1. NGS panel - Genetic testing for retinitis pigmentosa

Retinitis pigmentosa

June 22, 2017

Clinical features

Retinitis pigmentosa (RP) refers to a group of rare inherited diseases characterized by abnormalities of the photoreceptors of the retina, leading to progressive visual loss. The prevalence of retinitis pigmentosa is 1:3000 to 1:7000 persons, or 14 to 33 per 100,000 1.

Retinitis pigmentosa that does not affect other organs or tissues is classified as non-syndromic or “simple” and if it is associated with neurosensory systems such as hearing it is classified as systemic retinitis pigmentosa 2. Nonsyndromic retinitis pigmentosa can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Rare digenic forms also occur (for example in individuals who are heterozygous for both a ROM1 pathogenic variant and a PRPH2 pathogenic variant) 3.

The most common clinical features of retinitis pigmentosa include the following 1:

  • Night blindness or defective adaptation to dark, also known as nyctalopia
  • Visual acuity e.g. early loss of cone function, resulting in loss of central visual acuity over time
  • Cystoid macular edema (CME) is estimated to occur in approximately 10-50% of individuals with RP, depending on the study, the genetic type, and the diagnostic tool 1, 13
  • Fundus appearance: the earliest observed changes in the fundus are arteriolar narrowing, fine dust-like intraretinal pigmentation, and loss of pigment from the pigment epithelium
  • Moderate to severe retinal vessel attenuation and waxy pallor of the optic nerve
  • Posterior subcapsular cataracts characterized by yellowish crystalline changes in the visual axis of the posterior lens cortex
  • Dust-like particles in the vitreous
  • Hyaline bodies of the optic nerve head
  • Exudative vasculopathy, known also as Coats-like disease.

The diagnosis of retinitis pigmentosa is established based on the level of rod dysfunction, intensity of photoreceptor function loss and loss of peripheral vision, as well as a positive family history of retinal disease. Retinitis pigmentosa can be inherited in autosomal dominant (adRP: 15-25%), autosomal recessive (arRP: 5-20%), X-linked (xlRP: 5-15%), and digenic fashion (rare)1.

The genes associated with nonsyndromic autosomal recessive retinitis pigmentosa (arRP) are listed in Table 1, while the genes associated with autosomal dominant forms of retinitis pigmentosa are listed in Table 2.

There is no cure for retinitis pigmentosa, however measures are available to help patients, including vitamin A/beta-carotene and antioxidans in general. Macular edema can be reduced using acetazolamide, lutein, and other drugs.

CENTOGENE offers full gene sequencing and deletion/duplication analysis for the following panels:

Retinitis pigmentosa panel, autosomal recessive (ABCA4, ARL6, BBS1, BEST1, C2ORF71, C8ORF37, CERKL, CNGA1, CNGB1, CRB1, DHDDS, EYS, FAM161A, FLVCR1, GNPTG, IDH3B, IMPG2, LRAT, MAK, MERTK, NR2E3, NRL, PDE6A, PDE6B, PDE6G, PRCD, PROM1, RBP3, RDH12, RGR, RHO, RLBP1, RP1, RP2, RPE65, RPGR, SAG, SEMA4A, SPATA7, TTC8, TULP1, USH2A, ZNF513)

Retinitis pigmentosa panel, autosomal dominant (ABCA4, BEST1, CA4, CRX, CLRN1, FSCN2, GUCA1B, IMPDH1, KLHL7, NR2E3, NRL, PRPF3, PRPF31, PRPF6, PRPF8, PRPH2, RDH12, RGR, RHO, ROM1, RP1, RP2, RP9, RPE65, RPGR, SEMA4A, SNRNP200, TOPORS.


Table 1: Overview of genes included in Retinitis pigmentosa panel, autosomal recessive offered by CENTOGENE

