Background
Methods
Clinical investigation
Previous molecular genetic analysis
Molecular genetic analysis using NGS
Number
|
Gene name
|
---|---|
1 |
ABCA4
|
2 |
ABCC6
|
3 |
ADAM9
|
4 |
AHI1
|
5 |
AIPL1
|
6 |
ALMS1
|
7 |
ARL6
|
8 |
ARMS2
|
9 |
ATXN7
|
10 |
BBS10
|
11 |
BBS12
|
12 |
BBS2
|
13 |
BBS4
|
14 |
BBS5
|
15 |
BBS7
|
16 |
BBS9
|
17 |
BEST1
|
18 |
C1QTNF5
|
19 |
C2
|
20 |
C2orf71
|
21 |
C3
|
22 |
CA4
|
23 |
CABP4
|
24 |
CACNA1F
|
25 |
CACNA2D4
|
26 |
CC2D2A
|
27 |
CDH23
|
28 |
CDH3
|
29 |
CEP290
|
30 |
CERKL
|
31 |
CFB
|
32 |
CFH
|
33 |
CHM
|
34 |
CLN3
|
35 |
CLRN1
|
36 |
CNGA1
|
37 |
CNGA3
|
38 |
CNGB1
|
39 |
CNGB3
|
40 |
CNNM4
|
41 |
COL11A1
|
42 |
COL2A1
|
43 |
COL9A1
|
44 |
CRB1
|
45 |
CRX
|
46 |
CYP4V2
|
47 |
DFNB31
|
48 |
DMD
|
49 |
DPP3
|
50 |
EFEMP1
|
51 |
ELOVL4
|
52 |
ERCC6
|
53 |
EYS
|
54 |
FAM161A
|
55 |
FBLN5
|
56 |
FSCN2
|
57 |
FZD4
|
58 |
GNAT1
|
59 |
GNAT2
|
60 |
GPR98
|
61 |
GRK1
|
62 |
GRM6
|
63 |
GUCA1A
|
64 |
GUCA1B
|
65 |
GUCY2D
|
66 |
HMCN1
|
67 |
HTRA1
|
68 |
IDH3B
|
69 |
IMPDH1
|
70 |
IMPG2
|
71 |
INPP5E
|
72 |
INVS
|
73 |
IQCB1
|
74 |
JAG1
|
75 |
KCNJ13
|
76 |
KCNV2
|
77 |
KLHL7
|
78 |
LCA5
|
79 |
LRAT
|
80 |
LRP5
|
81 |
MERTK
|
82 |
MFRP
|
83 |
MKKS
|
84 |
MKS1
|
85 |
MTND1
|
86 |
MTND6
|
87 |
MT-AP6
|
88 |
MTND2
|
89 |
MTND5
|
90 |
MTND4
|
91 |
MYO7A
|
92 |
NDP
|
93 |
NPHP1
|
94 |
NPHP3
|
95 |
NPHP4
|
96 |
NR2E3
|
97 |
NRL
|
98 |
NYX
|
99 |
OAT
|
100 |
OFD1
|
101 |
OPA1
|
102 |
OPA3
|
103 |
OPN1LW
|
104 |
OPN1MW
|
105 |
OPN1Sw
|
106 |
OTX2
|
107 |
PANK2
|
108 |
PAX2
|
109 |
PCDH15
|
110 |
PCDH21
|
111 |
PDE6A
|
112 |
PDE6B
|
113 |
PDE6C
|
114 |
PDE6G
|
115 |
PDZD7
|
116 |
PEX1
|
117 |
PEX2
|
118 |
PEX7
|
119 |
PGK1
|
120 |
PHYH
|
121 |
PITPNM3
|
122 |
PRCD
|
123 |
PROM1
|
124 |
PRPF3
|
125 |
PRPF31
|
126 |
PRPF8
|
127 |
PRPH2
|
128 |
RAX2
|
129 |
RB1
|
130 |
RBP3
|
131 |
RBP4
|
132 |
RD3
|
133 |
RDH12
|
134 |
RDH5
|
135 |
RGR
|
136 |
RGS9
|
137 |
RGS9BP
|
138 |
RHO
|
139 |
RIMS1
|
140 |
RLBP1
|
141 |
ROM1
|
142 |
RP1
|
143 |
RP1L1
|
144 |
RP2
|
145 |
RP9
|
146 |
RPE65
|
147 |
RPGR
|
148 |
RPGRIP1
|
149 |
RPGRIP1L
|
150 |
RS1
|
151 |
SAG
|
152 |
SDCCAG8
|
153 |
SEMA4A
|
154 |
SLC24A1
|
155 |
SNRNP200
|
156 |
SPATA7
|
157 |
TEAD1
|
158 |
TIMM8A
|
159 |
TIMP3
|
160 |
TLR3
|
161 |
TLR4
|
162 |
TMEM126A
|
163 |
TOPORS
|
164 |
TREX1
|
165 |
TRIM32
|
166 |
TRPM1
|
167 |
TSPAN12
|
168 |
TTC8
|
169 |
TTPA
|
170 |
TULP1
|
171 |
UNC119
|
172 |
USH1C
|
173 |
USH1G
|
174 |
USH2A
|
175 |
VCAN
|
176 |
WFS1
|
177 |
ZNF513
|
Number
|
Gene name
|
Reason
|
References
|
---|---|---|---|
1 |
ADCY1
| diff. Expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
2 |
ANKRD33
| diff. Expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
3 |
ANXA2
| Promotion of choroidal neovascularization | [36] |
4 |
ARL13B
| Cilia protein, mutations lead to Joubert Syndrome | [37] |
5 |
BMP7
| Regulation of Pax 2 in mouse retina | [38] |
6 |
BSG
| - | Thierry Leveillard personal commmunication |
7 |
CAMK2D
| diff. Expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
8 |
CCDC28B
| Modifier for BBS | |
9 |
CLCN7
| Cln7-/- mice severe osteopetrosis and retinal degeneration | [41] |
10 |
COL4A3
| Alport syndrome, with eye abnormalities | |
11 |
COL4A4
| Alport syndrome, with eye abnormalities | |
12 |
COL4A5
