USHER SYNDROME

Usher Syndrome — the most common genetic cause of combined deafness and blindness, where identifying the specific gene determines the timeline of vision loss and eligibility for gene therapy trials that could preserve remaining sight.

Whole genome sequencing evaluates all 10+ Usher syndrome genes simultaneously — including USH2A, which requires detection of deep intronic variants missed by standard exon sequencing — providing the molecular diagnosis that determines gene therapy eligibility.

USH2A
MYO7A
CDH23
ADGRV1
CLRN1

About this condition

Usher Syndrome

Usher syndrome is the most common genetic cause of combined hearing loss and vision loss (deaf-blindness), accounting for approximately 50% of hereditary deaf-blindness worldwide. It is an autosomal recessive condition classified into three clinical types: type 1 (congenital profound sensorineural hearing loss, absent vestibular function, prepubertal onset retinitis pigmentosa), type 2 (congenital moderate-to-severe hearing loss, normal vestibular function, teenage-onset RP), and type 3 (progressive hearing loss, variable RP onset). Usher syndrome affects approximately 1 in 6,000-10,000 people.

The genetic basis involves at least 10 genes: USH1 is caused by variants in MYO7A (USH1B, most common type 1), CDH23 (USH1D), PCDH15 (USH1F), USH1C, or USH1G. USH2 is caused by variants in USH2A (the single most common Usher gene, accounting for approximately 50% of all Usher syndrome cases), ADGRV1 (USH2C), or WHRN (USH2D). USH3 is caused by CLRN1 variants (common in Finnish and Ashkenazi Jewish populations). USH2A is among the largest genes in the genome (51 exons spanning ~800kb of genomic DNA), and pathogenic variants include deep intronic variants that create aberrant splice sites — variants that standard exon-sequencing panels do not detect.

Gene therapy clinical trials are actively underway for Usher syndrome — particularly for USH1B (MYO7A) and USH2A retinal degeneration. Subretinal and intravitreal AAV-based gene delivery aims to preserve remaining photoreceptor function in patients with early-stage retinitis pigmentosa. Eligibility for these trials requires molecular confirmation of the specific causative gene and variant, and typically requires sufficient residual retinal function for measurable therapeutic benefit. Early molecular diagnosis — before vision loss becomes severe — maximizes the treatment window for gene therapy intervention.

USH2A deep intronic variants (such as c.7595-2144A>G) create aberrant splice sites that are missed by standard exon-sequencing panels. These variants account for a meaningful proportion of 'missing' USH2A alleles in patients with clinical Usher type 2 and only one identified coding variant.

Gene locus: USH2A (1q41), MYO7A (11q13.5), CDH23 (10q22.1), ADGRV1 (5q14.3), CLRN1 (3q25.1)

USH2A deep intronic pathogenic variants are invisible to exon-panel sequencing. Whole genome sequencing reads across the entire 800kb USH2A locus, detecting the intronic splice variants that resolve previously unsolved Usher type 2 cases.

Gene therapy eligibility requires confirmed molecular diagnosis — and early treatment preserves more vision

Multiple gene therapy clinical trials are in progress for Usher syndrome retinal degeneration, with specific programs targeting MYO7A (USH1B), USH2A, and other genes. Eligibility requires molecular confirmation of the specific causative gene, and most trials require sufficient residual photoreceptor function for measurable therapeutic effect. Because retinitis pigmentosa in Usher syndrome is progressive and irreversible, every year of delayed molecular diagnosis is a year of vision loss that reduces the potential benefit of future gene therapy. Whole genome sequencing in children with sensorineural hearing loss identifies Usher syndrome genotypes before vision symptoms appear — the optimal window for intervention.

Every child with unexplained sensorineural hearing loss should have Usher syndrome evaluated — before RP symptoms appear

Retinitis pigmentosa in Usher syndrome type 2 typically begins with night blindness in the teenage years, with progressive visual field constriction over subsequent decades. By the time RP is clinically apparent, significant photoreceptor loss has already occurred. Identifying USH2A or other Usher gene variants in a child diagnosed with sensorineural hearing loss — years before any visual symptoms — enables proactive ophthalmological monitoring, early enrollment in prevention trials, and psychological preparation for progressive vision loss. This early identification is only possible through molecular testing at the time of hearing loss diagnosis.

Usher Syndrome — the most common genetic cause of combined deafness and blindness, where identifying the specific gene determines the timeline of vision loss and eligibility for gene therapy trials that could preserve remaining sight.

Usher Syndrome

USH2A deep intronic pathogenic variants are invisible to exon-panel sequencing. Whole genome sequencing reads across the entire 800kb USH2A locus, detecting the intronic splice variants that resolve previously unsolved Usher type 2 cases.

Gene therapy eligibility requires confirmed molecular diagnosis — and early treatment preserves more vision

Every child with unexplained sensorineural hearing loss should have Usher syndrome evaluated — before RP symptoms appear

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