Glossary

The words, in plain language

Every technical term on this site is defined here. On the other pages, words with a dotted underline and a small ? can be tapped to show a short version in place, with a link back here for the fuller one.

Å (ångström): A very small unit of length: one ten-billionth of a meter, about the size of an atom. Distances inside proteins are measured in ångströms. Atoms closer than about 4 Å are effectively touching. On this site, distances in Å describe how close a variant's position is to ROM1 or to one of the D2-loop cysteines.
amino acid: One of the 20 building blocks that proteins are made of. Peripherin-2 is a chain of 346 of them, numbered from 1 at the start to 346 at the end, which is where the position numbers in variant names come from. Each has a three-letter name (Gly for glycine, Arg for arginine) and a one-letter code (G, R). They differ in size, electric charge and whether they prefer water or oil, so swapping one for another can matter a lot or very little depending on which two and where.
antisense oligonucleotide (ASO): A short synthetic strand of genetic code designed to stick to a gene's message and switch it down or change how it is spliced. For a dominant-negative variant, the idea is to silence the faulty copy's message while leaving the healthy copy alone. For the eye it is given by injection into the eye, repeated at intervals, often months apart. The first PRPH2-specific treatment given to a person is an ASO made for one variant (G208D).
autosomal dominant: One altered copy of the gene, inherited from one parent, is enough to cause disease. Each child of a person who carries it has a 1 in 2 chance of inheriting it, and the chance is the same for every pregnancy and for sons and daughters. PRPH2 disease is dominant in about 95% of families. Because penetrance is incomplete and severity varies, a parent who carries the variant may have mild signs or none at all.
c. notation: How a variant is written at the DNA level, following an international standard (HGVS). c.623G>A means that position 623 of the gene's coding sequence changed from G to A. c.828+1G>A means one base into the intron after position 828, which affects splicing. Names like this depend on the reference sequence used; this site uses NM_000322.5, which most laboratories also use for PRPH2.
cis / trans: When someone has two variants in the same gene, cis means both are on the same copy (so the other copy is fine) and trans means one is on each copy (so there is no fully normal copy). A standard genetic test often cannot tell which, because it reads both copies together. Testing parents, or special long-read sequencing, can sort it out. It matters for understanding severity, for the chance of passing on both variants, and for some treatments that target one copy.
ClinVar: A public database run by the US National Institutes of Health where laboratories report how they classified a variant. The categories are pathogenic (disease-causing), likely pathogenic, uncertain significance, likely benign, and benign. Each record shows how many laboratories submitted and whether they agree, summarized as review stars. ClinVar is a useful snapshot of expert opinion, but your own laboratory's report, which can draw on your family's information, is what counts for you.
CNV (choroidal neovascularization): Abnormal new blood vessels growing from the layer under the retina, which can leak fluid or blood and damage central vision quickly. Warning signs are new distortion (straight lines looking wavy), a new blur or dark spot, usually in one eye. It happens in roughly one PRPH2 patient in six, and it is the one complication that a drug treats well: injections into the eye (anti-VEGF medicines) can dry up the vessels. Treatment works best when started early, so anyone with PRPH2 disease who notices these changes should call their retina specialist the same day.
cohort: A group of patients studied together. "The 241-patient cohort" means a published study that pooled 241 people with PRPH2 variants. Larger cohorts give more reliable averages, but an average describes a group, not any one person. Many statements on this site about how often something happens come from cohorts like this.
cryo-EM structure: A 3D picture of a protein made by freezing it in a thin layer of ice and imaging it with an electron microscope. Thousands of images of individual molecules are combined into one model. The 2022 structure of peripherin-2 with ROM1 (PDB 7ZW1) shows where each amino acid sits, which helps explain why some variants are more damaging than others. The 3D viewer on the Explore page is based on it.
cysteine: An amino acid whose sulfur atom can form a strong covalent link (a disulfide bond) with another cysteine. Peripherin-2 uses seven of them in the D2 loop as staples, six to hold its own shape and one to link to a neighboring molecule. Variants that remove a cysteine, or add a new one, can break these staples or create wrong ones. That is why cysteine changes in the D2 loop draw particular attention.
