Novel EYA4 variant in Slovak family with late onset autosomal dominant hearing loss: a case report

Abstract

Background Progressive bilateral sensorineural deafness in postlingual period may be linked to many different etiologies including genetic factors. Identification of the exact deafness cause may, therefore, be quite challenging. Here we present a family with late-onset hearing loss as an autosomal dominant trait caused by a novel EYA4 mutation. Case presentation Forty-four years old female proband clinically investigated for progressive hearing loss and occasional dizziness with positive family history for deafness was subject to molecular-genetic testing. Patient’s DNA sample was analyzed by whole exome sequencing. We identified a novel missense variant c.804G > C located at the last base pair of exon 10 in EYA4 . Candidate variant was confirmed by Sanger sequencing in the proband and her family members. In silico prediction tools and co-segregation analysis were used to indicate pathogenicity of the identified variant. To confirm our hypothesis, we performed minigene assay to demonstrate if the transcript of exon 10 in EYA4 is present. We provide evidence that this mutation in vitro compromises donor site functionality and causes exon 10 skipping and frameshift that most likely results in nonsense-mediated mRNA decay. The onset of moderate to severe hearing loss in the family ranged from 10 to 40 years. The normal cardiac phenotype was confirmed by ECG and echocardiography. Conclusions We identified a novel EYA4 mutation associated with adult-onset autosomal dominant sensorineural hearing loss. This report extends the knowledge of spectrum of EYA4 mutations and demonstrates the pathogenicity of a variant affecting specific position in the gene. A comprehensive review of known EYA4 mutations is also given and their impact on cardiac phenotype is discussed. Our findings highlight the importance of genetic testing and complex clinical assessment in patients with familial progressive hearing loss.

Identification of a novel mutation of EYA4 in a Chinese family with delayed nonsyndromic hearing loss and analysis of molecular epidemiology of EYA4 mutations

“…The most commonly reported hearing loss is mild to moderate mid-frequency hearing loss at onset, which is called "Cookie-bite" audiogram. Subsequent hearing loss also affects high frequencies, resulting in moderate to severely at or downward-sloping audiograms [11]. The proband in this study showed mild-to-moderate hearing loss with medium-and high-frequency descending hearing loss.…”

Identification of a Novel Copy Number Variation of EYA4 Causing Autosomal Dominant Non-syndromic Hearing Loss

“…Our results indicated that the region of amino acids 124 to 343 may not play a key role in the maintenance of normal cardiac gene regulation and may not be the pathogenic region causing dilated cardiomyopathy, because the genotype–phenotype correlation of EYA4 mutations has been previously suggested to contribute to hearing loss and associated dilated cardiomyopathy (8,10). Furthermore, analyzed from the nonsense or deletion mutations in EYA4 gene including our result (1,8,10,19,23,25–31), it is suggested that the theory of genotype–phenotype correlation of EYA4 mutations about the prevalence of dilated cardiomyopathy should be rejected because of the non-correspondence of deleted amino acid region with the prevalence of dilated cardiomyopathy (Fig. 6).…”

Principles and Practical Considerations for the Analysis of Disease-Associated Alternative Splicing Events Using the Gateway Cloning-Based Minigene Vectors pDESTsplice and pSpliceExpress

“…Depending on the objectives of the study, different experimental settings and laboratory protocols can be used. To give an overview of the potential applications of the pDESTsplice and pSpliceExpress vectors, we have compiled 25 published studies [ 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 ], in which these minigene systems were used ( Table 1 and Table 2 ). In most of the works, the usage of pSpliceExpress has been described ( n = 18).…”

“…In most of these studies, the assumed Expression clone was sequenced ( n = 10) or a combination of sequencing and control cleavage with restriction enzymes was performed ( n = 7). Varga et al checked their Expression clones by colony PCR in addition to sequencing [ 56 ].…”