Table 1.
List of likely causative variants identified by TRS.
| Family ID | Locus | Gene | cDNA change | Amino acid change | Protein domain | gnomAD | GERP++ | Polyphen-2 | SIFT | Mutation Taster | CADD | References |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Familial case_1 | DFNA2A | KCNQ4 (NM_004700.3) | c.947G>T#(het) | p.(Gly316Val) | Transmembrane region | NA | 5.27 | D | D | D | 26 | NA |
| c.1600A>G#(het) | p.(Ile534Val) | NA | NA | 5.51 | P | T | D | 20.5 | NA | |||
| Familial case_2 | DFNA8/12 | TECTA (NM_005422.2) | c.589G>A (het) | p.(Asp197Asn) | NIDO domain | NA | 5.37 | P | D | D | 23 | Hildebrand et al., 2011 |
| Familial case_3 | DFNA15 | POU4F3 (NM_002700.2) | c.690G>C (het) | p.(Arg230Ser) | POU domain | rs781045522; MAF: 4,063e-6 | 4.62 | D | D | D | 16.22 | NA |
| Familial case_4 | DFNA20/26 | ACTG1 (NM_001199954.1) | c.847A>G (het) | p.(Met283Val) | ACTIN domain | NA | 0.704 | B | NA | D | 13.71 | NA |
| Familial case_5 | DFNA22 | MYO6 (NM_004999.3) | c.599A>G (het) | p.(Asn200Ser) | MYSc ATPase domain | NA | 4.98 | D | D | D | 23.4 | NA |
| Familial case_6 | DFNB16 | STRC (NM_153700.2) CATSPER2 (NM_172095.2) | deletion 49,23Kb 15q15.3 | NA | NA | NA | NA | NA | NA | NA | Vona et al., 2015 | |
| Familial case_7 | DFNA5 | DFNA5 (NM_001127454.1) | c.666_669delCTAC (het) | p.(Tyr223Serfs*49) | NA | NA | NA | NA | NA | D | NA | NA |
| Familial case_8 | DFNA8/12 | TECTA (NM_005422.2) | c.775G>C het) | p.(Gly259Arg) | NA | NA | 4.92 | D | D | D | 24.6 | Vozzi et al., 2014 |
| Familial case_9 | DFNB8/ 10 | TMPRSS3 (NM_024022.2) | c.1019C>G (het) | p.(Thr340Arg) | Tryp_SPc domain | NA | 4.37 | D | D | D | NA | Vozzi et al., 2014 |
| c.1291C>T (het) | p.(Pro431Ser) | Tryp_SPc domain | rs767931569, MAF: 2,437e-5 | 5.13 | D | D | D | 25.9 | ||||
| Familial case_10 | DFNB2 | MYO7A (NM_000260.3) | c.1556G>A (het) | p.(Gly519Asp) | MYSc ATPase domain | rs111033206, MAF: 1,22e-5 | 5.02 | D | D | D | 19.77 | Bharadwaj et al., 2000 |
| c.3670G>A (het) | p.(Ala1224Thr) | MyTH4 domain | rs748928605, MAF: 2,825e-5 | 5.31 | D | D | D | 31 | NA | |||
| Familial case_11 | DFNA11 | MYO7A (NM_000260.3) | c.4268C>T (het) | p.(Thr1423Met) | B41 domain | rs779964645, MAF: 3,734e-5 | 4.85 | P | T | D | 19 | NA |
| Familial case_12 | DFNA4 | MYH14 (NM_001145809.1) | c.1150G>T (het) | p.(Gly384Cys) | MYSc domain | rs119103280, MAF: 0,002917 | 3.42 | D | D | A | 14.73 | Donaudy et al., 2004 |
| Familial case_13 | DFNA8/12 | TECTA (NM_005422.2) | c.6000-1G>T (het) | NA | NA | NA | NA | NA | NA | D | NA | NA |
| Familial case_14 | DFNA6/14/38 | WFS1 (NM_006005.3) | c.2501G>A (het) | p.(Gly834Asp) | NA | NA | 5.35 | D | D | D | 21.1 | NA |
| Familial case_15 | DFNX4 | SMPX (NM_014332.2) | c.162delG (het) | p.(Lys55Serfs*25) | NA | NA | NA | NA | NA | NA | NA | NA |
| Familial case_16 | DFNA22 | MYO6 (NM_004999.3) | deletion 75,8Kb 6q14 | NA | NA | NA | NA | NA | NA | NA | ||
| Familial case_17 | DFNA48 | MYO1A (NM_005379.3) | c.2468T>C denovo (het) | p.(Leu823Pro) denovo | NA | NA | 4.3 | B | D | D | 24.5 | NA |
| Sporadic case_1 | DFNB22 | OTOA (NM_144672.3) | deletion 228,5Kb 16p12.2 | Fontana et al., 2017 | ||||||||
| c.1865T>A (hemizygous) | p.(Leu622His) | NA | rs750007142, MAF: 4,063e-6 | 4.77 | D | D | D | 19.03 | ||||
| Sporadic case_2 | DFNB8/10 | TMPRSS3 (NM_024022.2) | c.731G>A (het) | p.(Gly244Asp) | Tryp_SPc domain | rs397517377, MAF: 8,126e-6 | 5.33 | D | NA | D | 31 | NA |
