Reevaluating Usher syndrome: Transitioning from traditional subtypes to precision diagnosis

Abstract

Usher syndrome (USH) should no longer be considered a fixed diagnosis limited to syndromic early-onset sensorineural hearing loss and progressive vision decline due to rod-cone retinal dystrophy. Patients increasingly present with partial or delayed retinal manifestations, often lacking a clinically relevant audiological history. Concurrently, genomic testing uncovers variants that challenge the practical relevance of the traditional definition of type I, II, and III subclassifications. This review argues for a paradigm shift toward genotype-first diagnosis led by ophthalmologists, integrating retinal findings and audiological evaluations with comprehensive genetic information. The rise of gene-specific molecular therapies, including antisense oligonucleotides and CRISPR-mediated gene editing for USH2A and MYO7A, demands timely and accurate molecular categorization for each patient. Delays in precise molecular diagnosis may risk excluding patients from potentially vision-saving trials. Diagnostic gaps persist, including limited variant interpretation tools, underrepresentation of non-Caucasian populations in reference databases, and a lack of standardized retinal imaging protocols. The establishment of centralized, real-time Usher registries and interdisciplinary diagnostic models is essential. The future of USH management lies in anticipatory, individualized care that begins in the retina clinic.

Key Words: Usher syndrome; Precision medicine; Inherited retinal dystrophies; Syndromic retinitis pigmentosa; Gene therapy; Genotype-first diagnostics

Core Tip: Usher syndrome is a genetically and phenotypically heterogeneous disease that can no longer be approached with rigid subtype-based diagnostic criteria. This opinion review highlights the urgent need for genotype-first diagnostic pathways, identifies current limitations in variant interpretation and imaging standardization, and advocates for interdisciplinary care models. It also emphasizes how emerging gene therapies for USH2A, MYO7A, and CLRN1 necessitate early molecular diagnosis to ensure patient eligibility and optimal treatment outcomes.

INTRODUCTION

Usher syndrome (USH), the predominant kind of hereditary deaf-blindness, impacts around 4-17 individuals per 100000 globally[1]. Historically, it has been categorized into three subtypes-USH1, USH2, and USH3-according to the age of onset, severity of hearing impairment, and the presence or absence of vestibular dysfunction. This classification, although useful in clinical practice, fails to encompass the complete range of phenotypic variety seen in contemporary individuals. The rising utilization of next-generation sequencing (NGS) has questioned the adequacy of the subtype-based paradigm[2]. Molecular testing frequently uncovers unforeseen or aberrant genotypes in patients who do not conform to the USH 1-3 classifications[3]. Additionally, certain patients have isolated visual symptoms and are identified as possessing biallelic pathogenic variants in Usher-related genes, despite the absence of characteristic audiological indicators[4,5]. This has resulted in diagnostic delays and lost opportunities for early intervention. The current diagnostic framework for inherited retinal dystrophies (IRDs) necessitates a novel approach that emphasizes genotypic data in conjunction with meticulous phenotyping. Ophthalmologists, frequently the initial contact for patients with retinitis pigmentosa (RP)-like symptoms, are ideally situated to lead the shift towards precise diagnosis. This review consolidates the latest findings from the recent literature and suggests practical techniques to enhance the diagnosis, classification, and treatment of persons with USH.

METHODOLOGY

This narrative opinion review was created to consolidate and critically evaluate recent findings regarding the diagnosis and molecular treatment of USH. A focused literature search was performed on PubMed to locate all publications published in recent years utilizing the search terms, including "Usher syndrome", "inherited retinal dystrophies", "gene therapy", "precision medicine", "CRISPR", and "variant interpretation”. Only articles in the English language were included. Studies were included if they addressed molecular categorization, diagnostic problems, or treatment advancements in USH. Special emphasis was placed on multi-center investigations, opinion reviews, gene therapy trials, and articles concerning variant curation, transcriptomics, and multidisciplinary diagnostic models. Duplicate papers and those lacking original data or expert consensus were omitted. References are mentioned numerically in the text[1-26] and elaborated upon in the final reference list in accordance with journal specifications.

