CoGenesis® Hearing & Ear

CoGenesis® Hearing & Ear is a targeted next-generation sequencing (NGS) panel covering 589 genes across four disease categories of hereditary hearing and ear disorders. It is designed to identify the underlying genetic cause in patients with congenital or progressive hearing loss, auditory neuropathy, vestibular dysfunction, or ear malformations.

Hearing loss is a common sensory disorder in humans, often with a genetic basis. It is clinically and genetically heterogeneous: more than 100 genes are implicated in hereditary hearing loss, with autosomal recessive, autosomal dominant, and X-linked all represented. Early molecular diagnosis enables audiological management planning, determination of progression risk, family counselling, and access to cochlear implantation programmes that require genetic eligibility criteria.

Non-syndromic hearing loss: The largest disease category. GJB2 (connexin 26) is the single most common cause of hereditary non-syndromic sensorineural hearing loss (SNHL) worldwide, accounting for up to 50% of cases in some populations; the panel comprehensively covers GJB2 and its co-implicated connexins GJB3, GJB4, GJB5, and GJB6. Other key non-syndromic genes include OTOF (DFNB9, auditory neuropathy), SLC26A4 (DFNB4/Pendred syndrome), COCH (DFNA9, late-onset dominant SNHL), KCNQ4 (DFNA2), DIAPH1, DIAPH3, ACTG1, ESPN, ESRRB, LHFPL5, LOXHD1, MARVELD2, MSRB3, OTOA, OTOG, OTOGL, P2RX2, RIPOR2, SERPINB6, TMIE, and numerous MYO family genes (MYO7A, MYO6, MYO15A, MYO3A).

Syndromic hearing loss: A substantial portion of hereditary hearing loss occurs as part of broader syndromes. Usher syndrome is the leading cause of combined deaf-blindness, and it is caused by mutations in CDH23, ADGRV1, MYO7A, PCDH15, CLRN1, CLRN2, and PDZD7. Waardenburg syndrome (PAX3, MITF, EDN3, EDNRB) combines hearing loss with pigmentation anomalies and is the most common cause of autosomal dominant syndromic hearing loss. Branchio-oto-renal (BOR) syndrome (EYA1, SIX1) presents with branchial cysts, ear anomalies, and renal malformations. CHARGE syndrome (CHD7) causes coloboma, heart defects, choanal atresia, growth retardation, genital anomalies, and ear anomalies. Alport syndrome (COL4A3, COL4A4, COL4A5, COL4A6) causes progressive nephropathy with SNHL. Stickler syndrome (COL11A1, COL11A2, COL2A1) presents with sensorineural or mixed hearing loss and vitreoretinal degeneration. Pendred syndrome (SLC26A4) is the leading cause of syndromic autosomal recessive SNHL with enlarged vestibular aqueduct.

Auditory neuropathy and X-linked hearing loss: OTOF mutations cause auditory neuropathy spectrum disorder (ANSD), characterised by present otoacoustic emissions but absent or abnormal ABR, a distinction critical for cochlear implant candidacy. POU3F4 and PRPS1 underlie the most common X-linked forms.

A confirmed genetic diagnosis may guide clinical implications: cochlear implant candidacy criteria in several programmes require molecular confirmation; OTOF mutations predict implant or gene therapy outcomes.

1. Infants and children with congenital or early-onset sensorineural hearing loss identified on universal newborn hearing screening, in whom genetic diagnosis will guide audiological management, cochlear implant assessment, and parental recurrence risk counselling.

2. Patients of any age with progressive, fluctuating, or asymmetric SNHL of unexplained aetiology, including those with enlarged vestibular aqueduct on imaging (SLC26A4 screening) or those with a family history pattern consistent with autosomal dominant, recessive, or X-linked inheritance.

3. Children or adults with auditory neuropathy spectrum disorder (ANSD), characterised by present OAEs and absent/abnormal ABR, where OTOF mutation confirmation predicts favourable cochlear implant outcomes and guides counselling regarding implantation timing.

