Disease Name and Definition
Usher syndrome
Background
Materials and methods
Subjects
Mutation analysis
Predictions of the pathogenic effect of missense variations
-
Sort Intolerant From Tolerant (SIFT) (available at http://sift.jcvi.org) uses sequence homology to predict whether a change is tolerated or deleterious.
-
The polymorphism phenotyping program, PolyPhen (available at http://genetics.bwh.harvard.edu/pph/) uses sequence conservation, structure and SWISS-PROT annotation to characterize an amino acid substitution as benign, possibly deleterious or probably deleterious.
-
Pmut (available at http://mmb2.pcb.ub.es:8080/PMut/) provides prediction by neural networks, which use internal databases, secondary structure prediction and sequence conservation. This program provides a binary prediction of "neutral" or "pathologic".
Splice-site Prediction programs
Minigene constructions and expression
Results
Nucleotide change | Exon | Predicted effect | Predicted pathology | No. of alleles | References |
---|---|---|---|---|---|
Nonsense mutations
| |||||
c.820C > T
| 5 |
p.R274X
| + | 2 | Present study |
c.1518T > A | 8 | p.Y506X | + | 1 | Bernal et al., 2005 |
c.3883C > T | 18 | p.R1295X | + | 1 | Dreyer et al., 2000 |
c.4474G > T | 21 | p.E1492X | + | 2 | Bernal et al., 2005 |
c.4645C > T | 22 | p.R1549X | + | 1 | Baux et al., 2007 |
c.7854G > C
| 41 |
p.W2618X
| + | 1 | Present study |
c.9753T > A
| 50 |
p.C3251X
| + | 2 | Present study |
c.10102C > T
| 51 |
p.Q3368X
a
| + | 1 | Present study |
c.10759C > T | 55 | p.Q3587X | + | 2 | Baux et al., 2007 |
c.11146C > T
| 57 |
p.Q3716X
| + | 1 | Present study |
c.14175G > A
| 65 |
P.W4725X
| + | 1 | Present study |
Deletions and insertions
| |||||
c.918_919insGCTG
| 6 |
p.S307AfsX17
| + | 1 | Present study |
c.1214delA | 7 | p.N405IfsX3 | + | 5 | Bernal et al., 2005 |
c.1629_1645del
| 10 |
p.F543LfsX2
| + | 1 | Present study |
c.2299delG | 13 | p.E767SfsX21 | + | 8 | Eudy et al., 1998 |
c.5278delG
| 26 |
p.D1760MfsX10
a
| + | 1 | Present study |
c.5540_5541dup
| 27 |
p.N1848X
| + | 1 | Present study |
c.6319_6324delinsTAAA
| 32 |
p.V2107X
| + | 1 | Present study |
c.8890dupT
| 45 |
p.W2964LfsX89
| + | 1 | Present study |
c.8954delG
| 45 |
p.G2985AfsX3
| + | 1 | Present study |
c.9261delT
| 47 |
p.E3088KfsX9
| + | 1 | Present study |
c.10272_10273dupTT | 52 | p.C3425FfsX4 | + | 1 | Aller et al., 2006 |
c.11566delA
| 60 |
p.S3856VfsX28
| + | 1 | Present study |
c.12093delC
| 62 |
p.Y4031X
| + | 1 | Present study |
c.13140delA
| 63 |
p.V4381CfsX10
| + | 1 | Present study |
Splice-site
mutations
| |||||
c.1328 + 1G > T
| IVS7 | Ex7 splice defect | + | 1 | Present study |
c.1841-2A > G | IVS10 | Ex11 splice defect | + | 2 | Bernal et al., 2003 |