Gene
(OMIM)
RP type
(chr. locus)
Frequency of mutations Allelic and associated disorders
(OMIM)
ABCA4
(601691)
RP19
(1p22.1 )
Rare for adRP 1
2%-5% for arRP 4
Retinitis pigmentosa 19 (601718);
Stargardt disease 1 (248200);
Age related macular degeneration (153800);
Cone-rod dystrophy 3 (604116);
Fundus flavimaculatis; Bull's eye maculopathy (unknown)
ARL6
(608845)
RP55
(3q11.2)
Rare 1 Retinitis pigmentosa 55 (613575);
Bardet-Biedl syndrome 3 (600151)
BBS1
(209901)
BBS1
(11q13.2)
≤1% 1
~23.2% for BBS 7
Bardet-Biedl syndrome 1 (209901)
BEST1
(607854)
RP50
(11q12.3)
Rare 1 Retinitis pigmentosa 50 (613194);
Bestrophinopathy (611809);
Vitreoretinochoroidopathy (193220);
Macular dystrophy, vitelliform, 2 (153700)
C2ORF71
(613425)
RP54
(2p23.2)
≤1% 1 Retinitis pigmentosa 54 (613428);
Cone-rod dystrophy, Atypical Usher syndrome (unknown)
C8ORF37
(614477)
RP64
(8q22.1)
≤1% 1 Retinitis pigmentosa 64 (614500);
Bardet-Biedl syndrome 21 (617406);
Cone-rod dystrophy 16 (614500)
CERKL
(608381)
RP26
(2q31.3)
3%-4% in Spain 1, 4 Retinitis pigmentosa 26 (608380);
Cone-rod dystrophy (unknown)
CNGA1
(123825)
RP49
(4p12)
1%-2% 1
5.1% (5/99) in Japan 4
Retinitis pigmentosa 49 (613756);
Usher syndrome (unknown)
CNGB1
(600724)
RP45
(16q21)
≤1% 1 Retinitis pigmentosa 45 (613767)
CRB1
(604210)
RP12
(1q31.3)
6%-7% (Spain) 1
10% (18/179) for LCA 5
Retinitis pigmentosa-12, autosomal recessive (600105);
Leber congenital amaurosis 8 (613835);
Pigmented paravenous chorioretinal atrophy (172870)
DHDDS
(608172)
RP59
(1p36.11)
≤1% 1, 4 Retinitis pigmentosa 59 (613861);
Congenital disorder of glycosylation (unknown)
EYS
(612424)
RP25
(6q12)
10%-30% in Spain;
common in China 1, 6
Retinitis pigmentosa 25 (602772);
Leber congenital amaurosis; Usher syndrome; Peripheral dystrophy (unknown)
FAM161A
(613596)
RP28
(2p15)
≤1% 1 Retinitis pigmentosa 28 (606068)
FLVCR1
(609144)
AXPC1
(1q32.3)
2/58 Swiss patients 7 Ataxia, posterior column, with retinitis pigmentosa (609033)
GNPTG
(607838)
RP-related
(1613.3)
1 family 1 Retinitis pigmentosa and spondylo-epiphyseal dysplasia (unknown);
Mucolipidosis III gamma (252605)
IDH3B
(604526)
RP46
(20p13)
≤1% 1 Retinitis pigmentosa 46 (612572)
IMPG2
(607056)
RP56
(3q12.3)
≤1% 1 Retinitis pigmentosa 56 (616152),
Macular dystrophy, vitelliform, 5 (613581)
LRAT
(604863)
LCA14
(4q32.1)
≤1% 1
1,1% in Saudi Arabian population 13
Retinitis pigmentosa, juvenile,
Leber congenital amaurosis 14 (613341);
Usher syndrome (unknown)
MAK
(154235)
RP62
(6p24.2)
≤1% 1
1 in 55 (Ashkenazi Jews 8)
Retinitis pigmentosa 62 (614181);
Retinal dystrophy (unknown)
MERTK
(604705)
RP38
(2q13)
≤1% 1 Retinitis pigmentosa 38 (613862);
Leber congenital amaurosis; Cone-rod dystrophy (unknown)
NR2E3
(604485)
RP37
(15q23)
1-2% 1, 9 Retinitis pigmentosa 37 (611131);
Enhanced S-cone syndrome (268100);
Cone-rod dystrophy, Goldman-Favre syndrome, Helicoid subretinal fibrosis (unknown)
NRL
(162080)
RP27
(14q11-q12)
Rare 1 Retinitis pigmentosa 27 (613750);
Leber congenital amaurosis;
Clumped pigmentary retinal degeneration;
Enhanced S cone syndrome;
Cone dysfunction syndrome (unknown)
PDE6A
(180071)
RP43
(5q32)
2%-5% 1
3%-4% of arRP in North America 10