The literature review included articles published from January 2015 to July 2025. The inclusion criteria comprised English-language publications centered on molecular diagnosis, variant interpretation, or therapeutic improvements in USH. Studies devoid of molecular or clinical connections were excluded. A total of 347 records were found, with 216 remaining after the elimination of duplicates. After reviewing the titles and abstracts, 74 papers satisfied the inclusion criteria for comprehensive evaluation. Out of these, 26 references were finally chosen for citation in the publication due to their methodological rigor, clinical significance, and representation of the most recent and influential contributions to the area.

HISTORICAL PERSPECTIVE: THE SUBTYPE FRAMEWORK

USH is classified into three clinical subtypes-USH1, USH2, and USH3-based on specific phenotypes defined in a period when genetic testing was not widely available, necessitating reliance on identifiable clinical patterns for diagnosis. USH1 has historically been linked to congenital, severe hearing impairment, vestibular dysfunction, and early-onset RP. USH2 is defined by moderate, non-progressive auditory impairment, the absence of vestibular symptoms, and visual deterioration commencing in adolescence. USH3, the most uncommon variant, generally entails increasing postlingual hearing impairment, inconsistent vestibular involvement, and a markedly varied start of visual symptoms[2].

This paradigm assisted doctors in prioritizing patients for additional testing and enabled researchers to associate characteristics with newly identified genes. Each subtype was linked to specific genes, including MYO7A, USH1C, CDH23, PCDH15, SANS for USH1; USH2A, ADGRV1, WHRN for USH2; and CLRN1 for USH3[6,7]. This gene-subtype correlation has demonstrated imperfection. Numerous genes, such as USH2A, have been associated with a range of symptoms, while certain patients with MYO7A pathogenic variants have aberrant or isolated characteristics[8]. Moreover, the implementation of the subtype model across several populations has revealed discrepancies. In specific ethnic groups, unique or rare mutations exhibit traits that do not correspond with the anticipated subtype. This has resulted in misdiagnosis and unwarranted delays in diagnosis or misdirected genetic counseling. The variations are exacerbated by the lack of standardized diagnostic techniques, particularly in low-resource environments where genetic testing may not be readily accessible[9].

Recent data indicates that strict compliance with the subtype model may obstruct rather than facilitate prompt and precise diagnosis. A recent study revealed that approximately 25% of patients clinically diagnosed with USH2 were subsequently identified as possessing genotypes typically linked to USH1 or USH3 following comprehensive genomic sequencing[10]. This highlights the necessity to transcend subtype-based frameworks and implement a more adaptable, genotype-oriented diagnostic approach that embraces phenotypic variability and improves diagnostic accuracy.

TRANSCENDING CONVENTIONAL BOUNDARIES: CLINICAL COMPLEXITY

The clinical presentation of patients with USH increasingly challenges conventional classification systems. A consistent number of patients with molecularly verified pathogenic variants in USH2A only exhibit retinal degeneration and lack any documented history of sensorineural hearing loss, even into mid-adulthood[11]. In contrast, children diagnosed with congenital deafness and moderate vestibular symptoms have subsequently developed RP due to genes not often linked to USH, such as ABHD12 and HARS[12]. These examples highlight a significant diagnostic deficiency that occurs when doctors excessively depend on standard symptomatology while neglecting molecular evidence.

Moreover, overlapping syndromes like polyneuropathy, hearing loss, ataxia, RP, and cataract, attributed to biallelic ABHD12 pathogenic variants, frequently resemble Usher disease, leading to misdiagnosis[13]. These conditions are clinically indistinguishable in the early stages without genetic sequencing assistance. Moreover, novel pathologic traits associated with HARS, CEP78, and CEP250 exhibit syndromic characteristics that integrate retinal degeneration and auditory impairment, yet they remain unrecognized within the USH nomenclature[14]. This flexibility in presentation necessitates a diagnostic approach that initiates with an extensive molecular evaluation, rather than relying on inflexible phenotypic assumptions.

