New insights into Perrault syndrome, a clinically and genetically heterogeneous disorder

• Published in: Human genetics Vol. 141; no. 3-4; pp. 805 - 819
• Main Authors: Faridi, Rabia, Rea, Alessandro, Fenollar-Ferrer, Cristina, O’Keefe, Raymond T., Gu, Shoujun, Munir, Zunaira, Khan, Asma Ali, Riazuddin, Sheikh, Hoa, Michael, Naz, Sadaf, Newman, William G., Friedman, Thomas B.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.04.2022; Springer; Springer Nature B.V
• Subjects: Amino Acyl-tRNA Synthetases - genetics; Biomedical and Life Sciences; Biomedicine; Cell Cycle Proteins - genetics; Child; Children; Computational neuroscience; Deafness; Development and progression; Female; Fertility; Gene Function; Genetic aspects; Genetic diversity; Gonadal Dysgenesis, 46,XX - genetics; Hearing loss; Hearing Loss, Sensorineural - genetics; Hereditary diseases; Human Genetics; Humans; Karyotypes; Male; Medical research; Medicine, Experimental; Metabolic Diseases; Molecular genetics; Molecular Medicine; Mutation; Pedigree; Phenotypes; Review; The Molecular Genetics of Hearing and Deafness
• ISSN: 0340-6717; 1432-1203; 1432-1203
• DOI: 10.1007/s00439-021-02319-7

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.