Table 3 Summary of all known EYA4 variants and their hearing loss phenotypes
| Variant type | Nucleotide Change | Exon/Intron | Amino Acid Change | Origin | Age at HL on set | HL degree | Audiogram profile | References |
|---|---|---|---|---|---|---|---|---|
| Splicing | c.84-2A > G | Intron 3 |
Chinese Indian | N/A | N/A | N/A |
Chen et al. 2016 [36] Panigrahi et al. [37] | |
| Missense | c.152C > T | Exon 4 | p.Ser51Phe | America | N/A | N/A | N/A | Sloan-Heggen et al. [38] |
| Nonsense | c.160G > T | Exon 4 | p.Glu54* | Spanish | 42 years | Mild | MF/flat | Morín et al. [13] |
| Frameshift | c.222_223del | Exon 5 | p.Val75Phefs*32 | Japanese | 61 years | Mild to moderate | HF/LF | Shinagawa et al. [9] |
| Frameshift | c.464delC | Exon 8 | p.Pro155Glnfs*43 | Swedish Dutch | N.A Childhood |
N.A Moderate |
N.A MF/HF |
Neveling et al. [39] Van Beelen et al. [40] |
| Frameshift | c.498del | Exon 8 | p.Thr167Leufs*31 | Japanese | 13 years | Mild | LF | Shinagawa et al. [9] |
| Missense | c.511G > C | Exon 8 | p.Gly171Arg | Chinese | 6–50 years | Mild to severe | HF/flat | Liu [15] |
| Nonsense | c.517C > T | Exon 8 | p.Gln173* | Japanese | 48 years | Moderate | Flat | Shinagawa et al. [9] |
| Missense | c.543C > G | Exon 8 | p.Tyr181Ter | Chinese | Second to the fourth decade | Severe to profound | Flat | Mi et al. [32] |
| Frameshift | c.579_580insTACC | Exon 8 | p.Asp194Tyrfs*52 | Swedish | 4–40 years | Mild to profound | N/A | Frykholm et al. [41] |
| c.580 + 1G > A | Intron 8 | Japanese | 45 years | Moderate | Flat | Shinagawa et al. [9] | ||
| Frameshift | c.614dupA | Exon 9 | p.Glu205Argfs*40 | Chinese | 20–40 years | Moderate to profound | HF/flat | Huang et al. [42] |
| Frameshift | c.781del | Exon 10 | p.Thr261Argfs*34 | Spanish | 26–44 years | Mild to moderate | Gently downsloping | Morín et al. [13] |
| Missense | c.804G > C | Exon 10 | p.Gln268His | Slovak | 10–40 years | Moderate | Gently downsloping | Varga et al. [43] |
| Nonsense | c.863C > A | Exon 11 | p.Ser288* | Korean Korean |
N.A N.A |
Moderate Moderate to severe |
Reverse U-shaped Flat |
Baek et al. [44] Kim et al. [10] |
| Missense | c.866C > T | Exon 11 | p.Thr289Met | American | N.A | N.A | N.A | Miszalski-Jamka et al. [45] |
| Frameshift | c.910del | Exon 11 | p.Ser305Leufs*15 | Japanese | 30 years | Severe | Flat | Shinagawa et al. [9] |
| Missense | c. 978C > G | Exon 12 | p.Phe326Leu | Korean | N.A | Moderate | Down sloping | Choi et al. [46] |
| Nonsense | c.988C > T | Exon 12 | p.Gln330* | Japanese | 16 years | Moderate | Flat | Shinagawa et al. [9] |
| Frameshift | c.1026_1027dupAA | Exon 12 | p.Thr343Lysfs*62 | American | N.A | Moderate to profound | Flat/Gently sloping | Wayne et al. [12] |
| Frameshift | c.1048_1049dupAA | Exon 12 | p.Arg352Profs*53 | American | N.A | Moderate to severe | MF/HF | Makishima et al. [47] |
| Missense | c.1078C > A | Exon 12 | p.Pro360Thr | Spanish | 44 years | Mild to moderate | Gently downsloping | Morín et al. [13] |
| Missense | c.1107G > T | Exon 12 | p.Glu369Asp | Spanish | 10–11 years | Moderate to severe | Gently downsloping | Morín et al. [13] |
| Missense | c.1109G > A | Exon 13 | p.Arg370His | Philippines | N.A | N.A | N.A | Truong et al. 2019 [48] |
| Missense | c.1109G > C | Exon 13 | p.Arg370Pro | Japanese | 30 years | Mild to moderate | MF | Shinagawa et al. [9] |
| Missense | c.1109G > C | Exon 13 | p.Val371Met | Belgium | N.A | N.A | N.A | Sommen et al. [49] |