Retinitis pigmentosa 43 (613810);
Retinal dystrophy (unknown)
PDE6B
(180072)
RP40
(4p16.3)
2%-5% 1, 10 Retinitis pigmentosa-40 (613801);
Night blindness, congenital stationary, autosomal dominant 2 (163500);
Retinal dystrophy;
Leber congenital amaurosis (unknown)
PDE6G
(180073)
RP57
(17q25.3)
Rare 1, 10 Retinitis pigmentosa 57 (613582)
PRCD
(610598)
RP36
(17q25.1)
≤1% 1 Retinitis pigmentosa 36 (610599)
PROM1
(604365)
RP41
(4p15.32)
≤1% 1
3,5% in Belgian population 11
Retinitis pigmentosa 41 (612095);
Stargardt disease 4 (603786);
Cone-rod dystrophy  12 (612657);
Macular dystrophy, retinal, 2 (608051)
RBP3
(180290)
RP66
(10q11.22)
≤1% 1 Retinitis pigmentosa 66 (615233);
Leber congenital amaurosis, Retinal dystrophy
RDH12
(608830)
RP53
(14q24.1)
Rare 1, 12
0,6% (Chinese)  12
Retinitis pigmentosa 53;
Leber congenital amaurosis 13 (612712)
RGR
(600342)
RP44
(10q23.1)
≤1% 1 Retinitis pigmentosa 44 (613769)
RHO
(180380)
RP4
(3q22.1)
20-30% 1 Retinitis pigmentosa 4, autosomal dominant or recessive (613731);
Night blindness, congenital stationary, autosomal dominant 1 (610445);
Retinitis punctata albescens (136880)
RLBP1
(180090)
RPA
(15q26.1)
≤1% 1 Retinitis pigmentosa (unknown);
Bothnia retinal dystrophy (607475);
Fundus albipunctatus (136880);
Newfoundland rod-cone dystrophy (607476);
Retinitis punctata albescens (136880);
Cone-rod dystrophy (unknown)
RP1
(603937)
RP1
(8q11.2-q12.1)
1% 1
3-4% for adRP 1
Retinitis pigmentosa 1 (180100);
Leber congenital amaurosis, Night blindness, Macular dystrophy, Retinal dystrophy (unknown)
RP2
(312600)
RP2
(Xp11.3)
10-20% for X-linked RP 1 Retinitis pigmentosa 2 (312600);
Cone-rod dystrophy;
Pattern dystrophy;
X-linked retinitis pigmentosa;
Leber congenital amaurosis, Night blindness, Macular dystrophy, Retinal dystrophy (unknown)
RPE65
(180069)
RP20
(1p31.3)
2-5% for adRP 1
3-16% for LCA2 13
Retinitis pigmentosa 20 (613794);
Leber congenital amaurosis 2 (204100);
Cone-rod dystrophy, Fundus albipunctatus (unknown)
RPGR
(312610)
RP3
(X11.4)
70-90% of X-linked RP4 Retinitis pigmentosa 3 (300029);
Cone-rod dystrophy, X-linked, 1 (304020);
Macular degeneration, X-linked atrophic (300834);
Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness, Leber congenital amaurosis (unknown)
SAG
(181031)
RP47
(613758)
2%-3% in Japan 1, 4 Retinitis pigmentosa 47 (613758);
Oguchi disease-1 (258100)
SEMA4A
(607292)
RP35
(1q22)
3%-4% in Pakistan 14 Retinitis pigmentosa 35 (610282);
Cone-rod dystrophy 10 (610283);
Leber congenital amaurosis (unknown)
SPATA7
(609868)
LCA3
(14q31.3)
≤1% 1 Retinitis pigmentosa, juvenile, Leber congenital amaurosis 3 (604232)
TTC8
(608132)
RP51
(14q31.3)
≤1% 1 Retinitis pigmentosa 51 (613464);
Bardet-Biedl syndrome 8 (615985)
TULP1
(602280)
RP14
(6p21.31)
≤1% 1 Retinitis pigmentosa 14 (600132);
Leber congenital amaurosis 15 (613843)
USH2A
(608400)
RP39
(1q41)
10%-15% 1
57%-79% for Usher syndrome 15
Retinitis pigmentosa 39 (613809);
Usher syndrome 2A (276901); Deafness; Retinal dystrophy; Autism; amyotrophic lateral sclerosis; High myopia; Stargardt disease; Leber congenital amaurosis (unknown)
ZNF513
(613598)
RP58
(2p23.3)
≤1% 1 Retinitis pigmentosa 58 (613617)

