You idea for a plague is a good one.

It is logical & explains a lot. I vote for a plague death for Giselle rather than a murder.

A murder would lead to an investigation, which may expose Beryl.
A plague would serve to explain why the Heir has no living grandparents (he doesn't find out he's the heir until after he's accused of murdering his grandfather, the King). And Queen Beryl is one of the Bad Guys... there's this ultra-creepy bit of dialogue she says in the torture chamber when the heir is tied to the rack, and I remember thinking that it's CREEPY to say stuff like that to your own grandson (by that time she knew who the real heir was, although he didn't; he doesn't find out until after he's rescued).
So when I had a second look at the portraits puzzle and noticed that the King had
two wives, one living, one dead, I reasoned that the deceased Queen (Giselle) must have been the mother to the dead Prince Thomas, who in turn was father to the heir (he never knew he'd fathered a son, since he was killed on the battlefield several months before his son was born). And in turn, Queen Beryl has this creepy, slimy way of speaking to her step-grandson who has no idea that there's any kind of familial relationship going on.
(I'm not making that characterization up, btw; it's in the game... the only thing I made up about Queen Beryl is her name and part of her backstory).
I guess at this time it might help to show wtf I'm talking about:
This is the royal lineage/portraits puzzle, and the goal is to slide the portraits into the correct place to show the previous few generations' lineage that leads to the Heir being revealed (this puzzle is hidden in a secret panel in the Duke of Ulmer's study).
Note the small portraits beside the empty frames on the left side of the puzzle. Those are the monarchs' spouses. I found the first one fascinating, because the official monarch was a queen and the small portrait shows her consort. I decided to use this fact as an way to explain why the opening dialogue talks about "the last Great King of Griffinvale" and I wondered why he was the last. Were all his heirs inept? Was the kingdom exterminated? Or more likely, maybe his heirs were female.
This portrait puzzle makes it clear that Queen Regnants are possible and acceptable in Griffinvale, so I decided that this long-ago Queen (I guesstimate she must have lived maybe a couple of centuries before the game events) was Queen Gabriella, who was a very smart woman and did an excellent job of ruling before her son took over (I never decided on any names for her consort or son). And this makes it easy to decide that the new King (the "Heir" in the title of the game) will have a daughter as his eldest child, and will make her his heir.
I'm having conflicting thoughts about that, however. Every time I try to think of Princess Angela Rose Harding as an upcoming capable ruler, she does a left turn at Albuquerque in my mind and comes out with some bit of nasty, self-entitled dialogue and her father wonders wtf he did wrong in raising her. I might have to un-kill her brother (died due to miscarriage) to make the story work in later in-universe decades.
Anyway... have a look at the five portraits on the right. The one at the top centre is Queen Gabriella. Her heir is the man to her right, and
his heir is the man in the bottom left corner. Note that both men have only one consort's portrait beside them. Note also the skulls, denoting people who are dead.
Now we come to the fun stuff to do with Queen Beryl. The King who is murdered is the portrait in the lower right corner (I gave him the name of Osmund). Match King Osmund's portrait to the space for him in the puzzle (you can tell by the unique shape of each frame, for which portrait belongs where)... and you see
two consorts' portraits. The one on top is a younger woman, who I gave the name Giselle, and you can see the skull that indicates she is dead. The one on the bottom is an older woman, who I gave the name Beryl, and she is the Queen in the game (not gonna spoil it as to what happens to her!) who instigates her own husband's murder.
Prince Thomas (the son of King Osmund and Queen Giselle, and father of the Heir) is the young, dark-haired man in the centre, and when you match him to his proper place in the puzzle, you see that he has a consort, Princess Rose, who is dead (she died in childbirth, when the Heir was born).
The final portrait has yet to be revealed in this screenshot, but will be very soon as the puzzle is completed in the game. Sir Edmund has a surprise coming when he figures this out.
None of the intricacies of the familial relations shown in this puzzle are actually discussed by any of the characters in the game. Nobody tells the Heir that the Queen is his step-grandmother, or even speculates why the Queen would decide to murder the King. This is something I've remedied in my story, because it's pretty damned important for the characters to figure out all this stuff so they know who the guilty parties are and have an idea as to why all of this was set in motion.
For that matter, there isn't even one syllable of dialogue in the game where anyone tells the Heir, "Oh btw, you know how you thought you were _______ all your life? Turns out you're not; you're really the late King's grandson, and since your father the Crown Prince died before you were born, that means you're really the King now."
It's one of those things that the player is meant to assume happened off-stage, which annoyed me, so I've written a few variants of possible scenes where this life-changing information is explained to him. And he does not take it lightly in any of them. When you've been part of a loving family and trained to know your place and temper your aspirations accordingly for 30+ years and you suddenly find out a huge part of it has been an elaborate lie (one perpetrated for your own safety, but nevertheless a lie), you're going to have mixed feelings about it
at best.
I gave King Osmund a daughter as well, btw. She's not mentioned anywhere in the portrait puzzle because it only shows monarchs, their consorts, and their direct heirs. Princess Alicia (daughter of Osmund and Giselle, and sister of Thomas) was married off to the Crown Prince of Stormhaven (another kingdom I made up), and by the time of the game events, they have succeeded to the rulership of that kingdom. Queen Alicia has five children (3 boys, 2 girls), and I decided that the Heir having cousins who are also grandchildren of King Osmund would give him an incentive to do right by the kingdom so his out-of-kingdom cousins would not be able to swoop in and claim everything. Besides, it made sense that he might have previously-unknown family somewhere. I've written several different scenarios in which Queen Alicia is told that not only was her father (King Osmund) murdered, but her sons aren't going to inherit because surprise! there's a grandson with a direct claim that supersedes any others.
I rather like Queen Alicia. She's one of the more interesting characters I made up for this story, because she has to balance her loyalties to her husband and children in Stormhaven with her old loyalties to her father (she's devastated by King Osmund's murder), and her newfound liking and respect for the nephew she never knew she had, who is the new King.
I don't like her husband, King Charles, much. Of course he's got a legitimate concern that his oldest son is the heir to Stormhaven, but for the past three decades, he's expected that his second son would inherit Griffinvale, as the next-eldest male grandson of King Osmund (his father-in-law). So Charles isn't happy to find out he has a nephew-in-law with a better claim. He immediately starts hatching a plan to offer his youngest daughter to her newfound cousin as a wife, to consolidate the two kingdoms when they have children...
Except that's not gonna happen. Nope. No way. I have the Heir's wife picked out, and their children's names picked out. And since cousin marriages aren't a thing in Griffinvale, King Charles is going to be made rather emphatically aware of that.
Sounds like a soap opera, right? There's actually action going on as well, and I do have this AU version I'm writing that's not so compact and tied-up-with-a-ribbon as the game is. The AU version branches off when Sir Edmund (the POV character in the game) is killed, instead of rescued, and the story takes a sharp turn into much darker territory after that. The AU version is actually going to have the war that was avoided in the original game, and I'll have some hard decisions to make. Logically, all my favorite characters can't make it through, so it will be hard to decide who's going to die during this three-year in-universe timeframe (the events of the game itself happen over less than 24 hours).