| IVS4-6G>A (het) | NA | NA | rs374793617, MAF: 4,877e-5 | NA | NA | NA | NA | NA | Scott et al., 2001 | |||
| Sporadic case_3 | DFNB4 | SLC26A4 (NM_000441.1) | c.1229C>T (het) | p.(Thr410Met) | NA | rs111033220, MAF: 0,0001844 | 5.1 | D | D | D | 23.6 | Coyle et al., 1998 |
| c.2048T>C (het) | p.(Phe683Ser) | NA | MAF: 9,081e-6 | 5.42 | D | D | D | 20.8 | Prasad et al., 2004 | |||
| Sporadic case_4 | DFNB77 | LOXHD1 (NM_144612.6) | c.3071A>G (UPD Chr 18) | p.(Tyr1024Cys) | LH2 domain | NA | 4.53 | D | D | D | 14.99 | NA |
| Sporadic case_5 | DFNB3 | MYO15A (NM_016239.3) | c.8090T>C (het) | p.(Val2697Ala) | NA | rs200451098, MAF: 0,0002671 | 5.19 | D | D | D | 22.2 | Schrauwen et al., 2013 |
| c.8183G>A (het) | p.(Arg2728His) | NA | rs184435771, MAF: 0,0001915 | 5.34 | D | D | D | 26.9 | Brownstein et al., 2011 | |||
| Sporadic case_6 | DFNA20/26 | ACTG1 (NM_001199954.1) | c.548G>A denovo (het) | p.(Arg183Gln) denovo | ACTIN domain | rs781945750, MAF: 4,072e-6 | 3.57 | P | D | D | 17.61 | NA |
| Sporadic case_7 | NA | PDZD7 (NM_001195263.1) | c.2850delC (het) | p.(Ser953Alafs*91) | NA | MAF: 0,0001122 | NA | NA | NA | NA | NA | NA |
| c.1841G>C (het) | p.(Arg614Thr) | NA | rs773503851, MAF: 2,092e-5 | 5.42 | D | NA | D | 27.1 | NA | |||
| Sporadic case_8 | DFNB21 | TECTA (NM_005422.2) | c.6000-1G>A (het) | NA | NA | NA | NA | NA | NA | D | NA | NA |
| c.2020C>T (het) | p.(Gln674*) | NA | NA | NA | NA | T | A | NA | NA | |||
| Sporadic case_9 | DFNX2 | POU3F4 (NM_000307.4) | c.989G>A (hemizygous) | p.(Arg330Lys) | HOX domain | NA | 5.07 | D | D | D | 25 | NA |
| Sporadic case_10 | NA | PDZD7 (NM_024895.4) | c.329G>A (hom) | p.(Gly110Asp) | PDZ domain | NA | 5 | D | D | D | 32 | NA |
| Sporadic case_11 | DFNB12 | CDH23 (NM_022124.5) | c.4562A>G (het) | p.(Asn1521Ser) | CA domain | rs780987516 MAF:1,804e-5 | 5.23 | P | NA | D | 25.2 | Sloan-Heggen et al., 2015 |
| c.8377C>T (het) | p.(Arg2793Trp) | CA domain | rs749203752 MAF:4,068e-6 | 3.71 | D | D | D | 34 | NA | |||
| Sporadic case_12 | DFNB8/10 | TMPRSS3 (NM_024022.2) | c.718delC (het) | p.(His240Thrfs*35) | Tryp_SPc domain | NA | NA | NA | NA | NA | NA | NA |
| c.579dupA (het) | p.(C194Metfs*17) | SR domain | NA | NA | NA | NA | NA | NA | Battelino et al., 2016; Lechowicz et al., 2017 | |||
| Sporadic case_13 | DFNA20/26 | ACTG1 (NM_001199954.1) | c.197C>T denovo(het) | p.(Thr66Ile) denovo | ACTIN domain | NA | 3.99 | B | NA | D | 22 | NA |
| Sporadic case_14 | DFNX2 | POU3F4 (NM_000307.4) | c.967C>G (hemizygous) | p.(Arg323Gly) | HOX domain | rs104894924 | 4.14 | D | D | D | 16.53 | Cremers et al., 2000 |
| Sporadic case_15 | DFNB16 | STRC (NM_153700.2) | deletion 49kb 15q15.3 | NA | NA | NA | NA | NA | NA | NA | ||
All mutations have been classified based on their frequency reported in Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/) and their pathogenicity. In particular, the following tools have been used: GERP++ (higher number is more conserved), Polyphen-2 (D, Probably damaging; P, possibly damaging; B, benign), SIFT (D, deleterious; T, tolerated), MutationTaster “A” (“disease_causing_automatic”); “D” (“disease_causing”); “N”(“polymorphism”); “P” (“polymorphism_automatic”), and CADD (Pathogenicity score: > 10 predicted to be deleterious). NA, not available. DN, de novo mutation; #, mutation in cis.