Table 2: Overview of genes included in Retinitis pigmentosa panel, autosomal dominant offered by CENTOGENE

Gene
(OMIM)
RP type
(chr. locus)
Frequency of mutations Allelic and associated disorders
(OMIM)
ABCA4
(601691)
RP19
(1p22.1)
Rare for adRP 1
2%-5% for arRP 4
Retinitis pigmentosa 19 (601718);
Stargardt disease 1 (248200);
Age related macular degeneration (153800);
Cone-rod dystrophy 3 (604116);
Fundus flavimaculatis;
Bull's eye maculopathy (unknown)
BEST1
(607854)
RP50
(11q12.3)
Rare 1 Retinitis pigmentosa 50 (613194);
Vitreoretinochoroidopathy (193220);
Macular dystrophy, vitelliform, 2 (153700);
Bestrophinopathy autosomal recessive (611809)
CA4
(114760)
RP17
(17q23.1)
Rare 1 Retinitis pigmentosa 17 (600852)
CRX
(602225)
CORD2
(19q13.33)
1% for adRP 1
~3% for LCA7 16
Cone-rod retinal dystrophy-2 (120970);
Leber congenital amaurosis 7 (613829);
Bull's eye maculopathy;
Retinal dystrophy;
Retinitis pigmentosa & rod cone dystrophy (unknown)
CLRN1
(606397)
RP61
(3q25.1)
≤1% 1 Retinitis pigmentosa 61 (614180);
Usher syndrome 3A (276902);
Retinal dystrophy;
Usher syndrome 1, 3, 2, 1d (unknown)
FSCN2
(607643)
RP30
(17q25.3)
Rare 1 Retinitis pigmentosa 30 (607921)
GUCA1B
(602275)
RP48
(6p21.1)
5% in Japan 1, 17 Retinitis pigmentosa 48 (613827);
Leber congenital amaurosis; Retinal dystrophy (unknown)
IMPDH1
(146690)
RP10
(7q32.1)
2-3% 1 Retinitis pigmentosa 10 (180105);
Leber congenital amaurosis (613837)
KLHL7
(611119)
RP42
(7p15.3)
1-2% 1 Retinitis pigmentosa 42 (612943);
Cold-induced sweating syndrome 3 (617055)
NR2E3
(604485)
RP37
(15q23)
1-2% 1 Retinitis pigmentosa 37 (611131);
Enhanced S-cone syndrome (268100);
Cone-rod dystrophy, Goldman-Favre syndrome, Helicoid subretinal fibrosis (unknown)
NRL
(162080)
RP27
(14q11-q12)
Rare 1 Retinitis pigmentosa 27 (613750);
Leber congenital amaurosis; Clumped pigmentary retinal degeneration; Enhanced S cone syndrome; Cone dysfunction syndrome (unknown)
PRPF3
(607301)
RP18
(1q21.2)
1% 1, 4
p.T494M in 1% adRP in Japan 18
Retinitis pigmentosa 18 (601414)
PRPF31
(606419)
RP11
(19q13.42)
8% of adRP 1 Retinitis pigmentosa 11 (600138)
PRPF6
(613979)
RP60
(20q13.33)
Rare 1, 4 Retinitis pigmentosa 60 (613983)
PRPF8
(607300)
RP13
(17p13.3)
2-3% 1 Retinitis pigmentosa 13 (600059)
PRPH2
(179605)
RP7 digenic
(6p21.1)
5-10% 1 Retinitis pigmentosa 7 and digenic (608133);
Retinitis punctata albescens (136880);
Macular dystrophy, vitelliform, 3 (608161);
Macular dystrophy, patterned, 1 (169150);
Leber congenital amaurosis 18 (608133);
Choriodal dystrophy, central areolar 2 (613105)
RDH12
(608830)
RP53
(14q24.1)
0,6% (Chinese) 12 Retinitis pigmentosa 53; Leber congenital amaurosis 13 (612712)
RGR
(600342)
RP44
(10q23.1)
≤1% 1 Retinitis pigmentosa 44 (613769)
RHO
(180380)
RP4
(3q22.1)
20-30% 1 Retinitis pigmentosa 4, autosomal dominant or recessive (613731);
Night blindness, congenital stationary, autosomal dominant 1 (610445);
Retinitis punctata albescens (136880)
ROM1
(180721)
RP7 digenic
(11q12.3)
Rare 1 Retinitis pigmentosa 7, digenic (608133);
Cone/cone-rod dystrophy; High myopia (unknown)
RP1
(603937)
RP1
(8q11.2-q12.1)
1% 1
3-4% for adRP 1
Retinitis pigmentosa 1 (180100);
Leber congenital amaurosis, Night blindness, Macular dystrophy, Retinal dystrophy (unknown)
RP2
(312600)
RP2
(Xp11.3)
10-20% for X-linked RP 1 Retinitis pigmentosa 2 (312600);
Cone-rod dystrophy; Pattern dystrophy; X-linked retinitis pigmentosa; Leber congenital amaurosis, Night blindness, Macular dystrophy, Retinal dystrophy (unknown)
RP9
(607331)
RP9
(7p14.3)
Rare 1 Retinitis pigmentosa 9 (180104)
RPE65
(180069)
RP20
(1p31.3)
2-5% for adRP 1
3-16% for LCA2 10
Retinitis pigmentosa 20 (613794);
Leber congenital amaurosis 2 (204100);
Cone-rod dystrophy, Fundus albipunctatus (unknown)
RPGR
(312610)
RP3
(X11.4)
70-90% of X-linked RP 1 Retinitis pigmentosa 3 (300029);
Cone-rod dystrophy, X-linked, 1 (304020);
Macular degeneration, X-linked atrophic (300834);
Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness, Leber congenital amaurosis (unknown)
SEMA4A
(607292)
RP35
(1q22)
3%-4% in Pakistan 1 Retinitis pigmentosa 35 (610282);
Cone-rod dystrophy 10 (610283);
Leber congenital amaurosis (unknown)
SNRNP200
(601664)
RP33
(2q11.2)
1-2% 1 Retinitis pigmentosa 33 (610359)
TOPORS
(609507)
RP31
(9p21.1)
1% 1 Retinitis pigmentosa 31 (609923);
Leber congenital amaurosis; Retinal dystrophy (unknown)