D2 loop: The large part of peripherin-2 that sits inside the disc, residues 124 to 264. About seven in ten disease-causing variants are here, because this is the part that links peripherin-2 molecules to each other and to ROM1. It contains seven cysteines that act as staples, holding the loop in shape and joining molecules together. A missense change here can spoil that assembly, which is why D2-loop variants are often studied separately.
dominant-negative: When the faulty protein does not just fail to work but actively interferes with the normal protein made by the other copy of the gene. In PRPH2 this can happen when a faulty molecule joins a group of healthy ones and spoils it. Function can then fall well below the half you would get from simply losing one copy. This is the main reason some PRPH2 missense variants cause more serious disease than variants that switch off one copy completely.
ERG (electroretinogram): A test that measures the retina's electrical response to flashes of light. A small electrode rests on or near the eye, often after some time in the dark. Different flash settings separate rod responses from cone responses, so the test shows whether rods, cones or both are underperforming, sometimes before changes are visible on a scan. Some versions (multifocal ERG) look specifically at the macula.
exon: One of the pieces of a gene that actually codes for protein. Genes are split into exons separated by introns, stretches that are cut out of the message before the protein is made. PRPH2 has three exons. The D2 loop, where most disease-causing variants sit, is coded by the end of exon 1 and most of exon 2.
FAF (fundus autofluorescence): A photograph of the back of the eye taken with blue light that makes lipofuscin, a waste pigment in the RPE, glow. Areas that are brighter than normal suggest stressed, overloaded cells; dark areas suggest the RPE has been lost there. The pattern of bright and dark is one of the main ways PRPH2 conditions such as butterfly-shaped pattern dystrophy are recognized. It is quick, painless and done with the same kind of camera as an ordinary retinal photograph.
gene: A stretch of DNA that carries the instructions for making one protein. You have two copies of almost every gene, one from each parent. PRPH2 is a gene on chromosome 6; peripherin-2 is the protein it makes. Genes are usually written in italic capitals (PRPH2) and their proteins in plain text (peripherin-2), which is a handy way to tell which one a sentence is about.
gene augmentation: Another name for gene therapy that adds a working copy of the gene. "Augmentation" stresses that the faulty copy is left in place and a healthy copy is added alongside it. This suits variants where the problem is simply too little protein. Where the faulty protein actively causes harm, augmentation alone may not be enough, which is why it is sometimes paired with silencing the faulty copy.
gene therapy: Delivering a working copy of a gene into cells, usually packaged in a harmless virus (AAV) injected under the retina. It helps when the problem is too little protein, as in haploinsufficiency. It does not remove a harmful protein, so for dominant-negative variants it may need to be combined with an approach that silences the faulty copy. Gene therapy is already approved for RPE65-related retinal disease; none exists yet for PRPH2.
gene-agnostic: A treatment that works regardless of which gene is faulty, because it targets the retina's response to damage rather than the specific cause. Examples include approaches that help photoreceptors survive longer or that protect the RPE. Because they do not depend on a particular variant, they could help many conditions at once. The trade-off is that they slow damage rather than fixing the underlying problem.
gnomAD: A database of DNA from about 800,000 people, most without a known retinal disease. If a variant is common there, it is unlikely to cause a rare dominant disease like PRPH2 disease. If it is absent or very rare, that is consistent with being harmful but does not prove it, because most rare variants of every kind are harmless. gnomAD records DNA, not eye examinations, so a few people in it may have mild disease no one has found.
haploinsufficiency: When one copy of the gene makes nothing and half the normal amount of protein is not quite enough. This is generally milder than a dominant-negative effect, because all the protein that is made is normal. Many truncating PRPH2 variants work this way. It is also why adding extra healthy protein, for example by gene therapy, is a reasonable idea for this kind of variant.
heterozygous: Having one altered copy and one usual copy of the gene. This is the normal situation in PRPH2 disease, and it is what most genetic reports will say. Having two altered copies (the same variant twice, or two different variants on different copies) is rare in PRPH2. The few reported families have often had earlier and more severe disease, but there are too few cases to say what applies to any one person.
