A 6-month-old male infant is referred to audiology following failed newborn hearing screening with absent otoacoustic emissions (OAE) bilaterally. Audiometric testing reveals the pattern marked **D** in the diagram — bilateral symmetric mid-frequency sensorineural hearing loss with preserved low and high frequencies. The child's parents are unrelated and both have normal hearing. Which of the following genetic mutations is the MOST LIKELY cause of this audiogram pattern, and what is the inheritance pattern?

Explanation

## Why Connexin 26 (GJB2) mutation; autosomal recessive is right The cookie-bite audiogram pattern (bilateral symmetric mid-frequency SNHL with preserved low and high frequencies, marked **D**) is the characteristic audiometric signature of NON-SYNDROMIC HEREDITARY HEARING LOSS caused by CONNEXIN 26 (GJB2) mutations. Connexin 26 is a gap junction protein in the cochlear stria vascularis and supporting cells, essential for potassium recycling and cochlear homeostasis. GJB2 mutations account for approximately 50% of all non-syndromic genetic SNHL worldwide and are the most common cause of congenital and early-onset hearing loss. The autosomal recessive inheritance pattern fits perfectly with unaffected parents (both heterozygous carriers) and an affected child. Early identification via UNHS (OAE/AABR by 1 month) and audiometric pattern recognition allows intervention by the critical 3-6 month window for optimal speech-language development (Dhingra ENT 7e; AAP UNHS Guidelines). ## Why each distractor is wrong - **Mitochondrial DNA mutation (m.1555A>G); maternal inheritance**: While this mutation causes SNHL, it typically presents as HIGH-FREQUENCY sensorineural loss (especially after aminoglycoside exposure) and shows maternal inheritance, NOT the bilateral symmetric mid-frequency pattern of the cookie-bite audiogram. The inheritance pattern (unaffected parents with affected child) rules out maternal inheritance. - **Pendrin (SLC26A4) mutation; autosomal recessive**: Pendrin mutations cause SYNDROMIC hearing loss (Pendred syndrome) characterized by thyroid goiter and ENLARGED VESTIBULAR AQUEDUCT (EVA) with fluctuating or progressive SNHL, often triggered by minor head trauma. While autosomal recessive, the audiogram pattern is typically LOW-FREQUENCY or FLAT, not the characteristic cookie-bite mid-frequency loss. Pendrin-related hearing loss is also associated with cochlear deformities (Mondini malformation), not the pattern shown. - **Otoraplin (OTOA) mutation; X-linked recessive**: OTOA mutations cause X-linked progressive SNHL, which would NOT present in an unaffected father with an affected son (X-linked recessive males inherit the mutation from carrier mothers). Additionally, OTOA-related hearing loss is typically progressive and associated with cochlear nerve hypoplasia, not the cookie-bite pattern. **High-Yield:** Cookie-bite audiogram (mid-frequency loss, preserved low + high frequencies) = think GJB2 (Connexin 26) mutation, autosomal recessive, ~50% of non-syndromic genetic SNHL — screen by 1 month, diagnose by 3 months, intervene by 6 months for optimal outcomes. [cite: Dhingra ENT 7e; AAP UNHS Guidelines; Connexin 26 and non-syndromic hearing loss epidemiology]