1. NGS panel - Genetic testing for flecked retina

Flecked retina

August 28, 2017

Clinical features

Familial benign fleck retina is an autosomal recessive condition associated with a distinctive retinal appearance and no apparent visual or electrophysiologic deficits 1. Affected individuals are asymptomatic, but fundus examination reveals a striking pattern of diffuse, yellow-white, fleck-like lesions extending to the far periphery of the retina but sparing the foveal region. Flecked retina ranges from the asymptomatic and benign forms to visually damaging conditions, and it may be in a stationary or progressive form 1, 2.

Flecked-retina comprises a group of disorders with widespread or limited distribution of yellow-white retinal lesions of various sizes and configurations. The following conditions are grouped into the “flecked retina disease“ cluster 1, 2:

  • Choroideremia, caused by mutations in CHM 3, characterized by an X-linked inheritance, and degeneration of the choriocapillaris, the retinal pigment epithelium, and the photoreceptor of the eye
  • Doyne honeycomb degeneration of retina, caused by mutations in EFEMP1, characterized by small round white spots in the posterior pole of the eye, including the areas of the macula and optic disc, appearing in early adult life 4
  • Fleck retina of Kandori, caused by mutations in PLA2G5, characterized by a distinctive retinal appearance and no apparent visual or electrophysiologic deficits 5
  • Retinitis punctata albescens and fundus albipunctatus, caused by mutations in RDH5 and RLBP1, characterized vy white uniformly distributed dots over the entire fundus, night blindness and no macular involvement 6
  • Bothnia type retinal dystrophy and Newfoundland type of retinal dystrophy, both caused by mutations in RLBP1, characterized by childhood onset night blindness 7
  • Juvenile retinoschisis, caused by mutations in RS1, characterized by splitting of the neural retina leading to reduced visual acuity in affected men 8
  • Cohen syndrome, an autosomal recessive multisystem disorder caused by mutations in VPS13B, characterized by facial dysmorphism, microcephaly, truncal obesity, intellectual disability, progressive retinopathy and intermittent congenital neutropenia 9

Retinal flecks have been observed in association with many disorders, including spastic paraplegia 15, Alport syndrome, hyperoxaluria, Sjogren-Larsson syndrome, Leber congenital amaurosis, and Bardet-Biedl syndrome.

Mutations in several different genes have been associated with flecked retina disease, including the following: CHM, EFEMP1, PLA2G5, RDH5, RLBP1, RS1, VPS13B (table).


Overview of genes included in Flecked retina panel

Gene
(OMIM)
Chr. locus Protein Associated/allelic disorders (OMIM)
CHM
(300390)
Xq21.1 RAB geranylgeranyl transferase Choroideremia (303100)
EFEMP1
(601548)
2p16.1 EGF-containing fibulin-like extracellular matrix protein 1 Doyne honeycomb degeneration of retina (126600)
PLA2G5
(601192)
1p36.13 Phospholipase A2 Fleck retina, familial benign (228980)
RDH5
(601617)
12q13.2 Retinol dehydrogenase 5 Fundus albipunctatus (136880)
RLBP1
(180090)
15q26.1 Retinaldehyde-binding protein 1 Bothnia retinal dystrophy (607475); Fundus albipunctatus (136880); Newfoundland rod-cone dystrophy (607476)
RS1
(300839)
Xp22.13 Retinoschisin 1 Retinoschisis (312700)
VPS13B
(607817)
8q22.2 Vacuolar protein sorting 13 Cohen syndrome (216550)

For many forms of flecked retina there is no need for treatment, however, vision aids may be useful when macular disease is present. Recent research reports improvement of vision and rod function following administration of high-doses of beta-carotene 13.

CENTOGENE offers full gene sequencing and deletion/duplication analysis for genes in the Flecked retina panel: CHM, EFEMP1, PLA2G5, RDH5, RLBP1, RS1, VPS13B.


Differential diagnosis

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

  • Cone or cone-rod dystrophy
  • Leber congenital amaurosis (LCA)
  • Central areolar choroidal dystrophy (CACD)
  • Achromatopsia
  • Mitochondrial disorders with retinal findings
  • Gyrate atrophy of the choroid and retina.

Testing strategy

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of entire gene with more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for flecked retina panel using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Flecked retina panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the flecked retina panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.


Referral reasons

The following individuals are candidates for flecked retina testing:

  • Individuals with a family history of flecked retina and presentation of the most common symptoms
  • Individuals without a positive family history of flecked retina, but with symptoms resembling the disease
  • Individuals with a negative but suspected family history of flecked retina, in order to perform proper genetic counseling.

Test utility

Sequencing, deletion/duplication of the flecked retina panel genes should be performed in all individuals suspected of having flecked retina disease 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 flecked retina 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 Flecked retina panel can be found in our genetic test catalogue.