in-silico prediction: A computer model's estimate of whether a variant damages the protein, made without any laboratory experiment. Different models look at different things, such as how unchanged the position is across species, the protein's 3D structure, or patterns learned from millions of protein sequences. They are useful hints and laboratories use them as one small piece of evidence. They are never a diagnosis, and different models can disagree about the same variant.
macula: The small central area of the retina responsible for reading, recognizing faces and seeing fine detail. It is only a few millimeters across but does most of the work of everyday sight. Most PRPH2 disease affects the macula first. Side (peripheral) vision is often kept for much longer, which helps with getting around.
microperimetry: A test that maps how sensitive each small spot of the central retina is. You look at a target while small lights flash at different points, and press a button when you see one; the machine tracks your eye so each light lands on the intended spot. The result is a map of where the macula is working well and where it is weaker. It is increasingly used in research studies because it can show small changes over time.
missense: A variant that swaps one amino acid for another, so the protein is still made in full but with one wrong building block. It is written like p.Gly208Asp or G208D: glycine at position 208 replaced by aspartate. Most disease-causing PRPH2 variants are missense changes. Whether one matters depends on where it sits and how different the new amino acid is, which is why some missense changes are harmful and others are not.
modifier gene: A second gene whose variants change how severe a disease is, without causing it on their own. For PRPH2 the best-known modifiers are ROM1, peripherin-2's partner protein, and ABCA4, a gene that helps clear a by-product of light sensing out of the discs. Modifiers are one likely reason people with the same PRPH2 variant can be affected so differently. Most are still being studied, so they are rarely tested for routinely.
natural history study: A study that follows people with a disease over time without treating them, to measure how it changes. It answers questions like how fast vision changes and which tests pick up change soonest. Treatment trials need this information to choose what to measure and to show that a treatment made a difference. Taking part usually means regular eye examinations and imaging at a research center.
OCT (optical coherence tomography): A painless scan that takes cross-section pictures of the retina's layers, a bit like an ultrasound that uses light instead of sound. It takes a few seconds per eye and does not touch the eye. It shows the photoreceptor layer, the RPE and any fluid or scarring in fine detail. It is the main tool for tracking structural change over time and for spotting CNV.
outer segment: The part of a photoreceptor that catches light: a stack of hundreds of flattened membrane discs, like a stack of coins. Peripherin-2 lines the curved rim of each disc and holds that curve in shape. New discs are added at the base every day while old ones are shed from the tip. When peripherin-2 is missing or faulty, the discs form poorly and the outer segment becomes short and disorganized.
p. notation: How a variant is written at the protein level: p.Gly208Asp means the amino acid glycine at position 208 became aspartate. It is often shortened to G208D using one-letter codes. Other forms you may see: p.Arg172* or R172X means a premature stop, and fs means a frameshift. A report may give the same variant in both c. and p. notation, and this site accepts either.
penetrance: How often people who carry a variant actually develop the disease. If penetrance is incomplete, some carriers never show symptoms. In the largest PRPH2 study, about 6% of carriers had no signs of disease when examined. Penetrance can also look lower than it is if mild changes are only visible on detailed imaging, which is one reason relatives are sometimes examined even if their sight seems fine.
photoreceptor: A light-sensing cell in the retina. Rods work in dim light and cover most of the retina outside the center; cones give sharp daytime and color vision and are packed into the macula. Both depend on peripherin-2 to build their light-catching discs. Which type is affected more, and in which part of the retina, is a large part of what separates the different PRPH2 conditions.
