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.

Autor: Velde HM; Department of Otorhinolaryngology, Radboudumc, Nijmegen, The Netherlands.; Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands., Vaseghi-Shanjani M; Department of Pediatrics, The University of British Columbia and BC Children's Hospital, Vancouver, BC, Canada., Smits JJ; Department of Otorhinolaryngology, Radboudumc, Nijmegen, The Netherlands.; Department of Clinical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., Ramakrishnan G; Department of Medical Biosciences, Radboudumc, Nijmegen, The Netherlands., Oostrik J; Department of Otorhinolaryngology, Radboudumc, Nijmegen, The Netherlands., Wesdorp M; Department of Otorhinolaryngology, Radboudumc, Nijmegen, The Netherlands., Astuti G; Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands., Yntema HG; Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands.; Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands., Hoefsloot L; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands., Lanting CP; Department of Otorhinolaryngology, Radboudumc, Nijmegen, The Netherlands.; Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands., Huynen MA; Center for Molecular and Biomolecular Informatics, Radboudumc, Nijmegen, The Netherlands., Lehman A; Department of Pediatrics, The University of British Columbia and BC Children's Hospital, Vancouver, BC, Canada., Turvey SE; Department of Pediatrics, The University of British Columbia and BC Children's Hospital, Vancouver, BC, Canada., Pennings RJE; Department of Otorhinolaryngology, Radboudumc, Nijmegen, The Netherlands.; Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands., Kremer H; Department of Otorhinolaryngology, Radboudumc, Nijmegen, The Netherlands. Hannie.Kremer@radboudumc.nl.; Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands. Hannie.Kremer@radboudumc.nl.
Jazyk: angličtina
Zdroj: Human genetics [Hum Genet] 2024 Oct 16. Date of Electronic Publication: 2024 Oct 16.
DOI: 10.1007/s00439-024-02706-w
Abstrakt: 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).)
Databáze: MEDLINE
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