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.

Publisher: Springer Verlag Country of Publication: Germany NLM ID: 7613873 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-1203 (Electronic) Linking ISSN: 03406717 NLM ISO Abbreviation: Hum Genet Subsets: MEDLINE

Publication: Berlin : Springer Verlag
Original Publication: Berlin, New York, Springer-Verlag.

Exome*/genetics ; Hearing Loss*/genetics ; Pedigree*; Humans ; Female ; Male ; Ikaros Transcription Factor/genetics ; Cohort Studies ; Mutation, Missense ; Exome Sequencing ; Genetic Predisposition to Disease ; Gene Frequency ; Adult ; Child ; Deafness/genetics

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).)

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Investigator: E Aten; MJ van den Boogaard; FLJ Cals; MF van Dooren; FA Ebbens; I Feenstra; RH Free; HHW de Gier; TPM Goderie; L Haer-Wigman; K Hellingman; EH Hoefsloot; JR Hof; J van de Kamp; SG Kant; JSK Wassink-Ruiter; H Kremer; M Kriek; AMA Lachmeijer; CP Lanting; SM Maas; P Merkus; RJE Pennings; A Plomp; FG Ropers; LJC Rotteveel; MP van der Schroeff; AL Smit; JJ Smits; V Vernimmen; JCC Widdershoven; HG Yntema

148971-36-2 (Ikaros Transcription Factor)

Date Created: 20241015 Date Completed: 20241029 Latest Revision: 20241101

20241101

PMC11522133

10.1007/s00439-024-02706-w

39406892