1. NGS Panel – Genetic Testing for Retinitis Pigmentosa

Retinitis Pigmentosa

June 22, 2017

Disease synonyms

Nonsyndromic Retinitis Pigmentosa, Autosomal recessive retinitis pigmentosa, arRP, Nonsyndromic Retinitis Pigmentosa, Autosomal dominant retinitis pigmentosa, adRP

Inheritance pattern

Autosomal recessive, autosomal dominant

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 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.

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 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 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.