Abstract
Hearing loss and impaired fertility are common human disorders each with multiple genetic causes. Sometimes deafness and impaired fertility, which are the hallmarks of Perrault syndrome, co-occur in a person. Perrault syndrome is inherited as an autosomal recessive disorder characterized by bilateral mild to severe childhood sensorineural hearing loss with variable age of onset in both sexes and ovarian dysfunction in females who have a 46, XX karyotype. Since the initial clinical description of Perrault syndrome 70 years ago, the phenotype of some subjects may additionally involve developmental delay, intellectual deficit and other neurological disabilities, which can vary in severity in part dependent upon the genetic variants and the gene involved. Here, we review the molecular genetics and clinical phenotype of Perrault syndrome and focus on supporting evidence for the eight genes (CLPP, ERAL1, GGPS1, HARS2, HSD17B4, LARS2, RMND1, TWNK) associated with Perrault syndrome. Variants of these eight genes only account for approximately half of the individuals with clinical features of Perrault syndrome where the molecular genetic base remains under investigation. Additional environmental etiologies and novel Perrault disease-associated genes remain to be identified to account for unresolved cases. We also report a new genetic variant of CLPP, computational structural insight about CLPP and single cell RNAseq data for eight reported Perrault syndrome genes suggesting a common cellular pathophysiology for this disorder. Some unanswered questions are raised to kindle future research about Perrault syndrome.
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Acknowledgements
We thank participants in our studies, Dr. Hafiz Muhammad Waqas Munir assistance with recruitment and Drs. Isabelle Roux and Mhamed Grati for critiques of our manuscript.
Funding
WGN was supported by Action Medical Research (GN2494) and the NIHR Manchester Biomedical Research Centre (IS-BRC-1215-20007) while SN was supported by the Higher Education Commission, Islamabad, Pakistan (HEC 3288). This research was also supported (in part) by the Intramural Research Programs of the NIH, NIDCD, DC000088 to M.H. and DC000039 to T.B.F.
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RF, AR, TBF, WGN, MH, CFF, SN, RTO’K wrote the manuscript, all authors revised drafts of the manuscript. Figures and tables were prepared by RF, TBF, CFF, SG, MH and AR. ZM ascertained family HLZM05 and arranged clinical testing.
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This study was approved by the Institutional Review Boards of the School of Biological Sciences, University of the Punjab, Lahore Pakistan (IRB No. 00005281 to SN), The National Centre of Excellence in Molecular Biology at the University of the Punjab (to SR) and Combined Neurosciences Blue Panel at the National Institutes of Health (OH-93-N-016 to TBF).
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Faridi, R., Rea, A., Fenollar-Ferrer, C. et al. New insights into Perrault syndrome, a clinically and genetically heterogeneous disorder. Hum Genet 141, 805–819 (2022). https://doi.org/10.1007/s00439-021-02319-7
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DOI: https://doi.org/10.1007/s00439-021-02319-7