Table 4. All rare variants that disrupt known nonsyndromic hearing loss genes discovered from two sequenced patients.
| Patients | Gene | Variants (dbSNP ID) | Zygosity | Allele frequencya | cDNA change | Protein change | Grantham score | Non-synonymous SNV predictionsb | PhyloPc | GERPc |
|---|---|---|---|---|---|---|---|---|---|---|
| III-4 | GPSM2 | 1:109472416 C>T (rs189033496) | Het | 0.0080 | NM_013296:exon15: c.1909C>T | p.R637W | 101 | +++ + | 3.05 | 5.05 |
| III-4 | MYO6 | 6:76618264 T>C (rs144816202) | Het | 0 | NM_004999:exon32: c.3332T>C | p.V1111A | 64 | +++ + | 4.87 | 6.07 |
| III-4 | CDH23 | 10:73466716 G>A | Het | 0 | NM_022124:exon25: c.3016G>A | p.E1006K | 56 | ? +?? | 5.98 | 5.28 |
| III-4, III-13 | CDH23 | 10:73537579 A>T | Het | 0 | NM_022124:exon37: c.4988A>T | p.D1663V | 152 | ? +?? | 5.12 | 2.18 |
| III-13 | OTOF | 2:26699868 T>A | Het | 0.0011 | NM_004802:exon5: c.326A>T | p.N109I | 149 | +++ + | 3.16 | 3.76 |
| III-13 | SLC26A4 | 7:107323898 A>G (rs111033313) | Hom | 0.0080 | NM_000441:exon8: c.919-2A>G | p.T307Vfs*5d | n.a. | 4.66 | 5.62 | |
| III-13 | MARVELD2 | 5:68715804 G>A | Het | 0.0023 | NM_001038603:exon2: c.592G>A | p.V198M | 21 | ++− − | 2.28 | 5.16 |
Allele frequencies were calculated from the in-house exome database of 440 unrelated samples (Feb 2013; X. Zhou unpublished data).
Results from four non-synonymous SNV effects prediction programs, from left to right: PolyPhen2, SIFT, LRT, MutationTaster. ‘+', deleterious or damaging; ‘−', benign; ‘?', not avaiable.
Measures of evolutionary constraint. PhyloP score is the −log10 of P-value for testing the null hypothesis of neutral evolution, based on 46-way whole-genome alignment of vertebrates. GERP score can be interpreted as the substitutions expected under neutrality minus the number of substitutions observed at the position, which was based on 35-way whole-genome alignment of mammals and had theoretical maximum value of 6.18.
This variant was predicted to abolish splice donor and cause exon 8 skipping.