive cases prompted carrier testing in partners, while dominant ones necessitated parental evaluation. These correlations enable personalized management, reducing long-term morbidity like language delays or cognitive impacts.

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Prevalence and Burden of Hearing Loss in Singapore

In Singapore, newborn hearing screening identifies permanent childhood hearing impairment in 4 per 1,000 births, with NSHL comprising ~70% of hereditary cases. Among adults, prevalence rises sharply: 16-65% in those over 60, exacerbated by noise exposure in urban settings and aging demographics. By 2030, over 360,000 Singaporeans may face disabling hearing loss, straining healthcare via increased hospitalizations, falls, and dementia risk.

Duke-NUS's Centre for Ageing Research and Education (CARE) complements this with studies linking hearing impairment to social isolation and cognitive decline. The new genomic data supports national programs like Healthier SG, emphasizing early genetic diagnosis to mitigate lifelong burdens.

For more on Singapore's hearing health initiatives, visit the Ministry of Health page.

Precision Medicine Implications for Singapore Healthcare

This study boosts diagnostic yield to 57%, surpassing global benchmarks, via targeted NSHL panels informed by local variants. It paves the way for precision interventions: pharmacogenomics for ototoxic drugs, gene therapy for monogenic forms (e.g., OTOF trials), and risk-stratified screening.

In Singapore's SingHealth Duke-NUS Academic Medical Centre, integration into electronic health records could enable cascade screening. Genetic counseling gains precision, aiding family planning in a low-consanguinity society. Economically, early diagnosis averts SGD millions in special education and lost productivity.

The full study is available here, offering detailed variant tables for clinicians.

Duke-NUS's Role in Singapore's Research Ecosystem

Duke-NUS exemplifies Singapore's higher education push in biomedical sciences, training PhD/MD-PhD students and fostering clinician-scientists. Affiliated with SingHealth, it drives translational research, with over 2,000 alumni advancing precision medicine. This NSHL study aligns with national priorities like the Research, Innovation and Enterprise 2025 Plan, emphasizing genomics.

Collaborations with Ngee Ann Polytechnic and international partners amplify impact, training next-gen researchers in bioinformatics and rare disease genomics.

Stakeholder Perspectives and Expert Opinions

Senior author Vanessa Tan emphasized: "This work empowers otolaryngologists with biomarkers for faster, accurate diagnoses, transforming NSHL management." Geneticists note the value for multi-ethnic panels, while policymakers see synergies with newborn screening expansions.

Challenges remain: undiagnosed 43% may harbor ultra-rare variants needing genome-wide approaches. Experts advocate expanded WES in public health for equity.

Future Directions: Therapies and Research Horizons

Emerging therapies like AAV-OTOF (REGENXBIO) and CRISPR editing hold promise, guided by this landscape. Duke-NUS plans longitudinal cohorts tracking progression and therapies. Broader implications include AI-driven variant prioritization and polygenic risk scores.

In Singapore, integrating into National Precision Medicine (NPM) could scale benefits. Ongoing trials and multi-omics will refine biomarkers, positioning Duke-NUS at the forefront.

Photo by Lhu Shi Hui on Unsplash

Actionable Insights for Researchers and Clinicians

• Prioritize GJB2/SLC26A4 panels for Singaporeans.
• Screen families post-diagnosis for recessives.
• Monitor EVA in SLC26A4 carriers.
• Advocate WES reimbursement for unresolved cases.
• Collaborate on gene therapy trials.

This Duke-NUS study not only illuminates NSHL genetics but catalyzes a precision era, enhancing lives across Singapore's universities and clinics.