c.11548 + 2T > G
| IVS59 | Ex59 splice defect | + | 1 | Present study |
c.12067-2A > G | IVS61 | Ex62 splice defect | + | 4 | Auslender et al., 2008 |
c.15053-1G > A
| IVS69 | Ex70 splice defect | + | 1 | Present study |
Nucleotide change | Exon | Amino acid change | Predicted pathology | No. of alleles | Ref. |
---|---|---|---|---|---|
c.373G > A | 2 | p.A125T | - | 81 | Dreyer et al., 2000 |
c.130G > A
| 2 |
p.G44R
| + | 1 | Present Study |
c.688G > A | 4 | p.V230M | - | 3 | Dreyer et al., 2000 |
c.908G > A | 6 | p.R303He | UV3 | 1 | Yan et al., 2009 |
c.1144G > A
| 7 |
p.V382M
b
| UV3 | 1 | Present Study |
c.1434G > C | 8 | p.E478D | - | 4 | Seyedahmadi et al., 2004 |
c.1663C > G | 10 | p.L555V | - | 2 | Bernal et al., 2003 |
c.1931A > T | 11 | p.D644V | - | 6 | Weston et al., 2000 |
c.2137G > C | 12 | P.G713R | UV2 | 2 | Dreyer et al., 2000 |
c.2276G > T | 13 | p.C759F | + | 3 | Dreyer et al., 2000 |
c.2522C > A | 13 | p.S841Y | UV2 | 1 | Jaijo et al., 2009 |
c.4457G > A | 21 | p.R1486K | - | 75 | Dreyer et al., 2000 |
c.4714C > T | 22 | p.L1572F | - | 7 | Dreyer et al., 2008 |
c.4994T > C | 25 | p.I1665T | - | 31 | Kaiserman et al., 2007 |
c.5975A > G | 30 | p.Y1992Ce | UV3 | 1 | McGee et al., 2010 |
c.6317T > C | 32 | p.I2106T | - | 117 | Aller et al., 2006 |
c.6506T > C | 34 | p.I2169T | - | 85 | Aller et al., 2006 |
c.6587G > C | 34 | p.S2196T | UV2 | 2 | Jaijo et al., 2009 |
c.6713A > C | 35 | p.E2238A | - | 1 | Aller et al., 2006 |
c.6875G > A | 36 | p.R2292H | - | 2 | Dreyer et al., 2008 |
c.7130A > G | 38 | p.N2377S | UV2 | 1 | Present Study |
c.7182C > A | 38 | p.N2394K | UV2 | 1 | Present Study |
c.7506G > A | 40 | p.P2502P | - | 11 | Baux et al., 2008 |
c.7685T > C | 41 | p.V2562A | - | 1 | Dreyer et al., 2008 |
c.7915T > C | 41 | p.S2639P | UV2 | 3 | McGee et al., 2010 |
c.8624G > A | 43 | p.R2875Q | - | 9 | Aller et al., 2006 |
c.8656C > T | 43 | p.L2886F | - | 9 | Aller et al., 2006 |
c.9262G > A | 47 | p.E3088K | - | 1 | Dreyer et al., 2008 |
c.9296A > G | 47 | p.N3099S | - | 12 | Aller et al., 2006 |
c.9343A > G | 47 | p.T3115A | - | 9 | Dreyer et al., 2008 |
c.9430G > A | 48 | p.D3144N | - | 8 | Aller et al., 2006 |
c.9595A > G | 49 | p.N3199D | - | 9 | Baux et al., 2007 |
c.9799T > C | 50 | p.C3267R | + | 5 | Aller et al., 2006 |
c.10073G > A | 51 | p.C3358Y | + | 1 | McGee et al., 2010 |
c.10232A > C | 52 | p.E3411A | - | 94 | Aller et al., 2006 |
c.10636G > A
| 54 |
p.G3546R
| + | 4 | Present Study |
c.11504C > T | 59 | p.T3835I | - | 30 | Present Study |
c.11602A > G | 60 | p.M3868V | - | 34 | Aller et al., 2006 |
c.11677C > A | 60 | p.P3893T | - | 2 | Dreyer et al., 2008 |
c.11680A > G
| 60 |
p.N3894D
| UV3 | 1 | Present Study |
c.12343C > T | 63 | p.R4115C | - | 2 | van Wijk et al., 2004 |
