A number sign (#) is used with this entry because of evidence that otosclerosis-12 (OTSC12) is caused by heterozygous mutation in the SMARCA4 gene (603254) on chromosome 19p13. One such family has been reported.

Otosclerosis-12 (OTSC12) is characterized by progressive hearing loss resulting from abnormal bone remodeling (summary by Drabkin et al., 2024).

For a general phenotypic description and discussion of genetic heterogeneity of otosclerosis, see OTSC1 (166800).

Drabkin et al. (2024) reported 7 members over 2 generations of a family with otosclerosis and mutation in the SMARCA4 gene. The proband (IV:1) was a man with progressive hearing loss beginning in his early thirties, who underwent bilateral stapedectomy with minimal improvement of hearing in his right ear; he used bilateral hearing aids. His mother and maternal grandparents reported normal hearing, although a maternal aunt (III:1) and uncle (III:2) had confirmed otosclerosis, with onset around age 30. The proband's second cousin (IV:2) experienced progressive hearing loss starting in early childhood; cranial CT revealed bilateral otosclerosis. Her father and paternal grandparents were deceased, but had no history of hearing loss. However, 3 paternal uncles had hearing loss, 2 with onset at age 65 (III:5 and III:6), and the third (III:7) with onset of progressive deafness in his late twenties. The authors noted that patients from generation III were not available for clinical evaluation; all information was gathered from family history. The affected individuals with hearing loss who participated in the study were otherwise healthy, with no chronic illnesses or other significant health problems.

The transmission pattern of OTSC12 in the family reported by Drabkin et al. (2024) was consistent with autosomal dominant inheritance with incomplete penetrance.

In 6 affected members of a 2-generation family with otosclerosis, Drabkin et al. (2024) identified heterozygosity for a missense mutation in the SMARCA4 gene (E1610K; 603254.0013). The pedigree showed incomplete penetrance, with obligate carrier parents reporting normal hearing.

Using CRISPR/Cas9, Drabkin et al. (2024) created transgenic mice carrying the human E1610K mutation in the mouse ortholog. Heterozygous mutant mice showed no overt morphologic or behavioral abnormalities compared to their wildtype littermates, and had no gross anatomic anomalies on whole-body X-rays. However, acoustic startle response testing in awake 4-month-old mutant mice revealed hearing impairment, with significantly reduced startle amplitudes at almost all tested stimulus volumes, compared to wildtype mice. Auditory brainstem response testing showed modest but consistently elevated thresholds in the mutant mice, both to pure tone stimuli across all tested frequencies and to broadband (click) stimuli. The authors also studied auditory bullae (the equivalent of the otic capsule in humans) from the mutant mice and observed malformations in the auditory ossicles. Detailed dissection revealed abnormal incus bones, with a malformed lentiform process showing thickening of the distal part of the long crus, as well as a hypoplastic short crus. Micro-CT 3D-reconstructed images of the auditory ossicles confirmed the results, demonstrating a highly irregular structure of the incus bone involving both the incudomalleolar and incudostapedial joints.