Journal Article
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
Hedwig M. Velde; Maryam Vaseghi-Shanjani; Jeroen J. Smits; Gayatri Ramakrishnan; Jaap Oostrik; Mieke Wesdorp; Galuh Astuti; Helger G. Yntema; Lies Hoefsloot; Cris P. Lanting; Martijn A. Huynen; Anna Lehman; Stuart E. Turvey; E. Aten; M. J. van den Boogaard; F. L. J. Cals; M. F. van Dooren; F. A. Ebbens; I. Feenstra; R. H. Free; H. H. W. de Gier; T. P. M. Goderie; L. Haer-Wigman; K. Hellingman; E. H. Hoefsloot; J. R. Hof; J. van de Kamp; S. G. Kant; J. S. Klein Wassink-Ruiter; H. Kremer; M. Kriek; A. M. A. Lachmeijer; C. P. Lanting; S. M. Maas; P. Merkus; R. J. E. Pennings; A. Plomp; F. G. Ropers; L. J. C. Rotteveel; M. P. van der Schroeff; A. L. Smit; J. J. Smits; V. Vernimmen; J. C. C. Widdershoven; H. G. Yntema; Ronald J. E. Pennings; Hannie Kremer
Human Genetics · Vol. 143, Issue 11 · pp. 1379-1399 · 2024
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.