Table 3.
Genetic panel testing results with variants, analysis of pathogenicity, and characteristic phenotype associated with identified genes or variants.
| ID | Phenotype | Genes | DFN | Variant(s) | Genotype | GPT | Analysis a | New Var | Gene- or Variant- Associated Phenotypes in Literature |
|---|---|---|---|---|---|---|---|---|---|
| 1 | Bilateral severe-to-profound SNHL present at birth | MYO15A | DFNB3 | c.7124_7127del (p.Asp2375Valfs*41) | Het | P | P | No | Gene b: Congenital bilateral severe-to-profound SNHL [32]. Variant: Steeply sloping severe, progressive SNHL [33]; childhood-onset bilateral severe–profound AR SNHL [15]. |
| MYO15A | DFNB3 | c.9109G>T (p.Glu3037*) | Het | P | P | Yes c | |||
| OTOG | DFNB18B | c.4856C>T (p.(Ser1619Leu)) | Het | VUS | -- | Yes | Prelingual moderate AR SNHL [34,35]. | ||
| DMXL2 | DFNA73 | c.7543A>G (p.(Met2515Val)) | Het | VUS | P | Yes | Bilateral mild-to-moderate AD SNHL beginning in 20s, progressing to severe to profound in 60s [36]. | ||
| 2 | Right moderately severe-to-profound SNHL and left severe SNHL present at birth | GJB2 | DFNB1A | c.35delG (p.Gly12Valfs*2) | Hom | P | P | No | Congenital moderate-to-profound bilateral SNHL; severity is variant-dependent [37]. |
| ALMS1 | -- | c.11708G>A (p.(Arg3903Gln)) | Het | VUS | -- | Yes | Associated with AR Alström Syndrome; progressive bilateral moderate SNHL in childhood [38]. | ||
| ADGRV1 | -- | c.13757A>G (p.(Glu4586Gly)) | Het | VUS | -- | Yes | Associated with AR Usher Syndrome type IIC causing congenital moderate-to-severe SNHL [39]. | ||
| KARS1 | DFNB89 | c.1259G>A (p.(Arg420Gln)) | Het | VUS | -- | Yes | Bilateral, symmetric severe-to-profound or moderate-to-severe AR SNHL [40]. | ||
| MYO15A | DFNB3 | c.9620G>A (p.Arg3207His) | Het | P | -- | No | See patient 1; MYO15A. | ||
| 3 | Bilateral mild-to-moderate SNHL, onset at 3 years old | MYO7A |
DFNB2/
DFNA11 |
c.2543G>A (p.(Arg848Gln)) | Het | VUS | P | Yes | Severe bilateral SNHL [41,42]. |
| LRP2 | -- | c.2426G>A (p.(Ser809Asn)) | Het | VUS | -- | Yes | Associated with AR Donnai–Barrow syndrome (Facio-oculoacousticorenal syndrome) with congenital bilateral profound SNHL though moderate SNHL was also reported [43,44]. May present as non-syndromic bilateral moderate HL in childhood [45]. |
||
| ADGRV1 | -- | c.12052G>A (p.(Val4018Ile)) | Het | VUS | -- | Yes | See patient 2; ADGRV1. | ||
| OTOG | DFNB18B | c.7817_7820dup (p.Tyr2608Serfs*76) | Het | P | -- | Yes | Prelingual bilateral moderate AR SNHL, stable throughout time [34,35]. | ||
| PEX26 | -- | c.98C>T (p.(Pro33Leu)) | Het | VUS | -- | Yes | Post-lingual bilateral moderate-to-severe SNHL [46]. AR Zellweger spectrum disorder results in moderately severe-to-severe SNHL [47]. | ||
| BTD | -- | c.1270G>C (p.Asp424His) | Het | P | -- | No | AR biotinidase deficiency may present with moderate-to-severe sloping SNHL within the 1st year [48]. No variant-specific hearing loss pattern reported previously. | ||
| 4 | Bilateral moderate-to-moderately severe SNHL, onset at 2 years old; retinitis pigmentosa at age 15 | USH2A | -- | c.13130C>A (p.Ser4377*) | Het | P | P | No | Usher Syndrome, type 2—moderate to severe congenital SNHL with retinitis pigmentosa presenting at age 20–30 years [49]. |
| USH2A | -- | c.2299del (p.Glu767Serfs*21) | Het | P | P | No | Variant: Variable severity of progressive HL according to variant [50]. | ||
| COL4A4 | -- | c.980A>G (p.(Glu327Gly)) | Het | VUS | -- | Yes | Associated with AR Alport Syndrome with progressive mild-to-moderate bilateral SNHL that affects mid-to-high frequencies [51]. | ||
| 5 d | Right moderate-to-severe SNHL and left mild-to-severe SNHL, onset at 3 years old | TMC1 |
DFNA36/DFNB7/
DFNB11 |
c.928A>G (p.(Thr310Ala)) | Het | VUS | P? | Yes | Congenital severe-to-profound SNHL if AR; bilateral, symmetric SNHL that begins at 5–10 years old and rapidly progresses to profound deafness within 10–15 years if AD [52,53]. |
| SLC26A4 | DFNB4 | c.1246A>C (p.Thr416Pro) | Het | P | -- | No | Bilateral fluctuating or progressive moderate-to-severe AR congenital SNHL [54]. | ||
| VCAN | -- | c.3917C>G (p.(Ala1306Gly)) | Het | VUS | -- | Yes | AD Wagner vitreoretinopathy. |
||
| 6 | Bilateral profound non-syndromic SNHL present at birth | TECTA | DFNA8/DFNA12 | c.2266 A>G (p.(Lys756Glu)) | Het | VUS | P | Yes | Moderate-to-severe AD SNHL, most pronounced in the mid-frequencies [55,56]. |
| MITF | -- | c.560-7T>A | Het | VUS | P | Yes | AD Waardenburg syndrome, type II, with congenital bilateral profound SNHL [57]. |
a GPT refers to the pathogenicity reported in the original report of the genetic panel testing, whereas Analysis refers to the pathogenicity (P) predicted in our independent analysis based on the variant MAF, deleteriousness, ACMG guidelines, and genotype given the associated AD or AR SNHL phenotype (see also Supplementary Table S2). b Gene refers to phenotypes reported in literature resulting from any variant within the gene. Variant refers to phenotypes reported in literature resulting from the specific variant the patient has. c These variants were reported to ClinVar by Invitae but not in a publication. d Patient 5 is heterozygous for a known pathogenic variant in SLC26A4; however, a second SLC26A4 variant was not identified. She also stayed at the NICU. Abbreviations: DFN, non-syndromic DeaFNess loci; Het, heterozygous; Hom, homozygous; P, pathogenic; VUS, variant of uncertain significance. Among the identified variants per patient, variants in bold are the most likely to be causal of SNHL.