ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.