c.14074G > A | 64 | p.G4692Rc | UV2 | 1 | McGee et al., 2010 |
c.14453C > T | 66 | p.P4818L | + | 1 | Aller et al., 2006 |
c.14513G > A | 66 | p.G4838E | - | 1 | McGee et al., 2010 |
c.14543G > A | 66 | p.R4848Q | - | 1 | McGee et al., 2010 |
c.14761G > A | 67 | p.E4921K | UV2 | 1 | Present Study |
c.15076A > G | 70 | p.K5026E | UV2 | 1 | McGee et al., 2010 |
c.15091C > T | 70 | p.R5031W | - | 2 | Dreyer et al., 2008 |
Nucleotide change | Exon | Amino acid position | Predicted pathology | No. of alleles | Ref. |
---|---|---|---|---|---|
c.504A > G | 3 | p.T168T | - | 75 | Baux et al., 2008 |
c.1179A > G | 7 | p.Q393Q | - | 1 | Aller, 2008 |
c.1419C > T | 8 | p.T473T | - | 36 | Dreyer et al., 2000 |
c.2109T > C | 12 | p.D703D | - | 7 | Weston et al., 2000 |
c.2256T > C | 13 | p.H752H | - | 3 | Dreyer et al., 2008 |
c.3945T > C | 18 | p.N1315N | UV2 | 3 | Present Study |
c.4371G > A | 20 | p.S1457S | - | 1 | Dreyer et al., 2000 |
c.5031C > A | 25 | p.G1671G | - | 22 | Aller et al., 2006 |
c.5751C > T | 28 | p.Y1917Y | UV2 | 1 | McGee et al., 2010 |
c.7488A > G
| 40 |
p.E2496E
b
| + | 1 | Present Study |
c.7506G > A | 40 | p.P2502P | - | 11 | McGee et al., 2010 |
c.11736G > A | 61 | p.E3912E | - | 2 | Dreyer et al., 2008 |
c.11907A > T | 61 | p.P3969P | - | 2 | Dreyer et al., 2008 |
c.11946A > T | 61 | p.L3982L | - | 29 | Dreyer et al., 2008 |
c.12093C > T | 62 | p.Y4031Y | - | 1 | Dreyer et al., 2008 |
c.12612A > G | 63 | p.T4204T | - | 129 | Dreyer et al., 2008 |
c.12666A > G | 63 | p.T4222T | - | 58 | Dreyer et al., 2008 |
c.13191G > A | 63 | p.E4397E | - | 23 | Dreyer et al., 2008 |
c.14481C > T | 66 | p.A4827A | - | 1 | McGee et al., 2010 |
c.14664G > A | 67 | p.T4888T | UV2 | 1 | Present Study |
Patient | Mutations | Year of Birth | Diagnosis | Age of diagnosis | Sensorineural Hearing Loss | Vestibular Function | Onset of Night Blindness | Onset of Visual Field Loss | Visual Field | Visual Acuity | Eye Fundus | ERG | Cataracts |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
RP1310*
|
c.12067-2A > G/c.12067-2A > G
|
USHNC
| |||||||||||
RP1274* | p.E1492X/p.E1492X | 1969 | USH2 | Moderate-severe and stable | NormalA | 1 | |||||||
RP1633 | p.E1492X/p.E1492X | 1962 | USH2 | 25 | Since infancy | NormalA | 25 | 25 | Concentric loss | 0,2/0,4 | 1 | No response | BE |
RP1607 | p.G3546R/p.G3546R | 1925 | USH2 | 33 | Mild-moderate | NormalA | 16 | 25 | Marked concentric loss | 0,6/0,6 | 1 | Moderate alteration | BE |
RP1599* | c.1214delA/c.1214delA | 1980 | USH2 | Moderate, since infancy | NormalA | 20 | 30 | Moderate concentric loss | 0,6/0,7 | 1 | Moderate alteration | BE | |
RP259
|
c.1214delA/p.C3267R
|
1974
|
USHA
|
19
|
Profound since 6 years
|
