Table 1. Clinical characteristics and genotype of the patients with USH2A-related disease without early-onset hearing loss (discovery cohort).
| Subject; family ID | Age *; gender | VA (LogMAR) | Presenting symptom (age) | Hearing loss | USH2A sequencing results b | FAF | Comments | Ethnicity | ||
|---|---|---|---|---|---|---|---|---|---|---|
| RE | LE | Subjective | Audiologya | |||||||
| D1; gc4627 | 34; M | 0.00 | 0.18 | NA | No | NA | c.[2276G>T(;)13010C>T], p.[(Cys759Phe)(;)(Thr4337Met)] | NA | — | European |
| D2; gc16390 | 35; M | 0.00 | −0.10 | Nyctalopia (23 y.o.) | No | Group 3 | c.[2299delG(;)12295-3T>A], p.[(Glu767Serfs *21)][?] | Ring BE | — | European |
| D3; gc15522 | 41; M | 0.18 | 0.18 | Nyctalopia (17 y.o.) | No | Group 1 A | c.[2276G>T(;)13316C>T], p.[(Cys759Phe)(;)(Thr4439Ile)] | Ring BE | — | European |
| D4; gc5134 | 42; F | 2.20 | 0.48 | Nyctalopia (20 y.o.) | No | Group 1A | c.[3724C>T(;)3724C>T], p.[(Pro1242Ser)(;)(Pro1242Ser)] | Atrophy BE | — | South Asian |
| D5; gc17134 | 42; F | 0.24 | 0.10 | Loss of peripheral vision (26 y.o.) | No | Group 1A | c.[2276G>T(;)2276G>T], p.[(Cys759Phe)(;)(Cys759Phe)] | Ring BE | CMO | European |
| D6; gc16520 | 42; F | 0.30 | 0.18 | Nyctalopia (27 y.o.) | Yes | NA | c.[2276G>T(;)12575G>A], p.[(Cys759Phe)(;)(Arg4192His)] | Ring BE | CMO | European |
| D7; gc17055 | 43; M | 0.48 | 0.60 | Nyctalopia (15 y.o.) | Yes | NA | c.[2276G>T(;)15031delT], p.[(Cys759Phe)(;)(Tyr5011fs)] | Ring BE | — | European |
| D8; gc16986 | 47; F | 0.00 | 0.00 | Nyctalopia (36 y.o.) | No | Group 1A | c.[2299delG(;)10073G>A] p.[(Glu767Serfs*21)(;)(Cys3358Tyr)] | Ring BE | — | European |
| D8a; gc16986 | 48; F | 0.18 | 0.18 | Nyctalopia (42 y.o.) | No | Group 2 | Ring BE | — | European | |
| D8b; gc16986 | 58; F | 0.60 | 0.60 | Nyctalopia (38 y.o.) | Yes | Group 1B | Ring BE | CMO, IOL LE | European | |
| D9; gc16172 | 48; M | −0.10 | 0.00 | Nyctalopia (30 y.o.) | No | Group 1B | c.[2332G>T(;)2332G>T], p.[(Asp778Tyr)][(Asp778Tyr)] | Ring BE | — | African |
| D14a; gc5204 | 50; M | 0.48 | 0.60 | Nyctalopia (18 y.o.) | No | NA | c.[2276G>T(;)14426C>T], p.[(Cys759Phe)(;)(Thr4809Ile)] | Ring BE | CMO | European |
| D14; gc5204 | 55; F | 0.22 | 0.40 | Dark adaptation (32 y.o.) | Yes | Group 1B | Ring BE | CMO | European | |
| D10; gc16891 | 51; F | 0.72 | 0.68 | Nyctalopia (23 y.o.) | No | Group 1A | c.[5776+1G>A(;)9056-2A>G], p.[?][?] | Small ring BE | — | European |
| D11a; gc1985 | 50; M | 0.20 | 0.22 | Nyctalopia (13 y.o.) | No | Group 2 | c.[2299delG(;)12295-3 T>A], p.[(Glu767Serfs*21)][?] | Small ring BE | CMO, IOL BE | European |
| D11; gc1985 | 52; F | 0.28 | 0.42 | Nyctalopia (17 y.o.) | No | Group 2 | Small ring BE | IOL BE | European | |
| D12; gc15971 | 52; M | 0.22 | 0.08 | Dark adaptation (42 y.o.) | No | Group 1A | c.[7595-3C>G(;)8546G>T], p.[Pro2533Asnfs*5(;)(Gly2849Val)] | Ring BE | CMO | European |