4. Patients with hearing loss as part of a recognised or suspected syndrome, including Usher syndrome (for early retinal surveillance and mobility planning), Waardenburg syndrome, Pendred syndrome, BOR syndrome, CHARGE syndrome, Alport syndrome, and Stickler syndrome, where molecular confirmation enables multi-system surveillance and specialist co-management.

4 sub-panels included:

4mL Peripheral blood (EDTA), 2mL saliva, or buccal swab

Preferred sample type:

• 4mL Blood (EDTA tube),
• Codex-provided buccal swabs (4 swabs)
• Codex-provided saliva collection kit (2mL)

Saliva or buccal swab sample collection: Follow the enclosed instructions; do not eat, drink, or smoke for 30 minutes before collection.

• Results may identify pathogenic, likely pathogenic, or variants of uncertain significance (VUS).
• Positive findings can inform risk‑reducing strategies and treatment options.
• Genetic counseling is recommended to help families understand implications.

Hereditary hearing loss is the most prevalent sensory disorder with a genetic basis, affecting approximately 1–3 per 1,000 newborns and rising to 1 in 500 by school age when late-onset forms are included. Over 50% of congenital hearing loss is genetic in origin. More than 120 genes are implicated, with an estimated 400 disease-causing variants identified in GJB2 alone. The genetic architecture spans all Mendelian inheritance modes: autosomal recessive (most common, ~80%), autosomal dominant (~15–20%), X-linked (~1–2%).

GJB2 (gap junction protein connexin 26) is the most extensively studied hearing loss gene globally. The c.35delG variant accounts for up to 70% of GJB2-related deafness in European populations; other common variants include c.167delT (prevalent in Ashkenazi Jewish populations) and c.235delC (prevalent in East Asian populations). GJB2-related SNHL is typically congenital, bilateral, and ranges from moderate to profound. Importantly, GJB2 mutations are the strongest positive predictor of successful cochlear implant outcomes. Despite GJB2's high prior probability, single-gene testing misses the substantial fraction attributable to GJB6 co-deletions and the remaining 40+ non-syndromic SNHL genes.

Usher syndrome is the leading cause of combined deaf-blindness, occurring in approximately 1 in 6,000–25,000 individuals. Type 1 (USH1; CDH23, MYO7A, PCDH15, ADGRV1) presents with profound congenital deafness, vestibular dysfunction, and prepubertal retinitis pigmentosa (RP) onset. Type 2 (USH2; ADGRV1, WHRN) causes moderate-severe HL with postpubertal RP and no vestibular involvement. Early molecular diagnosis is critical: RP in Usher syndrome is progressive and ultimately causes blindness, but early ophthalmological intervention and mobility planning (orientation/Braille training) can preserve quality of life. Gene therapy trials targeting MYO7A and CLRN1 are in progress.

Alport syndrome (COL4A3, COL4A4, COL4A5) causes progressive nephropathy alongside SNHL and ocular anomalies. X-linked Alport syndrome affects ~1 in 5,000 and results in end-stage renal disease by the third decade in males. Early diagnosis enables nephroprotective therapy (ACE inhibitors/ARBs) that demonstrably slows renal progression when initiated before proteinuria develops. Female carriers of COL4A5 mutations may have haematuria and late-onset renal involvement, warranting long-term monitoring.

The clinical urgency of molecular diagnosis in hearing loss is further reinforced by cochlear implantation access criteria: multiple paediatric cochlear implant programmes now require genetic confirmation as part of pre-implant evaluation, particularly for ANSD (OTOF diagnosis) and for post-lingual progressive SNHL (where identifying a causative gene refines prognosis and implantation timing). CoGenesis® Hearing & Ear provides comprehensive molecular coverage of this genetically complex landscape in a single efficient NGS workflow.