| Alport syndrome, with eye abnormalities | |
13 |
CUBN
| - | Personal communication Renata Kozyraki |
14 |
CYP1B1
| glaucoma | [46] |
15 |
DOHH
| diff. Expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
16 |
DSCAML1
| diff. Expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
17 |
ESRRB
| diff. Expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
18 |
FIZ1
| Interactor of NRL | [47] |
19 |
GJA9
| diff. Expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
20 |
GNAZ
| diff. Expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
21 |
GNGT1
| diff. Expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
22 |
GPR152
| diff. Expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
23 |
HCN1
| diff. Expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
24 |
HEATR5A
| diff. Expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
25 |
HIST1H1C
| Expressed in retina | Expression databases |
26 |
IMPG1
| diff. Expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
27 |
INSL5
| diff. Expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
28 |
KCNB1
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
29 |
KCTD7
| Expressed in retina | Expression databases |
30 |
LASS4
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
31 |
LRIT2
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom Rd1 mouse |
32 |
LRP2
| - | Personal communication Renata Kozyraki |
33 |
MAB21L1
| diff. expression Rd1 mouse | Chalmel et al., manuscript in preparatiom |
34 |
MAP2
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
35 |
MAS1
| Degeneration of cones due to expression of Mas1 | [48] |
36 |
MAST2
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
37 |
MPP4
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
38 |
MYOC
| glaucoma | [49] |
39 |
NDUFA12
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
40 |
NEUROD1
| BETA2/NeuroD1 -/- mouse: photoreceptor degeneration | [50] |
41 |
NOS2
| glaucoma | [51] |
42 |
NXNL1
| Rod-derived cone viability factor | [52] |
43 |
NXNL2
| Rod-derived cone viability factor 2 | [53] |
44 |
OPN1MW2
| Cone opsin, medium-wave-sensitive2 | [54] |
45 |
OPTN
| glaucoma | [55] |
46 |
PFKFB2
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
47 |
PIAS3
| Rod photoreceptor development | [56] |
48 |
PKD2L1
| Diff. expression in human retinal detachment | Delyfer et al. 2011 submitted |
49 |
PLEKHA1
| Age-related macular degeneratiom | [57] |
50 |
PPEF2
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
51 |
RAB8A
| Interacts with RPGR, role in cilia biogenesis and maintenance | [58] |
52 |
RABGEF1
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
53 |
RCVRN
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
54 |
RGS20
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
55 |
RNF144B
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
56 |
RORB
| Rod photoreceptor development in mice | [59] |
57 |
RXRG
| Retinoic acid receptor, highly expressed in the eye | Expression databases |
58 |
SGIP1
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
59 |
SLC16A8
| Altered visual function in ko-mice | [60] |
60 |
SLC17A7
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
61 |
STAM2
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
62 |
STK35
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
