Somatic mosaicism of a novel USH2A variant in Usher syndrome

To report the clinical and genetic features of a sporadic case of Usher syndrome type II and to explore the potential role of somatic mosaicism in its pathogenesis, thereby providing evidence for genetic counseling.

A 60-year-old Chinese male underwent comprehensive ophthalmic and audiological examinations. Genetic testing was performed using next-generation sequencing, followed by Sanger sequencing for validation. Ultra-deep sequencing (~10,000×) was conducted to quantify the mutant allele frequency. Short tandem repeat (STR) analysis was performed to evaluate parentage and further investigate the underlying genetic mechanism.

The patient presented with progressive visual decline since childhood, congenital sensorineural hearing loss, and night blindness. Ophthalmic evaluation revealed severe retinal degeneration, and audiological testing confirmed hearing impairment. Genetic analysis identified a novel homozygous nonsense mutation in USH2A (c.3020C>G; p.S1007*), while all other family members carried the reference allele. Sanger sequencing showed a low-level secondary peak, and ultra-deep sequencing demonstrated a mutant allele frequency of 98.2%, indicating somatic mosaicism. STR analysis confirmed normal maternal-offspring relationships but showed deviation at D1S1656, further supporting mosaicism. The patient's apparent homozygous mutation, absent in other family members, cannot be explained by classical Mendelian inheritance.

This case highlights a rare genetic mechanism of Usher syndrome type II associated with somatic mosaicism. The findings expand the mutational spectrum of USH2A, refine genotype-phenotype correlations, and underscore the importance of considering somatic mosaicism in sporadic cases for accurate genetic counseling and recurrence risk assessment.