Population-based research on consanguineous groups, particularly from South Asia and the Middle East, uncovers unique allelic combinations and atypical inheritance patterns that complicate clinical classification. For instance, extensive sequencing of families in Pakistan revealed dual molecular diagnoses in multiple instances, including compound heterozygosity for USH genes and simultaneous IRD-related mutations[15]. Such findings would be exceedingly difficult to identify using phenotype-first methodologies and underscore the transformational potential of unbiased genetic testing. Advancing imaging methods, such as wide-field autofluorescence and optical coherence tomography angiography, are uncovering novel phenotypic correlations in patients with mild or atypical forms of USH. These modalities, when analyzed in conjunction with genotype, can enhance diagnostic precision and facilitate earlier identification of disease development, especially in asymptomatic carriers or children with negligible functional complaints[16]. Table 1 provides a summary of the characteristic ocular features in USH subtypes and gene-specific manifestations, highlighting their diagnostic utility in conjunction with molecular data.

Table 1 Ocular manifestations of usher syndrome by subtype and gene involvement.

Usher subtype	Causative gene(s)	Onset of visual symptoms	Ocular findings	Imaging features
USH1	MYO7A, CDH23, PCDH15	Early childhood (1st decade)	Night blindness, peripheral vision loss, nystagmus	Bone-spicule pigmentation, attenuated vessels, waxy pallor of optic disc (OCT/FAF)
USH2	USH2A, ADGRV1	Adolescence (2nd decade)	Progressive peripheral visual field loss, nyctalopia	Mid-peripheral retinal degeneration, preserved macula until late (OCT/FAF)
USH3	CLRN1	Variable (2nd-4th decade)	Late-onset RP-like changes, high inter-individual variability	Variable OCT findings; mild-moderate outer retinal thinning
Atypical USH	CEP250, CEP78, HARS, ABHD12	Adolescence-adulthood	RP-like symptoms without classical syndromic hearing loss	Macular atrophy, outer retinal loss, sometimes with foveal sparing or asymmetric loss

FAF: Fundus autofluorescence; OCT: Optical coherence tomography; RP: Retinitis pigmentosa; USH: Usher syndrome.

Although the endorsement for a genotype-first diagnostic approach primarily stems from observational cohort studies and expert consensus, numerous studies have shown diminished diagnostic delays and enhanced patient stratification when genomic testing is conducted prior to audiological referral. The bulk of these studies have utilized non-randomized designs, and selection bias may affect the stated advantages, especially in referral centers with established genetic testing infrastructure. Moreover, the possibility of publishing bias favoring successful implementation models cannot be dismissed. Recognizing these limitations highlights the necessity for standardized prospective trials that compare phenotype-first and genotype-first approaches across various healthcare environments.

In low-income and middle-income countries (LMICs), the implementation of genotype-first diagnostics encounters substantial obstacles, including restricted access to NGS technologies, a shortage of qualified genomic counselors, and the elevated cost per test in relation to per capita health spending. Proposed solutions encompass the implementation of tiered testing frameworks (initiating with targeted founder mutation screening), establishment of regional shared sequencing facilities, and incorporation with teleophthalmology networks for distant variant analysis. International consortia, like IRDiRC and the Global Eye Genetics Consortium, are currently implementing subsidized genomic testing programs in LMIC contexts, which may function as scalable models for diagnosing USH.

FROM PANELS TO PRECISION: GENOMIC TECHNOLOGIES

In the past decade, genomic diagnostics for inherited retinal diseases (IRDs), including USH, have transitioned from phenotype-targeted panels to more comprehensive methods such as whole exome sequencing and whole genome sequencing. These approaches provide unparalleled sensitivity for identifying pathogenic variants, structural rearrangements, and deep intronic variants. Nonetheless, they present intricate interpretation difficulties, especially in USH2A, MYO7A, and ADGRV1, where the occurrence of variants of unknown significance (VUS) is notably elevated[17].

An essential concern is the inadequate annotation of retinal and cochlear-specific transcript isoforms, which hinders the classification of splice-site and deep intronic variations. Certain recognized pathogenic variations exist in non-coding areas that are inadequately represented in conventional panels or insufficiently annotated in reference transcriptomes. This frequently results in false negatives or misinterpretations in diagnostic contexts[18]. The situation is further aggravated by the underrepresentation of non-European ancestries in public genomic datasets, complicating the assessment of allele frequencies and pathogenicity for new variations in global populations[9,17]. Functional tests and transcriptomic data, including RNA sequencing of human retinal organoids, have recently surfaced as complimentary instruments for enhancing diagnostic output. In recent years, multiple studies utilized patient-derived stem cells to elucidate the pathogenic effects of VUS in USH2A, leading to the reclassification of roughly 20% of previously unclear variants[19]. These technologies provide in vitro validation of splicing anomalies or protein misfolding, hence providing essential context to genomic data. For VUS situated in non-coding regions, a pragmatic strategy encompasses: (1) Segregation analysis within extended family members to evaluate co-segregation with phenotype; (2) RNA investigations from patient-derived fibroblasts or induced pluripotent stem cell-derived retinal organoids to identify splicing irregularities; (3) Application of in silico splice prediction algorithms in conjunction with population frequency data; and (4) Regular reanalysis of variants in light of updated databases. Collaborative multicenter efforts to exchange anonymized VUS data, especially from marginalized groups, can expedite reclassification.