63 |
STX3
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
64 |
SV2B
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
65 |
TBC1D24
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
66 |
THRB
| Essential for M-cone development in rodents | [61] |
67 |
TMEM216
| Cilia protein, mutations lead to Joubert and Meckel syndrome | [62] |
68 |
TMEM67
| Cilia protein, mutations lead to Joubert | [63] |
69 |
TRPC1
| diff. expression rd1 mouse | diff. expression Rd1 mouse |
70 |
UHMK1
| diff. expression rd1 mouse | diff. expression Rd1 mouse |
71 |
VSX1
| Stimulator for promoter NXNL1 | [64] |
72 |
VSX2
| Stimulator for promoter NXNL1 | [64] |
73 |
WDR17
| diff. expression rd1 mouse | diff. expression Rd1 mouse |
74 |
WDR31
| diff. expression Nxnl1-/- mouse | [65] |
75 |
WISP1
| diff. expression rd1 mouse | Chalmel et al., manuscript in preparatiom |
76 |
XIAP
| Protects photoreceptors in animal models of RP | [66] |
77 |
ZDHHC2
| diff. expression Rd1 mouse | Chalmel et al., manuscript in preparatiom |
Investigation of annotated sequencing data
Assessment of the pathogenicity of variants
Results
Validation of the novel genetic testing tool for retinal disorders
Index | Phenotype | Gene | Mutation | Allele State | Read reference NGS | Read variant NGS | Mutation detected by NGS | Mean depth |
---|---|---|---|---|---|---|---|---|
CIC00034, F28 | adRP |
PRPF31
| c.666dup p.I223YfsX56 | het | 11 | 13 | yes | 21.3-22.5 |
CIC00140, F108 | adRP |
PRPF31
| c.997delG p.E333SfsX5 | het | - | - | no | 5.0-5.2 |
CIC00238, F165 | arCSNB |
TRPM1
| c.1418G > C p.R473P | homo | 0 | 38 | yes | 36.7 |
CIC00707, F470 | Best and adCSNB see Table 5 |
BEST1
| c.73C > T p.R25W | het | 40 | 38 | yes | 99.4 |
Detection of known and novel mutations
Index | Phenotype | Pre-screening | Gene | Mutation | Allele State | Read reference NGS | Read variant NGS | Reference | Mutation verified by Sanger and co-segregation |
---|---|---|---|---|---|---|---|---|---|
CIC00019, F16
| adRP | Linkage, RHO, PRPF31, PRPH2, RP1 |
PRPF3
|
c.1481C > T
p.T494M
| het | 25 | 22 | [67] | yes |
CIC0000893, F574
| adRP |
RHO, PRPF31, PRPH2, RP1
|
NR2E3
|
c.166G > A
p.G56R
| het | 5 | 3 | [68] | yes |
CIC000128, F100
| arRP, consang. | - |
EYS
|
c.408_423del p.N137VfsX24
| homo | - | 179 | yes | |
CIC0000943, F100 | arRP, consang | - |
EYS
| c.408_423del p.N137VfsX24 | homo | 0 | 193 | yes |
Index | Phenotype | Pre-screening | Gene | Mutation | Allele State | Read reference NGS | Read variant NGS | Mutation verified by Sanger and co-segregation | Conservation | Polyphen | Sift |
---|---|---|---|---|---|---|---|---|---|---|---|
CIC00707,
F470
| adCSNB and Best see Table 3 |
RHO, PDE6B, GNAT1
|
TRPM1
|
c.1961A > C
p.H654P
| het | 39 | 38 | yes | moderately conserved | possibly damaging | tolerated |
CIC000348, F232
| adRP, mild | RHO, PRPF31, PRPH2, RP1, adRP chip |
PRPF8
|
c.6992A > G
p.E2331G
| het | 13 | 10 | yes | moderately conserved | possibly damaging | affect protein function |
CIC000346, F232 | adRP | - |
PRPF8
| c.6992A > G p.E2331G | het | 5 | 9 | yes | moderately conserved | possibly damaging | affect protein function |
CIC000347, F232 | as adRP | - |
PRPF8
| c.6992A > G p.E2331G | het | 15 | 17 | yes | moderately conserved | possibly damaging | affect protein function |
