A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in...

Heterozygous variant in HOMER2 is associated with autosomal dominant nonsyndromic hearing loss (ADNSHL), designated as the locus of DFNA68. Only five pathogenic variants in HOMER2 have been identified to date.

The aim of this study is to investigate the molecular etiology of ADNSHL in a four-generation Chinese family.

Whole exome sequencing analysis was conducted to detect the disease-causing variant. Co-segregation analysis was performed using Sanger sequencing.

The family exhibited autosomal dominant, progressive, post-lingual, nonsyndromic sensorineural hearing loss, similar to that observed in previously reported DFNA68 families. Unlike the initially high-frequency hearing loss observed in the previously reported families, the young proband in our study (IV:4, 18 years old) exhibited typical low-frequency hearing loss. A novel frameshift variant, c.1023_1029del (p.Asp342ArgfsTer54), in HOMER2 was identified, which co-segregated with the hearing loss phenotype in the family. The variant deletes 7 nucleotides, leading to an extended incorrect protein C terminus. Based on the American College of Medical Genetics and Genomics guidelines, the variant c.1023_1029del (p.Asp342ArgfsTer54) is classified as likely pathogenic.

These findings may help expand the spectrum of pathogenic variants of the HOMER2 gene and provide a molecular interpretation for these patients with ADNSHL.