1. Exome variant prioritization in a large cohort of hearing-impaired individuals indicates IKZF2 to be associated with non-syndromic hearing loss and guides future research of unsolved cases.
- Author
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Velde HM, Vaseghi-Shanjani M, Smits JJ, Ramakrishnan G, Oostrik J, Wesdorp M, Astuti G, Yntema HG, Hoefsloot L, Lanting CP, Huynen MA, Lehman A, Turvey SE, Pennings RJE, and Kremer H
- Subjects
- Humans, Female, Male, Ikaros Transcription Factor genetics, Cohort Studies, Mutation, Missense, Exome Sequencing, Genetic Predisposition to Disease, Gene Frequency, Adult, Child, Deafness genetics, Exome genetics, Hearing Loss genetics, Pedigree
- Abstract
Although more than 140 genes have been associated with non-syndromic hereditary hearing loss (HL), at least half of the cases remain unexplained in medical genetic testing. One reason is that pathogenic variants are located in 'novel' deafness genes. A variant prioritization approach was used to identify novel (candidate) genes for HL. Exome-wide sequencing data were assessed for subjects with presumed hereditary HL that remained unexplained in medical genetic testing by gene-panel analysis. Cases in group AD had presumed autosomal dominantly inherited HL (n = 124), and in group AR, presumed autosomal recessive HL (n = 337). Variants in known and candidate deafness genes were prioritized based on allele frequencies and predicted effects. Selected variants were tested for their co-segregation with HL. Two cases were solved by variants in recently identified deafness genes (ABHD12, TRRAP). Variant prioritization also revealed potentially causative variants in candidate genes associated with recessive and X-linked HL. Importantly, missense variants in IKZF2 were found to co-segregate with dominantly inherited non-syndromic HL in three families. These variants specifically affected Zn
2+ -coordinating cysteine or histidine residues of the zinc finger motifs 2 and 3 of the encoded protein Helios. This finding indicates a complex genotype-phenotype correlation for IKZF2 defects, as this gene was previously associated with non-syndromic dysfunction of the immune system and ICHAD syndrome, including HL. The designed strategy for variant prioritization revealed that IKZF2 variants can underlie non-syndromic HL. The large number of candidate genes for HL and variants therein stress the importance of inclusion of family members for variant prioritization., (© 2024. The Author(s).)- Published
- 2024
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