Vestibular Dysfunction
A
|
6
|
Concentric loss (19 years)
|
0,35/0,35 (19 years)
|
1
|
No response
|
No (19 years)
| |
RP1349 | c.2299delG/c.1214delA | 1954 | USH2 | Moderate-severe | NormalB | 15 | 20 | Marked concentric loss | 0,4/0,3 (30 years) | 2 | |||
RP1493 | c.2299delG/c.8890dupT | 1973 | USH2 | 30 | Congenital, moderate and stable | NormalB | 29 | 29 | Concentric loss (at 31 years) | Normal (31 years) | 1 | No response (31 years) | No (31 years) |
RP1632 | c.2299delG/c.8954delG | 1961 | USH2 | Since infancy | NormalB | 23 | 25 | <0,1BE | 2 | No response | BE | ||
RP1715* | c.2299delG/c.1629_1645del | 1986 | USH2 | 22 | Moderate and stable since 6 years | NormalB | 16 | 20 | Slight concentric loss (at 25 years) | Normal (25 years) | 1 | No response | No |
RP1775
|
c.2299delG/p.R303H
#
|
1961
|
USHA
|
30
|
Moderate since 7 years and progressive
|
23
|
22
| ||||||
RP1618 | p.C3267R/c.6319_6324delinsTAAA | 1964 | USH2 | Severe-profound | NormalA | 30 | 30 | Marked concentric loss | 0,1/0,1 | 2 | No response | BE | |
RP1442* | p.C3267R/c.12093delC | 1962 | USH2 | 20 | Congenital, moderate and stable | NormalB | 15 | 20 | Concentric loss, 5° (at 43 years) | 0,5/0,2 (43 years) | 2 | LE (37 years) RE (43 years) | |
RP1703*
|
p.C3267R/p.C3358Y
|
1936
|
USHA
|
50
|
Since 64 years
|
50
|
55
|
Reduced (67 years)
|
1
|
Yes
| |||
RP1759 | p.C3267R/p.Y1992C# | 1945 | USH2 | 62 | Congenital, moderate and stable | NormalB | 62 | Abnormal response | Yes (62 years) | ||||
RP1625* | c.12067-2A > G/p.R274X | 1976 | USH2 | 25 | Since infancy | NormalA | 19 | 24 | Concentric loss | 0,1/0,1 | 2 | No response | BE |
RP1631 | c.1841-2A > G/p.R274X | 1976 | USH2 | Since infancy | NormalA | 28 | 28 | Concentric loss | 0,7/0,6 | 1 | No | ||
RP951 | c.1214delA/p.C3251X | 1969 | USH2 | 25 | Congenital, severe and stable | NormalB | 25 | 18 | Reduced (23 years) | 2 | No response (30 years) | No (30 years) | |
RP1558 | p.R1549X/c.1328 + 1G > T | 1933 | USH2 | 43 | Severe and progressive since 20 years | NormalB | Before puberty | -10°C | 0,007/0.03 | 2 | |||
RP1539* | p.R1295X/p.N3894D# | 1987 | USH2 | 20 | Congenital, moderate and stable | NormalB | 20 | 17 | Concentric loss (20 years) | 2 | |||
RP1172* | c.10272_10273dupTT/p.W2618X | 1964 | USH2 | 23 | Moderate and stable since 7 years | NormalB | 23 | 18 | Concentric loss (38 years) | No response (39 years) | |||
RP1641*
|
p.C759F/p.W4725X
|
1967
|
USHA
|
Moderate and progressive
|
Central vestibular pathology
A
|
18
|
22
|
Marked concentric loss
|
0,1/0,2
|
2
|
No response
|
BE
| |
RP1667* | p.C759F/c.11548 + 2T > G | 1954 | USH2 | 15 | Mild and slightly progressive | NormalB | 15 | 8 | RE (30 years) | ||||
