ADGRA3

ADGRA3 belongs to a large family of proteins called G protein-coupled receptors, which act like antennas on the cell surface that pick up outside signals and pass them inward. The gene was previously known by the symbol GPR125, so many older papers use that name. Beyond this general role, the supplied evidence does not spell out exactly what the protein does inside the retina. Because the gene has only recently been connected to retinal disease, its precise part in keeping the retina healthy is still being worked out.

ADGRA3 has been reported in the context of retinitis pigmentosa, a group of conditions in which the retina's light-detecting cells, the rods and cones, slowly break down. In retinitis pigmentosa generally, this often shows up first as difficulty seeing in dim light and a narrowing of side (peripheral) vision. The studies in this bundle described patients through broad retinal dystrophy panels rather than following the specific vision changes caused by ADGRA3 variants over time. For that reason, the supplied evidence cannot predict a particular pattern, age of onset, or speed of progression for someone with an ADGRA3 finding.

One study used exome sequencing in a large group of families with retinal dystrophy and proposed GPR125 (now ADGRA3) as a new candidate disease gene. A separate study of Chinese families with retinitis pigmentosa, focused mainly on the PDE6A and PDE6B genes, additionally identified a novel ADGRA3 variant (c.921-1G>A) in one patient. That study was also released earlier as a preprint reporting the same families and findings. The retinitis pigmentosa described in these reports was inherited in an autosomal recessive (definition: An inheritance pattern where a person needs an altered copy of a gene from both parents to be affected. Parents with only one copy are usually unaffected carriers.) pattern, meaning two altered copies of a gene are generally involved.

The strongest single caveat is that the human evidence for ADGRA3 in retinal disease remains thin. In the retinitis pigmentosa study, the patients' disease was attributed mainly to PDE6A or PDE6B variants, and the ADGRA3 change was found as a single (heterozygous) additional variant rather than a confirmed cause. In the exome study, GPR125 was listed as a candidate gene, which is a promising lead that still needs confirmation in more families. How ADGRA3 variants damage the retina, and which vision problems they produce, are not established by the supplied evidence.

The supplied evidence does not identify any approved treatment that targets ADGRA3. Current research on this gene in retinal disease is at an early stage, centered on identifying and confirming variants rather than testing therapies. Confirming ADGRA3's role in the retina would be an important next step before any gene-specific approach could be considered.

• Exome sequencing proposes GPR125 (ADGRA3) as a candidate retinal disease gene

  Human genetic study (candidate gene discovery).

  What was found:

  The study identified likely causes in most families and reported six new candidate genes, including GPR125, now known as ADGRA3.

  Why it matters:

  This is the report that first flagged ADGRA3 as potentially involved in retinal disease, making it a lead for further study.

  Limitation: Being named a candidate gene is not the same as confirmed proof; the finding needs verification in additional families.

• A novel ADGRA3 variant found in a retinitis pigmentosa cohort focused on PDE6 genes

  Human observational genetic study (small case series).

  What was found:

  Alongside the main PDE6 findings, the researchers reported an additional novel ADGRA3 variant (c.921-1G>A) in one patient.

  Why it matters:

  It adds a further human observation linking an ADGRA3 change to a patient with retinitis pigmentosa.

  Limitation: The disease was attributed mainly to PDE6 variants, and the ADGRA3 change was a single heterozygous finding of uncertain significance.

The retinitis pigmentosa reported with ADGRA3 followed an autosomal recessive (definition: An inheritance pattern where a person needs an altered copy of a gene from both parents to be affected. Parents with only one copy are usually unaffected carriers.) pattern, which can have implications worth discussing for siblings and other blood relatives. Aside from that inheritance point, this gene does not create distinct caregiver considerations in the supplied evidence, so the general guidance shown on every gene page applies.

• Does my genetic report list ADGRA3 as the likely cause of my condition, or as an uncertain or additional finding?
• Were one or two altered copies of ADGRA3 found, and how does that fit an autosomal recessive pattern?
• Could another gene on my panel better explain my vision changes?
• Would additional testing of me or my relatives help clarify whether this variant is significant?
• What type of retinal condition and progression, if any, is expected based on my overall results?
• How often should my vision be monitored given the uncertainty about this gene?

Because the ADGRA3 evidence is still emerging, it can help to review your genetic report with a retinal specialist or genetic counselor, who can explain what the specific variant means in your situation. They can also consider whether other genes on your panel, such as those more firmly tied to retinitis pigmentosa, might better explain your findings. RP Hope's genetic testing resource explains what testing involves and what questions to bring to that conversation. RP Hope's My Pathway guide can help you find support and information matched to where you are now.