| Frameshift | c.1115_1118dup TTGT | Exon 13 | p.Trp374Cysfs*6 | Hungarian | N.A | N.A | N.A | Pfister et al. [50] |
| Missense | c.1122G > T | Exon 13 | p.Trp374Cys | Australian | 10–25 years | Mild to severe | Gently downsloping | Morín et al. [13] |
| Missense | c.1154C > T | Exon 13 | p.Ser385Leu | Italian | N.A | Mild to profound | MF | Cesca et al. [51] |
| Nonsense | c.1177C > T | Exon 13 | p.Gln393* |
Korean Japanese |
N.A 26 years | moderate |
HF Flat |
Kim [10] Shinagawa et al. [9] |
| Frameshift | c.1194del | Exon 14 | p.Met401Trpfs*3 | Korean | N.A | Moderate | Down sloping | Choi et al. [46] |
| Missense | c.1216G > C | Exon 14 | p.Gly406Arg | Japanese | 5 years | Moderate | Flat | Shinagawa et al. [9] |
| Missense | c.1223G > A | Exon 14 | p.Arg408His | America | N.A | N.A | N.A | Miszalski-Jamka et al. [45] |
| Missense | c.1281G > A | Exon 14 | p.Glu427Glu | Spanish | 26 years | Moderate to profound | Flat | Morín et al. [13] |
| Splicing | c.1282-12T > A | Intron 14 | Australian | N.A | Mild to profound | Flat | Hildebrand et al. [52] | |
| Splicing | c.1282-1G > A | Intron 14 | Spanish | 12 years | Mild to moderate | MF/Flat | Morín et al. [13] | |
| Missense | c.1301T > A | Exon 15 | p.Ile434Lys | Chinese | 8–38 years | Mild to severe | MF/flat | Tan et al. [53] |
| Splicing | c.1341-19T > A | Intron 15 | Germany | N.A | N.A | N.A | Vona et al. [54] | |
| Nonsense | c.1601C > G | Exon 17 | p.Ser534* | Spanish | 3–16 years | Moderate to severe | MF/Flat | Morín et al. [13] |
| Missense | c.1643C > G | Exon 18 | p.Thr548Arg | Chinese | 17–40 years | Mild to profound | N.A | Sun et al. [11] |
| Missense | c.1663G > C | Exon 18 | p.Ala555Pro | Japanese | 25 years | Moderate | N.A | Shinagawa et al. [9] |
| Splicing | c.1739-1G > A | Intron 18 | America | 50 years | N.A | N.A | Cirino et al. [55] | |
| Nonsense | c.1759C > T | Exon 19 | p.Arg587* | Belgian | 6–40 years | Mild to moderate | N.A | Wayne et al. [12] |
| Frameshift | c.1790del | Exon 19 | p.Val597Glyfs*4 | Japanese | 35 years | Moderate | Flat | Iwasa et al. [56] |
| Missense | c.1810G > T | Exon 19 | p.Gly604Cys | Swedish Dutch | N.A | N.A | N.A |
Neveling et al. [39] Van Beelen et al. [40] |
| Nonsense | c.1834A > T | Exon 19 | p.Lys612* | Chinese | 27 years | Moderate | Gently downsloping | Hu et al. [16] |
| Missense | c.1855T > G | Exon 20 | p.Trp619Gly | Chinese | N.A | N.A | N.A | Xiao et al. [57] |
| CNV |
Deletion 7689 bp (Ex7 to Ex11) | Japanese | 25 years | Moderate to severe | LF/HF | Shinagawa et al. [9] | ||
| CNV |
Deletion 9.5 Mb (Ex4 to Ex 20) | Japanese | 13 years | Severe | LF/HF | Shinagawa et al. [9] | ||
| CNV |
Deletion 2747 bp (Ex15 to Ex17) | Spanish | 8 years | Moderate | Flat | Morín et al. [13] | ||
| CNV |
Deletion 9 Mb at 6q23.1–24.1 (Ex4–20) | p.Asp194Glyfs*30 | Polish | N.A | N.A | N.A | Dutrannoy et al. [30] | |
| CNV |
Deletion 4846 pb incl. intron 9, exon 10 and partial intron 10 c.581_804del (In9, Ex10, part of In10) | N.A | N.A | N.A | Schönberger et al. [34] | |||
| CNV | Deletion 10.4 Mb promoter and exon 1,2 (Ex1–2) | Japanese | 20-month-old | Moderate to severe | MF/flat | Abe et al. [31] | ||
| CNV |
Deletion 3.7 MB in 6q23.1q23.2 (Ex1–20) | Italian | 12 years | N.A | N.A | Gana et al. [58] | ||
| CNV | Deletion 12,835 bp (Ex6–10) | Japanese | 23 years | Mild to sereve | LF/HF/Flat | Ishino et al. [14] | ||
| CNV | Deletion 17.4 kb and 10 bp insertion (Ex8–11) | Chinese | 26–42 years | Moderate–severe | Flat | This work |