Notwithstanding these advancements, the absence of coordinated variant curation initiatives and the ongoing expansion of fragmented databases persist as obstacles. Collaborative initiatives to establish IRD-specific variant interpretation criteria, akin to the ClinGen framework, are under progress but have not yet achieved widespread adoption. Clinical laboratories frequently offer divergent interpretations of identical variants, resulting in inconsistent patient advice. Consequently, accurate diagnosis in USH will necessitate both enhanced sequencing accessibility and standardized protocols for interpretation and data exchange.

FROM GENE THERAPY TO NONSENSE MUTATION SUPPRESSION

The therapeutic landscape for USH has progressed swiftly, propelled by enhanced comprehension of disease mechanisms and advancements in gene-based technology. In 2025, multiple clinical trials focused on USH2A, MYO7A, and CLRN1 progressed to advanced phases, utilizing methodologies like dual adeno-associated viral (AAV) vector delivery, CRISPR-Cas9 editing, and antisense oligonucleotides (ASOs)[20]. In USH2A-related retinopathy, ASOs aimed at exon 13 (e.g., QR-421a) exhibited prolonged exon skipping and visual preservation in phase 2 studies[21]. CRISPR-based methodologies have arisen as a transformative advance in the domain. Ex vivo modification of patient-derived retinal cells utilizing base editors or prime editing tools facilitated the restoration of whole MYO7A transcripts with little off-target effects[22]. These techniques are particularly promising for big genes such as MYO7A, which surpass the packaging capability of AAV vectors.

Nonsense suppression treatments, including ataluren analogs and readthrough-enhancing peptides, are being studied for USH1C and other genotypes with premature stop codons. In 2025, preclinical models exhibited partial restoration of harmonin expression in organotypic retinal cells[23]. Nonetheless, clinical translation is impeded by inconsistent effectiveness and systemic toxicity profiles. Ongoing refinement of formulation and distribution will be essential prior to these drugs entering phase 3 studies. Gene supplementation with dual AAV vectors has advanced, especially for MYO7A, which cannot be encapsulated in single-vector constructions. Dual AAV experiments demonstrated effective restoration of protein expression and partial amelioration of retinal degeneration in mouse and monkey models[24].

All citations about 2025 clinical trial findings originate from peer-reviewed articles or data available on ClinicalTrials.gov as of July 2025. Therapeutic treatments labeled as ‘in progress’ or ‘anticipated’ indicate planned or current trials with publicly accessible protocols, although lack peer-reviewed efficacy data.

RECONCEPTUALIZING CLINICAL MODELS

As precision medicine transforms the management of hereditary retinal diseases, the clinical approach for treating USH must adapt accordingly. Conventional referral frameworks-where audiology, ophthalmology, and genetics operate independently rather than collaboratively-are inadequate for the requirements of molecular diagnosis. Several recent reports highlighted the efficacy of combined retina-audiology-genetics clinics in decreasing diagnostic delays and enhancing patient understanding of their disease[18,25]. These interdisciplinary models are especially vital for young patients, when early identification can greatly affect visual and auditory outcomes. Integrating genotype-first methodologies into ophthalmic practice necessitates the standardization of phenotypic assessment and genomic analysis. All patients exhibiting RP, regardless of hearing loss, should receive syndromic gene panel testing. Simultaneously, baseline audiometry and vestibular assessments should commence irrespective of subjective complaints. This proactive screening guarantees that atypical Usher cases are not neglected and facilitates early integration into suitable surveillance and treatment protocols.

