ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000006.11) (NC_000006.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
11159937 Wayne et al. (2001) performed sequence analysis on two large families (one American and one Belgian) with late-onset progressive autosomal dominant non-syndromic sensorineural hearing loss, each previously demonstrating linkage to the DFNA10 locus. In the American family, they identified an insertion of 2 adenines at nucleotide 1468 in exon 12 of the EYA4 gene, subsequently generating a frameshift and premature stop codon in exon 14. The variant segregated with NSHL in 14 family members. In the Belgian family, they identified a C-to-T transition at nucleotide 2200 in exon 20 of the EYA4 gene, generating a premature stop codon. The number of affecteds was not indicated for the Belgian family. The authors state that no cardiac issues were reported in either family.
17567890 Makishima et al. (2007) report a family with autosomal dominant, postlingual-onset, progressive, sensorineural hearing loss (SNHL) with a novel frameshift mutation, 1,490insAA, of EYA4. The 1,490insAA allele is predicted to encode a truncated protein with an intact N-terminal variable region, but lacking the entire C-terminal Eya domain. The variant segregated with SNHL in 10 family members. Several affected individuals underwent electrocardiography, echocardiography, and magnetic resonance imaging (MRI) of the heart, revealing no abnormalities. The authors propose that truncations of the C-terminal Eya domain cause isolated hearing loss, whereas upstream truncations of the N-terminal variable region cause hearing loss with dilated cardiomyopathy.
15735644 In a family with SNHL and dilated cardiomyopathy, Schonberger et al. (2005) demonstrated a 4,846-bp deletion that encompassed the last nucleotide of exon 9, intron 9, exon 10, and part of intron 10 of the EYA4 gene, resulting in deletion of nucleotides 1022-1245 (corresponding to exons 9 and 10) and a frameshift after residue 193, with 29 new residues and a premature stop codon. This deletion was present in 10 affected family members with SNHL and dilated cardiomyopathy and absent from 300 control chromosomes. No other mutations were identified in the remaining 19 exons of EYA4.

Haploinsufficiency phenotype comments:

Heterozygous, truncating EYA4 mutations cause nonsyndromic autosomal dominant deafness with or without dilated cardiomyopathy. It has been proposed that loss of the C-terminal Eya domain is associated with deafness while truncation further upstream involving the N-terminal variable region includes a cardiomyopathy phenotype. Additional references (this is not a comprehensive list): PMID: 26456090 - EYA4 (NM_004100.4) 175 kb partial gene deletion overlapping 5' end (exon 1-2; 5'UTR and first 11 amino acids; arr[GRCh37] 6q23.2(133517648_133693108)x1) identified in patient with hearing loss. PMID: 26015337 - EYA4 mutation, c.1194delT (p.Met401TrpfsX3), identified in Korean family, segregating with non-syndromic sensorineural hearing loss. PMID: 31101089 - EYA4 mutation in last nucleotide of exon 10, c.804C>G, p.(Gln268His). A minigene assay demonstrated compromised splice donor site functionality and exon 10 skipping, identified in 26 member Slovak family, segregating with moderate to severe hearing loss at age 10-40 years in 6 family members who were noted to have a normal cardiac phenotype (confirmed by ECG and echocardiography). PMID: 30155266 - EYA4 (NM_004100.4) mutations in exon 13, c.1177C>T, p.Q393X (hg19:chr6:g.133804239?C?>?T), identified in a Japanese family, segregating with sensorineural hearing loss and mild cardiac phenotype in 5 family members. PMID:26331839: - Describes a Dutch family with autosomal dominant sensorineural hearing loss and a putative loss of function variant (c.464del, p.Pro155fsX) in EYA4.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity