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POLD3 haploinsufficiency is linked to non-syndromic sensorineural adult-onset progressive hearing and balance impairments

European Journal of Human Genetics volume 33, pages 121–130 (2025)Cite this article

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Abstract

Hearing impairment (HI) is a significant health concern globally, influenced by genetic and environmental factors. We had identified a homozygous pathogenic variant in POLD3 in a Lebanese patient with an autosomal congenital recessive syndromic hearing loss (MIM#620869). This variant was found at heterozygous state in the parents, who developed progressive hearing impairment around age 40. We conducted a thorough clinical and genetic assessment of sixteen family members, including physical exams, audiometry and vestibular function evaluations. Additionally, gene expression analysis of the Pold3 gene was performed in mice using RNAscope. Twelve individuals were heterozygous for the variant in POLD3, of whom eight showed bilateral adult-onset HI, typically starting around ages 40–50, and two older patients displaying unilateral vestibular weakness. Additionally, two carriers of the variant developed cancer at an early age. RNAscope confirmed Pold3 expression in auditory and vestibular neurons. Exome sequencing analysis excluded the presence of pathogenic variants in any known hearing impairment or cancer predisposition genes. We present herein, for the first time, evidence of a heterozygous pathogenic POLD3 variant associated with a novel form of autosomal dominant progressive adult-onset hearing and vestibular impairments. We also highlight the necessity for further exploration of the role of POLD3 in cancer predisposition.

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Fig. 1: Pedigree of the investigated Lebanese family.
Fig. 2: Representative audiograms of three patients (III.19, III.4, and III.14) demonstrating intra- and inter-subject variability in hearing level.
Fig. 3: Representative Distortion Product Otoacoustic Emission (DPOAE) measurements of three patients demonstrating outer hair cell dysfunction in subjects with hearing loss.
Fig. 4: Cervical Vestibular Evoked Myogenic Potential (cVEMP) in three patients (III.19, III.4 and III.14).
Fig. 5: RNA-scope of Cacna1a and Pold3.

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Data availability

The datasets used and analyzed during the current study are available from the corresponding author upon a reasonable request.

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Acknowledgements

We express our deepest gratitude and sympathy to the family for their full cooperation throughout the study.

Funding

This study was funded by the President Intramural Research Fund (PIRF) of the Lebanese American University (PIRF- I0004). Authors did not receive any personal funding. Medical Research Council: MR/X012077/1 (LMF). Medical Research Council: MR/S002510/1 (MMustapha). Imaging work was performed at the Wolfson Light Microscopy Facility, using the Zeiss LSM 980 Airyscan 2 confocal microscope (MRC grant MR/X012077/1).

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Author notes

  1. These authors contributed equally: Eliane Chouery, Cybel Mehawej.

Authors and Affiliations

  1. Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon

    Eliane Chouery, Cybel Mehawej, Sandra Corbani, Rima Korban & Andre Megarbane

  2. Department of Otolaryngology-Head and Neck Surgery, Lebanese American University, Byblos, Lebanon

    Rami Saade & Rana Barake

  3. School of Biosciences, University of Sheffield, Sheffield, UK

    Patryk Zarecki, Catherine Gennery & Mirna Mustapha

  4. Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon

    Ali Hamam & Jade Nasser Eldin

  5. Yamout hearing center, Beirut, Lebanon

    Mohamad Yamout, Mazen Banna & Abdul Kader Afif Yamout

  6. Adhami Advanced Audiology Center, Tripoli, Lebanon

    Fawaz Adhami

  7. Institut Jérôme Lejeune, Paris, France

    Andre Megarbane

  8. Neuroscience Institute, University of Sheffield, Sheffield, UK

    Mirna Mustapha

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  1. Eliane Chouery
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Contributions

EC, CM, MM and AM conceived, designed the study, performed data interpretation, and wrote the manuscript. SC an RK performed DNA experiments and NGS analysis. PZ and CG performed gene expression analysis. RS, RB performed clinical and physical examinations of the patients. MY, MB, AKAY, and FA performed the audiological evaluation. AH and JNE performed the literature review and helped in writing the manuscript. All authors have read and approved the manuscript.

Corresponding authors

Correspondence to Eliane Chouery or Andre Megarbane.

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The authors declare no competing interests.

Ethics approval and consent

Approval to conduct the study was obtained from the Institutional Review Board of the Lebanese American University, Beirut, Lebanon (IRB #:LAU.SOM.EC1.2020.R3.1/Feb/2024). All family members signed an informed consent for participation and sample collection.

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All family members signed an informed consent for data publication.

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Chouery, E., Mehawej, C., Saade, R. et al. POLD3 haploinsufficiency is linked to non-syndromic sensorineural adult-onset progressive hearing and balance impairments. Eur J Hum Genet 33, 121–130 (2025). https://doi.org/10.1038/s41431-024-01715-7

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