Phred-scaled score: A logarithmic scale where 10 means top 10%, 20 means top 1%, 30 means top 0.1% and 40 means top 0.01%. Each step of 10 means ten times rarer. AlphaGenome uses it to rank how strongly a variant is predicted to change the gene's activity or splicing, compared with every possible change in the genome. A high score means a large predicted effect, not that the variant is proven to cause disease.
pLDDT: AlphaFold's confidence, from 0 to 100, that it placed a given amino acid correctly in its predicted structure. Above 90 is very confident, 70 to 90 is generally good, and below 50 usually means a floppy region that may not have one fixed shape. Low confidence is not a sign of a problem with the protein; some parts are naturally flexible. On this site it helps judge how much weight to give structural details at a position.
prime editing: A precise form of gene editing that rewrites a single variant back to the usual sequence inside the cell, without cutting both strands of DNA. In principle it fixes the cause permanently in the cells it reaches. It has been tested in cells and animals for some retinal genes, but not yet in people for PRPH2. Getting the editing tools into enough photoreceptors safely is the main hurdle.
protein: A molecule built from a chain of amino acids, folded into a precise shape that lets it do a job in the cell. Some proteins are enzymes that speed up chemistry; others, like peripherin-2, are structural and hold things in shape. Peripherin-2's job is to bend and hold the rim of each light-catching disc in a photoreceptor. Because the shape is what does the work, a single wrong building block in the wrong place can be enough to cause problems.
registry: A database of people with a disease who have agreed to be contacted about research and trials. For a rare condition like PRPH2 disease, researchers often struggle to find enough participants, and a registry is how they find you. Joining is usually free, done online, and does not commit you to anything. In the US, the main one for inherited retinal diseases is FFB's My Retina Tracker.
retinal pigment epithelium (RPE): The support layer of cells under the photoreceptors. Every day it takes in and digests the worn-out tips of the disc stacks, and it also recycles the chemicals photoreceptors need to sense light. Its leftover waste, lipofuscin, is what lights up on autofluorescence imaging. In PRPH2 disease the RPE can become overloaded or thinned, which shows up as the bright and dark patterns doctors look for.
rsID: A catalog number (like rs61755792) for a specific DNA change in the public dbSNP database. It is useful for searching, because papers and databases use different notations but often share the rsID. An rsID only means a variant has been recorded somewhere; it says nothing about whether it is harmful. Very rare variants may not have one yet.
splice variant: A change at or near the boundary of an exon that disturbs how the gene's message is cut and joined. Before a gene's message is used to build protein, the non-coding pieces (introns) are cut out and the exons stitched together. If the cut happens in the wrong place, the message can lose a piece or gain one. This often behaves like a loss-of-function variant, but not always; the PRPH2 c.828 splice variants, for example, have their own pattern.
tetramer / oligomer: A group of protein molecules locked together: four is a tetramer, eight an octamer, and longer chains are called oligomers. Peripherin-2 only works in these groups, usually alongside its partner protein ROM1. The groups line up along the rim of each disc to hold its curve. Because each group includes several molecules, one faulty molecule can spoil a group that also contains good ones.
truncating (loss-of-function): A variant that stops the protein being made properly, either by putting a premature stop signal in (nonsense) or by shifting the reading frame so the rest of the message is garbled (frameshift). The cell usually notices the faulty message and destroys it, so that copy of the gene makes little or nothing. The other, healthy copy still makes normal protein, about half the usual amount. In PRPH2, truncating variants more often lead to pattern dystrophy than to the more serious cone-involving forms, though there are exceptions.
variable expressivity: The same variant causing different severity in different people, even in the same family. One relative may have small pattern changes found by chance, while another has noticeable central vision loss. In PRPH2 this is common and well documented. Possible reasons include other genes (modifiers such as ROM1), the environment, and chance, but for most families the exact reason is not known.
variant: A change in the DNA sequence compared with the usual version. "Mutation" means the same thing; "variant" is the neutral word laboratories use because not every change causes disease. Everyone carries thousands of variants, and nearly all of them are harmless. A genetic report lists the variants that might explain a condition, together with the laboratory's view on how likely each one is to be the cause.
variant of uncertain significance (VUS): A variant that has been seen but for which there is not yet enough evidence to say whether it causes disease. It is not a verdict either way, and it should not be treated as a diagnosis on its own. Many VUS are later reclassified as more evidence arrives, most often to benign. Testing affected and unaffected relatives is one of the most useful ways to move a VUS one way or the other.