Recognize, test, refer.
A practical reference for optometrists, ophthalmologists, pediatricians, genetic counselors and primary care teams who see patients with possible inherited retinal disease.
When to suspect an IRD.
Symptoms
Nyctalopia, progressive peripheral field loss, photophobia, poor color discrimination, or unexplained reduced acuity, especially when bilateral and symmetric.
Findings
Bone-spicule pigment, arteriolar attenuation, flecks, bull's-eye maculopathy, vitelliform lesions, foveal schisis, or chorioretinal atrophy.
Context
Infantile nystagmus or poor visual behavior, a positive family history, consanguinity, or systemic features such as hearing loss, obesity, polydactyly or renal disease.
Suggested workup.
- Multimodal imaging: SD-OCT (ellipsoid zone integrity, schisis, CME), fundus autofluorescence (hyperautofluorescent rings, flecks, atrophy), and widefield color imaging.
- Electrophysiology: full-field ERG to the ISCEV standard to separate rod, cone and inner-retinal patterns. Use multifocal or pattern ERG for macular disease. An EOG helps when Best disease is suspected.
- Function: kinetic or static perimetry and color vision testing. Use dark adaptometry when relevant.
- Family history: a three-generation pedigree, and examination of relatives when it would help with phasing or diagnosis.
Genetic testing.
- A multigene IRD panel is a reasonable first-line test for most patients. It finds the cause in more than half of cases.
- Consider exome or genome sequencing when a panel is negative, when systemic features suggest a syndrome, or when copy-number and deep-intronic variants are suspected.
- Segregation testing of parents or relatives confirms that two recessive variants are on opposite chromosomes (in trans) and helps clarify variants of uncertain significance.
- Interpret variants using ACMG/AMP criteria. Arrange reanalysis of unsolved cases over time.
- Pre- and post-test genetic counseling is recommended. Tell patients about GINA protections and their limits.
Quick reference.
Typical features of common IRDs. Presentations vary widely, even within one family.
| Condition | Main genes | Inheritance | Key findings | Typical full-field ERG |
|---|---|---|---|---|
| Retinitis pigmentosa | RHO, USH2A, RPGR, PRPF31, EYS | AD, AR, XL | Bone-spicule pigment, attenuated vessels, waxy disc pallor, hyperautofluorescent ring, CME | Rod > cone loss, may be undetectable |
| Stargardt disease | ABCA4 | AR | Yellow-white flecks, macular atrophy, peripapillary sparing, dark choroid on FA | Often normal early; generalized cone or rod involvement in some |
| Best disease | BEST1 | AD (ARB: AR) | Vitelliform lesion evolving to pseudohypopyon, vitelliruptive and atrophic stages | Normal; reduced EOG light rise |
| Leber congenital amaurosis | CEP290, GUCY2D, CRB1, RPE65 | Mostly AR | Infantile nystagmus, poor fixation, oculodigital sign, variable fundus | Severely reduced or undetectable |
| Usher syndrome | MYO7A (type 1), USH2A (type 2), CLRN1 (type 3) | AR | RP with sensorineural hearing loss, with or without vestibular dysfunction | As for RP |
| Choroideremia | CHM | XL | Scalloped chorioretinal atrophy from the periphery inward; macula spared until late | Rod > cone loss |
| X-linked retinoschisis | RS1 | XL | Spoke-wheel foveal schisis, peripheral schisis, vitreous veils | Electronegative (reduced b:a ratio) |
| Cone-rod dystrophy | ABCA4, GUCY2D, CRX, PRPH2 | AD, AR, XL | Bull's-eye maculopathy, photophobia, dyschromatopsia | Cone > rod loss |
| Achromatopsia | CNGA3, CNGB3 | AR | Congenital nystagmus, photophobia, foveal ellipsoid-zone disruption on OCT | Absent cone, normal rod responses |
| Bietti crystalline dystrophy | CYP4V2 | AR | Glistening intraretinal crystals, progressive chorioretinal atrophy; more common in East Asian ancestry | Variable, declines with progression |
AD, autosomal dominant. AR, autosomal recessive. XL, X-linked. ARB, autosomal recessive bestrophinopathy. FA, fluorescein angiography. CME, cystoid macular edema.
Treatment and trials.
- Voretigene neparvovec-rzyl (Luxturna) was FDA-approved in December 2017 for patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy who have enough viable retinal cells. Check the FDA for current approvals.
- Trials are testing gene augmentation, gene editing, antisense oligonucleotides, optogenetics, cell therapy and neuroprotection. Use the trials tracker to search by gene or condition, and share a filtered link with patients.
- Natural history studies and registries need participants too, and many enroll patients with any genotype.
When to refer.
Refer to an inherited retinal disease specialist or ocular genetics clinic when a diagnosis is suspected but unconfirmed, when genetic results are uncertain, or when a patient is interested in treatment trials. Refer to low vision rehabilitation early, rather than waiting for severe loss.
Trusted references.
- GeneReviews for condition-specific clinical summaries
- RetNet for genes and loci causing retinal disease
- ClinGen for gene-disease validity and variant curation
- ClinicalTrials.gov for the full trial registry