Efficiency of Exploration of Molecular Genetic Etiology for Cochlear Implantees and Its Implication

Abstract

Objectives: Evaluate the efficiency of exploration of molecular genetic etiology for cochlear implantees (CI). Methods: Ninety-four patients of 273 CIs who consented to molecular genetic testing (MGT) were included. Patients with either a characteristic radiologic or audiologic marker were subject to Sanger sequencing of corresponding candidate genes. The GJB2 gene was sequenced in patients with no phenotypic marker. Targeted resequencing of known 200 deafness genes (TRS-200) was applied to GJB2-negative cases with no phenotypic marker. The recurrence risk of hearing loss (HL) between undiagnosed probands after TRS-200 and diagnosed probands with autosomal recessive genotype was evaluated. Results: Thirty of 42 probands (71.4%) who underwent the direct Sanger sequencing of candidate genes were diagnosed. The most rewarding phenotypic markers were enlarged vestibular aqueduct (with/without incomplete partition [IP] type II) and IP type III, followed by long QT syndrome, lateral semicircular canal dysplasia as a part of the constellation of anomalies suggesting a CHARGE syndrome, and ski-slope type high frequency HL. Focusing upon these 5 markers, the detection rate went up to 83.3% (30/36). Ten of 52 probands carried mutant allele of GJB2. The detection rate by TRS-200 was 26.0% (12/46). The recurrent risk of HL was calculated to 0.03 (95% confidence interval [CI] 0-0.13) in undiagnosed group and 0.18 (95% CI 0.09-0.34) in diagnosed probands. Conclusions: Molecular genetic diagnosis was made in 55.3% (52/94) of CIs through our hierarchical MGT. The sequencing of high-yield candidate genes associated with phenotypic markers will be useful for evaluating deaf patients cost-effectively before applying next generation sequencing. A Mendelian genetic etiology does not seem to contribute to undiagnosed probands after TRS-200.