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PubMed This is a summary of 16 peer-reviewed journal articles Updated
Ophthalmology

The Blueprint of Vision: Biology and Genetics

At a Glance

Central Areolar Choroidal Dystrophy (CACD) is primarily caused by mutations in the PRPH2 gene, leading to the breakdown of the retina's supporting layers. It is most commonly inherited in an autosomal dominant pattern, though symptom severity can vary widely among family members.

At its core, Central Areolar Choroidal Dystrophy (CACD) is a “blueprint” error. Your DNA provides the instructions for building and maintaining your eyes, but in CACD, a small change in one of these instructions causes the supporting layers of your retina to wear out prematurely [1][2].

The Role of the PRPH2 Gene

The most common cause of CACD is a mutation in the PRPH2 gene (formerly known as RDS) [2][3]. Think of this gene as the architect for the light-sensing cells in your eyes (the photoreceptors).

  • Disc Morphogenesis: Photoreceptors have tiny “discs” that capture light. The PRPH2 protein is responsible for shaping the edges of these discs [4][5].
  • The Breakdown: When the PRPH2 gene is mutated, these discs cannot form or be maintained correctly [4][6]. This puts immense stress on the Retinal Pigment Epithelium (RPE)—the layer that feeds and cleans the photoreceptors [7]. Eventually, the RPE and the blood vessels behind it (the choriocapillaris) begin to waste away, or atrophy [8][7].

While PRPH2 is the most common culprit, other genes like GUCA1A and CDHR1 can also cause CACD by disrupting different parts of this delicate support system [9][10].

How CACD is Inherited

Genetic conditions are passed down in different ways. Understanding your pattern can help you understand the risk to your family members.

Autosomal Dominant (The Most Common Form)

Most cases of CACD, especially those linked to PRPH2 and GUCA1A, are autosomal dominant [9][3].

  • “Dominant” means you only need one copy of the mutated gene (from one parent) to develop the condition.
  • Each child of an affected parent has a 50% chance of inheriting the mutation.
  • This pattern often shows up in every generation of a family.

Autosomal Recessive (The Rarer Form)

Some cases, particularly those linked to the CDHR1 gene, are autosomal recessive [10][11].

  • “Recessive” means you must inherit two copies of the mutated gene—one from each parent—to have the condition.
  • The parents are typically “carriers” who do not have any vision symptoms themselves.

Why Families Can Look Different

One of the most confusing things about CACD is that the exact same mutation can look different in two people, even siblings. This is due to two concepts:

  1. Variable Expressivity: This means the severity of the symptoms varies. One family member might have significant vision loss in their 40s, while another has only mild changes in their 60s [12][13].
  2. Pleiotropy: This is when one gene mutation causes different types of eye diseases. In the same family, one person might be diagnosed with CACD, while another is told they have “Pattern Dystrophy” or “Retinitis Pigmentosa” [3][14].

Scientists believe these differences happen because of “genetic modifiers”—other small variations in your DNA (like the ROM1 gene) that act like a volume knob, turning the effects of the primary mutation up or down [15][6].

The Importance of Genetic Counseling

Because the genetics of CACD are complex and variable, a genetic counselor can be an invaluable part of your care team. They can help you interpret your testing results, explain the specific risks to your children or siblings, and keep you informed about research that may be specific to your exact genetic mutation [16][12]. Obtaining a clear genetic diagnosis is the first step toward potential future therapies that target the root cause of the condition.

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Common questions in this guide

What gene causes Central Areolar Choroidal Dystrophy (CACD)?
The most common cause of CACD is a mutation in the PRPH2 gene. This gene provides instructions for shaping the light-sensing cells in your eyes. Other genes, including GUCA1A and CDHR1, can also disrupt this delicate system and cause the condition.
How is CACD inherited?
Most cases of CACD are autosomal dominant, meaning you only need to inherit one copy of the mutated gene from one parent to develop the condition. In rarer cases, it can be autosomal recessive, which requires inheriting two copies of the mutated gene.
Why do my siblings and I have different symptoms if we have the same CACD gene mutation?
This happens because of genetic modifiers, which are other small variations in your DNA that can alter the effects of the primary mutation. This can lead to variable expressivity, where symptom severity differs, or pleiotropy, where the same mutation causes different types of eye diseases.
What does a positive PRPH2 genetic test mean for my family?
Because PRPH2 mutations are typically autosomal dominant, each child of an affected parent has a 50 percent chance of inheriting the mutated gene. A genetic counselor can help you interpret your specific test results and understand what they mean for your children and siblings.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Based on my genetic report, which specific gene (e.g., PRPH2, CDHR1, or GUCA1A) is causing my CACD?
  2. 2.Does my mutation follow an autosomal dominant or autosomal recessive inheritance pattern, and what does that mean for my children?
  3. 3.Since PRPH2 can cause different symptoms in the same family, should my siblings be screened even if they don't have symptoms yet?
  4. 4.Are there any 'genetic modifiers' noted in my results, such as variants in the ROM1 gene, that might affect how my disease progresses?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (16)
  1. 1

    Phenotypic Differences in a PRPH2 Mutation in Members of the Same Family Assessed with OCT and OCTA.

    Albertos-Arranz H, Sánchez-Sáez X, Martínez-Gil N, et al.

    Diagnostics (Basel, Switzerland) 2021; (11(5)) doi:10.3390/diagnostics11050777.

