Unraveling the genetic complexities of combined retinal dystrophy and hearing impairment

• DOI: 10.1007/s00439-021-02303-1
• Publication Date: 2021-06-19T23:04:35Z
• Authors: Paulina Bahena; Narsis Daftarian; Reza Maroofian; Paola Linares; Daniel Villalobos; Mehraban Mirrahimi; Aboulfazl Rad; Julia Doll; Michaela A. H. Ho...; Asuman Koparir; Tabea Röder; Seungbin Han; Hamideh Sabbaghi; Hamid Ahmadieh; Hassan Behboudi; Cristina Villanue...; Vianney Cortés-Go...; Rocio Zamora-Ortiz; Susanne Kohl; Laura Kuehlewein; Hossein Darvish; Elham Alehabib; Maria de la Luz A...; Fatemeh Suri; Barbara Vona; Thomas Haaf
• Keywords: 0301 basic medicine; ddc:610; Retinal Degeneration; Mutation [MeSH] ; Humans [MeSH] ; Molecular Medicine ; Iran [MeSH] ; Original Investigation ; Pedigree [MeSH] ; Usher Syndromes/diagnosis [MeSH] ; Metabolic Diseases ; Usher Syndromes/genetics [MeSH] ; Gene Function ; Phenotype [MeSH] ; The Molecular Genetics of Hearing and Deafness ; Retinal Degeneration/genetics [MeSH] ; Human Genetics; Iran; Pedigree; 3. Good health; 03 medical and health sciences; Phenotype; Mutation; Humans; 10. No inequality; Usher Syndromes; Original Investigation

AbstractUsher syndrome, the most prevalent cause of combined hereditary vision and hearing impairment, is clinically and genetically heterogeneous. Moreover, several conditions with phenotypes overlapping Usher syndrome have been described. This makes the molecular diagnosis of hereditary deaf–blindness challenging. Here, we performed exome sequencing and analysis on 7 Mexican and 52 Iranian probands with combined retinal degeneration and hearing impairment (without intellectual disability). Clinical assessment involved ophthalmological examination and hearing loss questionnaire. Usher syndrome, most frequently due to biallelic variants in MYO7A (USH1B in 16 probands), USH2A (17 probands), and ADGRV1 (USH2C in 7 probands), was diagnosed in 44 of 59 (75%) unrelated probands. Almost half of the identified variants were novel. Nine of 59 (15%) probands displayed other genetic entities with dual sensory impairment, including Alström syndrome (3 patients), cone-rod dystrophy and hearing loss 1 (2 probands), and Heimler syndrome (1 patient). Unexpected findings included one proband each with Scheie syndrome, coenzyme Q10 deficiency, and pseudoxanthoma elasticum. In four probands, including three Usher cases, dual sensory impairment was either modified/aggravated or caused by variants in distinct genes associated with retinal degeneration and/or hearing loss. The overall diagnostic yield of whole exome analysis in our deaf–blind cohort was 92%. Two (3%) probands were partially solved and only 3 (5%) remained without any molecular diagnosis. In many cases, the molecular diagnosis is important to guide genetic counseling, to support prognostic outcomes and decisions with currently available and evolving treatment modalities.