RP690M* | p.P4818L/p.Q3368X + c.5278delG | 1972 | USH2 | 22 | Congenital, moderate and stable | NormalA | 22 | 8 | 0,3/0,3 (32 years) | 1 | No response (31 years) | BE (25 years) | |
RP532 | p.Y506X/p.Q3587X | 1968 | USH2 | Profound | NormalA | 15 | 20 | Marked concentric loss | 0,1/0,1 | 2 | No response | BE | |
RP946*
|
p.Q3587X/p.E2496E
|
1982
|
USHNC
|
17
| |||||||||
RP1613 | c.9260delT/p.G44R | 1971 | USH2 | 30 | Severe | NormalA | 20 | 20 | Marked concentric loss | 0,1/0,6 | 2 | Abnormal response | BE |
RP1615 | c.11566delA/c.15053-1G > A | 1975 | USH2 | 27 | Moderate since infancy | NormalA | 24 | 25 | Marked concentric loss | 0,5/0,5 | 2 | No response | BE |
Nucleotide change | Intron | Predicted pathology | No. of alleles |
---|---|---|---|
c.1328 + 52T > C | IVS7 | - | 3 |
c.1841-61G > A | IVS10 | - | 11 |
c.4627 + 32G > T | IVS21 | UV2 | 1 |
c.6485 + 18C > T | IVS33 | UV2 | 1 |
c.6486-54T > C | IVS33 | UV2 | 2 |
c.6486-43T > A | IVS33 | UV2 | 1 |
c.6657 + 29C > A | IVS34 | UV2 | 1 |
c.8681 + 18A > G | IVS43 | UV2 | 1 |
c.8681 + 53T > G | IVS43 | UV2 | 1 |
c.8681 + 118A > G | IVS43 | UV2 | 1 |
c.9056-52G > T | IVS45 | UV | 1 |
c.9372-50A > G | IVS47 | UV2 | 1 |
c.9740-59G > A | IVS49 | UV2 | 1 |
c.9958 + 128A > G | IVS50 | - | 4 |
c.10388-123T > C | IVS52 | UV2 | 1 |
c.13812-78A > G | IVS63 | UV2 | 1 |
c.14134-53T > C | IVS64 | UV2 | 1 |
c.14343 + 36G > C | IVS65 | UV2 | 1 |
c.15298-35T > A | IVS70 | UV2 | 1 |
c.15298-1153G > A(g.798209G > A) d | IVS71 | UV2 | 1 |
Missense variants
SIFT | PolyPhen | PMUT | |
---|---|---|---|
p.G44R
| Affect (Score 0.01) | Probably damaging | Pathogenic (NN output 0.5113) |
p.N2377S
| Tolerated (Score 0.44) | Possibly damaging | Neutral (NN output 0.2372) |
p.N2394K
| Tolerated (Score 0.23) | Possibly damaging | Neutral (NN output 0.5113) |
p.G3546R
| Affect (Score 0.01) | Probably damaging | Pathogenic (NN output 0.1799) |
p.N3894D
| Tolerated (Score 0.05) | Probably damaging | Neutral (NN output 0.0522) |
p.E4921K
| Tolerated (Score 0.85) | Benign | Neutral (NN output 0.3130) |
Silent variants
Intronic variants
Discussion
PRESENT REPORT SAMPLE | TOTAL SERIES# | |||||||
---|---|---|---|---|---|---|---|---|
0 MUT | 1 MUT | 2 MUT | 1 + 2 MUT* | 0 MUT | 1 MUT | 2 MUT | 1 + 2 MUT* | |
USH2
| 43.1% (25/58) | 22.4% (13/58) | 34.5% (20/58) | 56.9% (33/58) | 23.9% (32/134) | 16.4% (22/134) | 59.7% (80/134) | 76.1% (102/134) |
USHA
| 54.5% (6/11) | 18.2% (2/11) | 27.3% (3/11) | 45.5% (5/11) | 33.3% (8/24) | 25% (6/24) | 41.6% (10/24) | 66.7% (16/24) |
USHNC
| 73.7% (14/19) | 15.8% (3/19) | 10.5% (2/19) | 26.3% (5/19) | 64% (16/25) | 12% (3/25) | 24% (6/25) | 36% (9/25) |
TOTAL
| 51.1% (45/88) | 20.5% (18/88) | 28.4% (25/88) | 48.9% (43/88) | 30.6% (56/183) | 16.9% (31/183) | 52.5% (96/183) | 69.4% (127/183) |