    PMID: 33925984
  2. 2

    Prph2 knock-in mice recapitulate human central areolar choroidal dystrophy retinal degeneration and exhibit aberrant synaptic remodeling and microglial activation.

    Ruiz-Pastor MJ, Sánchez-Sáez X, Kutsyr O, et al.

    Cell death & disease 2023; (14(11)):711 doi:10.1038/s41419-023-06243-8.

    PMID: 37914688
  3. 3

    PRPH2-Related Retinal Diseases: Broadening the Clinical Spectrum and Describing a New Mutation.

    Coco-Martin RM, Sanchez-Tocino HT, Desco C, et al.

    Genes 2020; (11(7)) doi:10.3390/genes11070773.

    PMID: 32660024
  4. 4

    An inducible amphipathic helix within the intrinsically disordered C terminus can participate in membrane curvature generation by peripherin-2/rds.

    Milstein ML, Kimler VA, Ghatak C, et al.

    The Journal of biological chemistry 2017; (292(19)):7850-7865 doi:10.1074/jbc.M116.768143.

    PMID: 28325841
  5. 5

    Retinal dystrophies and variants in PRPH2.

    Palma MMD, Martin D, Salles MV, et al.

    Arquivos brasileiros de oftalmologia 2019; (82(2)):158-160 doi:10.5935/0004-2749.20190033.

    PMID: 30726412
  6. 6

    The Role of Peripherin-2/ROM1 Complexes in Photoreceptor Outer Segment Disc Morphogenesis.

    Lewis TR, Al-Ubaidi MR, Naash MI, Arshavsky VY

    Advances in experimental medicine and biology 2023; (1415()):277-281 doi:10.1007/978-3-031-27681-1_40.

    PMID: 37440045
  7. 7

    New Insights on the Regulatory Gene Network Disturbed in Central Areolar Choroidal Dystrophy-Beyond Classical Gene Candidates.

    Kazmierczak de Camargo JP, Prezia GNB, Shiokawa N, et al.

    Frontiers in genetics 2022; (13()):886461 doi:10.3389/fgene.2022.886461.

    PMID: 35656327
  8. 8

    MULTIMODAL RETINAL IMAGING REVEALS NEW PATHOGENIC INSIGHTS IN CENTRAL AREOLAR CHOROIDAL DYSTROPHY: A CASE SERIES.

    Romano F, Cozzi E, Boon CJF, et al.

    Retinal cases & brief reports 2024; (18(1)):32-38 doi:10.1097/ICB.0000000000001325.

    PMID: 36731070
  9. 9

    GUCA1A mutation causes maculopathy in a five-generation family with a wide spectrum of severity.

    Chen X, Sheng X, Zhuang W, et al.

    Genetics in medicine : official journal of the American College of Medical Genetics 2017; (19(8)):945-954 doi:10.1038/gim.2016.217.

    PMID: 28125083
  10. 10

    A Specific Macula-Predominant Retinal Phenotype Is Associated With the CDHR1 Variant c.783G>A, a Silent Mutation Leading to In-Frame Exon Skipping.

    Charbel Issa P, Gliem M, Yusuf IH, et al.

    Investigative ophthalmology & visual science 2019; (60(10)):3388-3397 doi:10.1167/iovs.18-26415.

    PMID: 31387115
  11. 11

    CDHR1-Related Cone-Rod Dystrophy: Clinical Characteristics, Imaging Findings, and Genetic Test Results-A Case Report.

    Sobolewska M, Świerczyńska M, Dorecka M, et al.

    Medicina (Kaunas, Lithuania) 2023; (59(2)) doi:10.3390/medicina59020399.

    PMID: 36837600
  12. 12

    Clinical and Imaging Characteristics of PRPH2 Retinopathies in a Longitudinal Cohort and Diagnostic Implications.

    Seddon JM, De D, Grunenkovaite L, Ferrara D

    Investigative ophthalmology & visual science 2024; (65(14)):31 doi:10.1167/iovs.65.14.31.

    PMID: 39693084
  13. 13

    LONG-TERM FOLLOW-UP OF PRPH2 -ASSOCIATED RETINAL DYSTROPHY.

    Zhao Z, Miere A, Le HM, Souied EH

    Retinal cases & brief reports 2024; (18(2)):236-241 doi:10.1097/ICB.0000000000001351.

    PMID: 36053859
  14. 14

    Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, in PRPH2 and Protein Haplotypes in trans as Modifiers.

    Shankar SP, Hughbanks-Wheaton DK, Birch DG, et al.

    Investigative ophthalmology & visual science 2016; (57(2)):349-59 doi:10.1167/iovs.15-16965.

    PMID: 26842753
  15. 15

    ROM1 contributes to phenotypic heterogeneity in PRPH2-associated retinal disease.

    Strayve D, Makia MS, Kakakhel M, et al.

    Human molecular genetics 2020; (29(16)):2708-2722 doi:10.1093/hmg/ddaa160.

    PMID: 32716032
  16. 16

    Genetic screening for macular dystrophies in patients clinically diagnosed with dry age-related macular degeneration.

    Kersten E, Geerlings MJ, Pauper M, et al.

    Clinical genetics 2018; (94(6)):569-574 doi:10.1111/cge.13447.

    PMID: 30215852

This page provides educational information about the genetics of Central Areolar Choroidal Dystrophy. Always consult a genetic counselor or ophthalmologist for advice regarding your specific genetic test results and family risks.

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