CIC04240,
F2025
| arRP, consang., detailed clinic in [70] |
RS1
|
CRB1
|
c.2219C > T
p.S740F
| homo | 2 | 194 | yes | highly conserved | probably damaging | affect protein function |
CIC00199,
F146
| adRP or x-linked RP with affected carrier | RHO, PRPF31, PRPH2, RP1, adRP chip |
RPGR
|
c.248-2A > G
splice defect
| hetero | 30 | 22 | yes | conserved splice site | n.a. | n.a. |
CIC04094,
F1915
| icCSNB | - |
CACNA1F
|
c.973C > T
p.Q325X
| hemi | 0 | 28 | yes | n.a. | n.a. | n.a. |
Unsolved cases
Index | Phenotype | Pre-screening | Gene | Mutation | Allele State | Read reference NGS | Read variant NGS | Mutation verified by Sanger and co-segregation | Comment |
---|---|---|---|---|---|---|---|---|---|
CIC03282,
F1388
| Stargardt | ABCA4 microarray |
ABCA4
|
c.1268A > G
p.H423R
| het | 77 | 61 | yes | but reported as polymorphism [71] |
c.6764G > T
p.S2255I
no additional variants in lower covered exons
| het | 2 | 7 | yes | but reported as polymorphism [72] | ||||
CFH
|
c.3482C > A
p.P1161Q
| het | 77 | 52 | yes | conserved, probably damaging | |||
c.1204C > T
p.H402Y
| het | 94 | 87 | yes | AMD | ||||
CIC01269, F761
| adRP |
-
|
RP1L1
|
c.5959C > T
p.Q1987X
| het | 145 | 150 | yes, did not co-segregate | pass to whole exome sequencing |
CIC01312,
F795
| adCD with post-receptoral defects | RHO, PDE6B, GNAT1 adRP chip |
CUBN
|
c.127C > T
p.R43X
| het | 139 | 102 | yes, did not co-segregate | pass to whole exome sequencing |
CUBN
|
c.9340G > A
p.G3114S
| het | 61 | 44 | yes, did not co-segregate | ||||
GUCY2D
|
c.1499C > T
p.P500L
| het | 41 | 34 | yes, did not co-segregate | ||||
TRPM1
|
c.3904T > C
p.C1302R
| het | 102 | 99 | yes, did not co-segregate | ||||
CIC03225,
F1362
| arRP consang. | arRP chip |
PROM1
|
c.314A > G
p.Y105C
| het | 120 | 115 | yes, but no additional mutation | no homo, no compound hets, pass to whole exome sequencing |
GUCY2D
|
c.2917G > A
p.V973L
| het | 6 | 2 | false positive, not found by Sanger | ||||
DSCAML1
|
c.592C > T
p.R198C
| het | 70 | 81 | yes, but no additional mutation | ||||
TBC1D24
|
c.641G > A
p.R214H
| het | 27 | 12 | yes, but no additional mutation | ||||
TMEM67
|
c.1700A > G
p.Y567C
| het | 80 | 58 | yes, but no additional mutation | ||||
CIC04757
F2364
| Index and affected sister early onset arCD, macro-cephaly and mental retardation in affected sister consang. | - |
IMPG2
|
c.3439C > T
p.P1147S
| homo | 0 | 140 | no | Polyphen and Sift benign, not conserved |
PKD2L1
|
c.1027C > T
p.R343C
| het | 63 | 68 | |||||
c.1202T > G
p.V401G
| het | 25 | 19 | appeared also het in 11 of our samples appeared also het in affected sister but no other mutation in less covered exons | |||||
DFNB31
|
c.1943C > A p.S648Y
| het | 7 | 7 | yes | affected sister also both variants but both come from father, no other variant in lower covered region. | |||
c.2644C > A
p.R882S
| het | 27 | 14 | yes | |||||
EYS
|
c.7597A > G
p.K2533E
| het | 151 | 149 | yes | Affected sister does not carry this variant | |||
RPGRIP1
|
c.2417C > T
p.T806I
| het | 138 | 132 | no | not conserved | |||
CIC04152, F1955
| male x-linked cCSNB, has affected nephew |
NYX
|
TRPM1
|
c.470C > T
p.S157F
| het | 118 | 130 | yes, no other het mutation. | x-linked inheritance and phenotype verification |