A 4-month-old girl born to non-consanguineous parents fails universal newborn hearing screening (absent OAE bilaterally). Audiometry confirms bilateral profound SNHL (90 dB across all frequencies). Tympanometry is normal (type A). MRI temporal bones shows normal cochleovestibular anatomy. Genetic testing reveals a single heterozygous GJB2 mutation (35delG) and a large deletion del(GJB6-D13S1830) on the opposite chromosome. The audiological and genetic findings shown in the diagram at **A** are consistent with which of the following pathophysiological mechanisms?

Question

A 4-month-old girl born to non-consanguineous parents fails universal newborn hearing screening (absent OAE bilaterally). Audiometry confirms bilateral profound SNHL (>90 dB across all frequencies). Tympanometry is normal (type A). MRI temporal bones shows normal cochleovestibular anatomy. Genetic testing reveals a single heterozygous GJB2 mutation (35delG) and a large deletion del(GJB6-D13S1830) on the opposite chromosome. The audiological and genetic findings shown in the diagram at **A** are consistent with which of the following pathophysiological mechanisms?

Accepted Answer

A. Digenic/compound heterozygous loss of gap junction function in cochlear supporting cells and stria vascularis, disrupting potassium recycling and endocochlear potential. ## Why option 1 is correct

The del(GJB6-D13S1830) deletion (~309 kb) removes the cis-acting regulatory element required for GJB2 expression, and when present in trans with a single GJB2 mutation (35delG), creates a digenic/compound heterozygous state with biallelic loss of function. Connexin-26 and connexin-30 form heteromeric gap junctions in cochlear supporting cells, fibrocytes, and stria vascularis that are essential for potassium recycling from hair cells back to endolymph. Loss of both proteins ablates the endocochlear potential, causing outer hair cell death and the severe-to-profound bilateral symmetric SNHL phenotype shown at **A**. This mechanism is indistinguishable clinically from biallelic GJB2 mutations (Cummings Otolaryngology 7e; Smith RJH GeneReviews DFNB1 2023).

## Why each distractor is wrong

- **Option 2**: The patient has one GJB2 mutation (35delG), not two homozygous GJB2 mutations. The second "hit" is the GJB6 deletion affecting GJB2 regulation, not a second GJB2 allele. This mischaracterizes the genetic architecture.
- **Option 3**: Haploinsufficiency (loss of one functional copy) does not explain profound hearing loss; connexin mutations typically require biallelic loss of function. The GJB6 deletion here acts by removing the regulatory element controlling GJB2, not by simple haploinsufficiency of GJB6 itself.
- **Option 4**: The GJB6 deletion does not spare GJB2 expression—it removes the cis-regulatory element needed for GJB2 transcription. GJB6 expression alone cannot compensate for loss of both connexin-26 and connexin-30 function in the potassium recycling pathway.

**High-Yield:** GJB6 del(GJB6-D13S1830) + single GJB2 mutation = digenic DFNB1 deafness; the deletion silences GJB2 via loss of shared regulatory element, not by GJB6 haploinsufficiency.

[cite: Cummings Otolaryngology 7e; Smith RJH GeneReviews — Nonsyndromic Hearing Loss and Deafness, DFNB1 2023]

Answer

B. Haploinsufficiency of GJB6 alone, with GJB2 remaining functionally intact

Answer

C. Regulatory element mutation in GJB2 promoter with preserved GJB6 expression compensating for connexin-26 loss

Answer

D. Homozygous GJB2 mutation causing connexin-26 deficiency with secondary GJB6 downregulation

Explanation

Why option 1 is correct

Why each distractor is wrong

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