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Clinical Characterizations and Molecular Genetic Study of Two Co-Segregating Variants in Pdzd7 and Pde6c Genes Leading Simultaneously to Non-Syndromic Hearing Loss and Achromatopsia Publisher Pubmed



Nouri Z1, 2 ; Sarmadi A1, 2 ; Narrei S1, 3 ; Kianersi H4 ; Kianersi F5 ; Tabatabaiefar MA1, 2, 6
Authors
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Authors Affiliations
  1. 1. Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
  2. 2. Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
  3. 3. Department of Research and Development, Harmonic Medical Genetics Lab, Isfahan, Iran
  4. 4. Isfahan Eye Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
  5. 5. Department of Ophthalmology, Isfahan University of Medical Sciences, Isfahan, Iran
  6. 6. University of Medical Sciences, Isfahan, 81746-73461, Iran

Source: BMC Medical Genomics Published:2024


Abstract

Background: Autosomal recessive non-syndromic hearing loss (NSHL) and cone dystrophies (CODs) are highly genetically and phenotypically heterogeneous disorders. In this study, we applied the whole exome sequencing (WES) to find the cause of HL and COD in an Iranian consanguineous family with three affected individuals. Methods: Three members from an Iranian consanguineous family who were suffering from NSHL and visual impairment were ascertained in this study. Comprehensive clinical evaluations and genetic analysis followed by bioinformatic and co-segregation studies were performed to diagnose the cause of these phenotypes. Data were collected from 2020 to 2022. Results: All cases showed congenital bilateral NSHL, decreased visual acuity, poor color discrimination, photophobia and macular atrophy. Moreover, cornea, iris and anterior vitreous were within normal limit in both eyes, decreased foveal sensitivity, central scotoma and generalized depression of visual field were seen in three cases. WES results showed two variants, a novel null variant (p.Trp548Ter) in the PDE6C gene causing COD type 4 (Achromatopsia) and a previously reported variant (p.Ile84Thr) in the PDZD7 gene causing NSHL. Both variants were found in the cis configuration on chromosome 10 with a genetic distance of about 8.3 cM, leading to their co-inheritance. However, two diseases could appear independently in subsequent generations due to crossover during meiosis. Conclusions: Here, we could successfully determine the etiology of a seemingly complex phenotype in two adjacent genes. We identified a novel variant in the PDE6C gene, related to achromatopsia. Interestingly, this variant could cooperatively cause visual disorders: cone dystrophy and cone-rod dystrophy. © The Author(s) 2024.
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