Differential diagnosis

The differential diagnosis of retinitis pigmentosa-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • Usher syndrome (types 1, 2, and 3)
  • Gyrate atrophy of the choroid and retina
  • Leber congenital amaurosis (LCA)
  • Cone or cone-rod dystrophy
  • Congenital disorders of glycosylation (CDG) type 1a
  • Best Disease
  • Central Serous Chorioretinopathy
  • Chronic Progressive External Ophthalmoplegia
  • Nonexudative (Dry) Age-Related Macular Degeneration (AMD)

Testing strategy

To confirm/establish the diagnosis, we offer retinitis pigmentosa panel sequencing and deletion/duplication gene testing. We also offer a broad selection of NGS panels that are designed for the molecular diagnostics of related conditions/phenotypes.

Thus, CENTOGENE offers the following testing strategy for retinitis pigmentosa gene testing

Step 1: Depending on the inheruitance mode:
Retinitis pigmentosa panel, autosomal recessive full gene sequencing – covers the entire coding region, exon/intron boundaries and 200 bp of the gene promoter for all the genes included in the panel.
Retinitis pigmentosa panel, autosomal dominant full gene sequencing – covers the entire coding region, exon/intron boundaries and 200 bp of the gene promoter for all the genes included in panel

Step 2: Deletion/duplication analysis/mutational scanning of selected retinitis pigmentosa panel genes.

Step 3: If no mutation is identified after analysis with the retinitis pigmentosa panel we can offer further whole genome sequencing, based on NGS technology.


Referral reasons

The following individuals are candidates for retinitis pigmentosa testing:

  • - Individuals with a family history of retinitis pigmentosa and presentation of the most common symptoms, including night blindness and loss of visual acuity
  • Individuals without a positive family history, but with symptoms resembling retinitis pigmentosa
  • Individuals with a negative but suspected family history of retinitis pigmentosa, in order to perform proper genetic counseling.

Test utility

Sequencing, deletion/duplication of the panel genes should be performed in all individuals suspected of having retinitis pigmentosa and suspected phenotypes. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the retinitis pigmentosa and related disorders identify at-risk family members, provide disease risks as well as appropriate referral for patient support and/or resources.


More information on CENTOGENE´s Retinitis pigmentosa panel, autosomal dominant and autosomal recessive can be found in our genetic test catalogue.