Telemedicine and regional referral networks have evolved as effective mechanisms for providing multidisciplinary treatment to disadvantaged populations. In nations with centralized healthcare systems, virtual IRD boards-comprising collaborative assessments of intricate cases by retina specialists, molecular geneticists, and neuro-otologists-have enhanced diagnostic outcomes and promoted equitable access[26]. To ensure the success of these new models, training programs in ophthalmology and audiology must incorporate cross-disciplinary experience. Proficiency in American College of Medical Genetics and Genomics variant interpretation standards, gene therapy trial design, and the natural history of IRDs is now essential for retina specialists. As genotyping emerges as the gateway to diagnosis and treatment, ophthalmologists must take a leading role in navigating patients through a progressively intricate clinical and therapeutic environment.

USHER REGISTRY: REAL-TIME, GENOTYPE-ASSOCIATED CLINICAL DATA

The absence of centralized, dynamic data collecting constitutes a significant constraint in the progression of treatment for USH. Despite the existence of national IRD registries, they frequently lack the necessary granularity and update frequency for clinical trial recruitment, epidemiological investigations, and real-world therapy monitoring. A strategy would be the establishment of a federated, multinational Usher registry that would include genetic, phenotypic, and longitudinal clinical data. This technology would facilitate genotype-phenotype association, monitor natural history by gene variant, and assist in timely trial matching.

This kind of registry must utilize established ontologies for phenotype description (e.g., Human Phenotype Ontology words), harmonized variant nomenclature (e.g., Human Genome Variation Society), and ensure interface with current databases like as Clin Var, gnomAD, and Leiden Open Variation Database to be effective. Furthermore, it should encompass longitudinal updates from collaborating providers and patients, preferably via user-friendly interfaces and automatic electronic health record integration.

Ethical considerations are also crucial. Cross-border data exchange must comply with General Data Protection Regulation and like standards, necessitating stringent consent management and de-identification methods. Patient advocacy organizations must play a central role in governance, prioritizing, and dissemination, rather than a marginal one. Enabling patients to provide data, obtain insights, and engage in trial readiness programs will expedite the shift from registry to research ecosystem.

The genotype-first diagnosis approach for USH commences with the detection of retinal anomalies, predominantly rod-cone dystrophy, by an ophthalmologist, irrespective of the patient's auditory condition. At this preliminary stage, extensive syndromic gene panel testing encompassing all identified USH genes and pertinent IRD-associated genes should commence. Upon detection of pathogenic or suspected pathogenic variations, focused audiometric and vestibular assessments should be conducted, even in asymptomatic people, to ascertain or exclude syndromic involvement. In instances where a variant of unknown importance is detected, it is advisable to do segregation analysis, functional assays, and periodic re-evaluation of the variant categorization. Upon establishing the genetic diagnosis, patients must be referred for a multidisciplinary evaluation encompassing ophthalmology, audiology, and clinical genetics, with incorporation into a real-time registry to enhance follow-up, trial preparedness, and longitudinal surveillance. This organized process guarantees prompt and precise molecular identification, minimizes diagnostic delays, and synchronizes clinical care with new gene-specific treatment options.

CONCLUSION

The domain of USH research and clinical management is at a pivotal juncture. Although historical subtype classification has established a valuable foundation, it fails to represent the molecular and clinical intricacies evident in actual cohorts. The increasing accessibility of molecular testing, alongside advancements in transcriptomics, imaging, and gene-targeted medicines, necessitates a comprehensive reassessment of diagnostic and therapeutic strategies. Ophthalmologists are now responsible for commencing the diagnosis process for several patients with syndromic retinal dystrophies. This obligation requires proficiency in retinal imaging, clinical genetics, the advancing field of pharmaceutical trials, and frameworks for variation interpretation. Timely molecular diagnosis is essential for facilitating prompt intervention and enhancing patient stratification for gene therapy.

The future of USH treatment will be collaborative, proactive, and based on molecular evidence. Integrated clinics, virtual care platforms, and centralized genotype-phenotype registries are essential. Precision medicine commences not in the laboratory but in the clinical setting-with professional dedicated retina experts who can recognize the potential complexity of signs and symptoms, and performing accurate genotype-phenotype correlations. In this evolving paradigm, USH is not merely a rare condition to categorize but a complex task to address-from the retina outward.