Non-invasive Prenatal MT-RNR1 Pharmacogenetic Testing for the Prevention of Aminoglycoside-Induced Profound Hearing Loss

Irreversible profound hearing loss in early childhood impairs severely the development of spoken language, behavior and cognition. Hearing loss caused by aminoglycoside antibiotics in neonates treated for sepsis in intensive care units is linked to variants in the MT-RNR1 gene. Identifying the population at risk in acute medical settings is substantially limited by genotyping restricted to m.1555A>G only with 20% failure rate of the currently approved point-of-care test. We report an innovative prenatal pharmacogenetic approach based on the parallel genome-wide analysis of mitochondrial and nuclear cell-free DNA which co-exist in routine non-invasive prenatal testing (NIPT) sequencing data. Following analysis of 5,529 NIPT cases, we reached to 99.3% cumulative call rate with100% sensitivity and specificity for the clinically actionable variants m.1095T>C, m.1494C>T and m.1555A>G. Since NIPT is a globally adopted first and second-tier prenatal test, our approach could revolutionize early intervention strategies for aminoglycoside-induced hearing loss and improve clinical decision-making.