A novel missense variant in MYO3A is associated with autosomal dominant high‐frequency hearing loss in a German family

• Published in: Molecular genetics & genomic medicine 2020-08, Vol.8 (8), p.e1343-n/a
• Main Authors: Doll, Julia, Hofrichter, Michaela A. H., Bahena, Paulina, Heihoff, Alfred, Segebarth, Dennis, Müller, Tobias, Dittrich, Marcus, Haaf, Thomas, Vona, Barbara
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Age; Amino acids; Auditory Threshold; autosomal dominant nonsyndromic hearing loss; Bioinformatics; Clinical Report; Clinical Reports; Correlation analysis; Deoxyribonucleic acid; DNA; Domains; Ears & hearing; Female; Genes; Genes, Dominant; Hearing; Hearing loss; Hearing Loss, Sensorineural - genetics; Hearing Loss, Sensorineural - pathology; Heredity; Humans; Kinases; Male; Mutation; Mutation, Missense; MYO3A; Myosin; Myosin Heavy Chains - chemistry; Myosin Heavy Chains - genetics; myosin IIIA; Myosin Type III - chemistry; Myosin Type III - genetics; Pattern analysis; Pedigree; progressive hearing loss; Protein Domains; Proteins; Regression analysis; sensorineural hearing loss; Software; Thresholds
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.1343

Background MYO3A, encoding the myosin IIIA protein, is associated with autosomal recessive and autosomal dominant nonsyndromic hearing loss. To date, only two missense variants located in the motor‐head domain of MYO3A have been described in autosomal dominant families with progressive, mild‐to‐profound sensorineural hearing loss. These variants alter the ATPase activity of myosin IIIA. Methods Exome sequencing of a proband from a three‐generation German family with prelingual, moderate‐to‐profound, high‐frequency hearing loss was performed. Segregation analysis confirmed a dominant inheritance pattern. Regression analysis of mean hearing level thresholds per individual and ear was performed at high‐, mid‐, and low‐frequencies. Results A novel heterozygous missense variant c.716T>C, p.(Leu239Pro) in the kinase domain of MYO3A was identified that is predicted in silico as disease causing. High‐frequency, progressive hearing loss was identified. Conclusion Correlation analysis of pure‐tone hearing thresholds revealed progressive hearing loss, especially in the high‐frequencies. In the present study, we report the first dominant likely pathogenic variant in MYO3A in a European family and further support MYO3A as an autosomal dominant hearing loss gene. A novel heterozygous missense variant c.716T>C, p.(Leu239Pro) in the kinase domain of MYO3A was identified in a German family with high‐frequency autosomal dominant sensorineural hearing loss. We provide in‐depth characterization of the hearing loss progression and confirmatory evidence of MYO3A being associated with autosomal dominant non‐syndromic hearing loss.