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

      Faridi, Rabia; orcid: 0000-0001-7788-8755; Rea, Alessandro; orcid: 0000-0002-6204-846X; Fenollar-Ferrer, Cristina; orcid: 0000-0003-4953-8891; O'Keefe, Raymond T; orcid: 0000-0001-8764-1289; Gu, Shoujun; Munir, Zunaira; orcid: 0000-0003-3342-9658; Khan, Asma Ali; orcid: 0000-0002-0894-3439; Riazuddin, Sheikh; orcid: 0000-0001-6012-0192; Hoa, Michael; orcid: 0000-0001-7469-2909; Naz, Sadaf; orcid: 0000-0002-1912-0235; et al. (2021-08-02)
      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. [Abstract copyright: © 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.]
    • Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney.

      Eales, James M; orcid: 0000-0001-6238-5952; Jiang, Xiao; orcid: 0000-0002-1442-8927; Xu, Xiaoguang; orcid: 0000-0003-4568-1623; Saluja, Sushant; Akbarov, Artur; Cano-Gamez, Eddie; McNulty, Michelle T; Finan, Christopher; orcid: 0000-0002-3319-1937; Guo, Hui; orcid: 0000-0003-0282-6933; Wystrychowski, Wojciech; et al. (2021-05-06)
      The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.