| D13; gc860 | 54; M | 0.18 | 0.18 | Nyctalopia (14 y.o.) | Yes | Group 1B | c.[12093C>A][12295-3T>A], p.[(Tyr4031*)][?] | Small ring BE | IOL BE | European |
| D15; gc4654 | 55; M | 0.18 | 0.18 | Nyctalopia (32 y.o.) | Yes | NA | c.[10073G>A(;)11156G>A], p.[(Cys3358Tyr)(;)(Arg3719His)] | Ring BE | — | European |
| D16; gc16801 | 55; M | 0.18 | 0.00 | Nyctalopia (30 y.o.) | No | NA | c.[2633G>A(;)3902G>T], p.[(Arg878His)(;)(Gly1301Val)] | NA | — | South Asian |
| D17; gc16524 | 56; F | 0.78 | 0.78 | Nyctalopia (35 y.o.) | No | Group 1A | c.[2276G>T(;)10073G>A], p.[(Cys759Phe)(;)(Cys3358Tyr)] | Central hyperAF BE | IOL BE | European |
| D18; gc5399 | 58; M | 0.36 | 0.20 | Nyctalopia (12 y.o.) | No | Group 1A | c.[2276G>T(;)2299delG], p.[(Cys759Phe)(;)(Glu767Serfs*21)] | Small ring BE | CMO | European |
| D19; gc5396 | 63; F | 1.30 | 0.60 | Nyctalopia (15 y.o.) | Yes | Group 1B | c.[2276G>T(;)2299delG], p.[(Cys759Phe)(;)(Glu767Serfs*21)] | Atrophy RE; Central hyperAF LE | CMO | European |
| D20; gc1802 | 66; F | 0.50 | 1.30 | Nyctalopia (28 y.o.) | No | NA | c.[14219C>A(;)11048-?_11711+?dup], p.[(Ala4740Asp)][?] | Central hyperAF BE | — | European |
| D21; gc2053 | 68; M | 2.20 | 2.20 | Nyctalopia (15 y.o.) | No | Group 1A | c.[2802T>G(;)12575G>A], p.[(Cys934Trp)(;)(Arg4192His)] | Atrophy BE | — | European |
| D22; gc4737 | 69; M | −0.10 | 0.20 | Nyctalopia (29 y.o.) | Yes | NA | c.[2276G>T(;)13010C>T], p.[(Cys759Phe)(;)(Thr4337Met)] | Small ring BE | IOL BE | European |
| D23; gc945 | 77; F | 2.20 | 0.48 | Nyctalopia (13 y.o.) | Yes | Group 3 | c.[1541T>C(;)9371+1G>C], p.[(Ile514Thr)][?] | Atrophy RE; Small ring LE | CMO | European |
| Median (range) | 52 (34, 77) | 0.24 (−0.10, 2.20) | 0.2 (−0.10, 2.20) | 24.5 (12, 42) | ||||||
Abbreviations: BE, both eyes; CMO, cystoid macular oedema; FAF, fundus autofluorescence imaging; hyperAF, hyperautofluorescence, IOL, intraocular lens implants; LE, left eye; NA, not applicable; RE, right eye; VA, visual acuity.
*Age at last examination.
Audiology data: Group 1 good hearing across all frequencies (1A if <40th percentile; 1B if 50–60th percentile); Group 2 marked high-frequency hearing loss compared with low-frequency percentiles; Group 3 atypical/abnormal audiometric configuration without other aetiological explanation. Notably, in subject D2, the audiogram, although abnormal, it was not consistent with Usher syndrome type II. Conversely, subject D23, who reported adult-onset hearing loss, had an audiogram consistent with Usher syndrome type II at age 75 years (see Discussion).
Variants that are novel to this study are presented in bold. Of these novel changes, only c.3724C>T is found in the ExAC (Exome Aggregation Consortium) browser (3/122810 alleles; accessed 31 December 2014).
Subjects D8, D8a and D8b; subjects D11 and D11a; and subjects D14 and D14a are siblings. Numbering of USH2A variants has been assigned in accordance with NCBI Reference Sequence NM_206933.2.