Figure 1.

Pedigree Drawings, Clinical Data, and Mutation Information for Families Affected by KARS Variants

(A–C) Family 4338 (A), affected by the c.1129G>A (p.Asp377Asn) variant, and families 4406 (B) and 4284 (C), affected by the c.517T>C (p.Tyr173His) variant segregating with hearing impairment. Each family has a unique haplotype within the DFNB89 locus.

(D) Air-conduction audiograms for individuals V-6 of family 4338 (black solid), IV-2 of family 4406 (gray), and IV-2 of family 4284 (black dotted). Circles are for the right ear, and crosses are for the left ear. All three individuals have symmetric, moderate-to-profound impairment across all frequencies.

(E) Multiple-sequence alignment showing evolutionary conservation of amino acid residues Asp377 and Tyr173 (black arrows) in humans, chickens, mice, and zebrafish.

(F) Chromatograms comparing an HI individual who is homozygous for each KARS variant, a heterozygous carrier, and an individual with normal hearing.

(G) Auditory brainstem response (ABR) tracings at 80–100 dB from two individuals from family 4406. Red lines are for the right ear, and blue lines are for the left ear. Crosses mark the latency peaks at waves I, III, and V. ABR waveforms were well formed in both individuals but showed unilateral delay in interpeak latencies I-III or I-V and a difference > 0.2 ms in the interaural latencies of wave V. For individual IV-2, the delay in interpeak I-III or I-V was seen only at 100 dB, but not at 90 dB. Additionally, individual IV-7 had an absent compliance peak from tympanometry on the left ear, suggesting otitis media or middle-ear effusion at the time of testing, which could explain the latency delays on the left ear compared to the right ear. Otoacoustic emissions (OAEs) were bilaterally absent in both individuals, ruling out auditory neuropathy.