• Fatemeh Bitarafan, Ehsan Razmara, Ehsan Jafarinia, Navid Almadani, and Masoud Garshasbi.
• Department of Cellular and Molecular Biology, North Tehran Branch, Islamic Azad University, Tehran, Iran.
• Eur. J. Clin. Invest. 2023 Apr 1; 53 (4): e13946e13946.

BackgroundDNA-directed RNA polymerase II subunit 3 (RPB3) is the third largest subunit of RNA polymerase II and is encoded by the POLR2C (OMIM:180663). A large Iranian family with congenital hearing loss and infertility is described here with genetic and clinical characterizations of five male patients.MethodsAfter doing clinical examinations, the proband was subjected to karyotyping and GJB2/6 sequencing to rule out the most evident chromosomal and gene abnormalities for male infertility and hearing loss, respectively. A custom-designed next-generation sequencing panel was also used to detect mutations in deafness-related genes. Finally, to reveal the underlying molecular cause(s) justifying hearing loss and male infertility, five male patients and 2 healthy male controls within the family were subjected to paired-end whole-exome sequencing (WES). Linkage analysis was also performed based on the data.ResultsAll male patients showed prelingual sensorineural hearing loss and also decreased sperm motility. Linkage analysis determined 16q21 as the most susceptible locus in which a missense variant in exon 7 of POLR2C-NM_032940.3:c.545T>C;p.(Val182Ala)-was identified as a 'likely pathogenic' variant co-segregated with phenotypes.ConclusionsUsing segregation and in silico analyses, for the first time, we suggested that the NM_032940.3:c.545T>C; p.(Val182Ala) in POLR2C is associated with hearing loss and male infertility.© 2023 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.

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