Things working against a possible Ryder series sequel as of right now

I'm not a writer so I wasn;t clear.  The issue we are dealing with is there are multiple possible ends of ME3 trillogy and one world state in ME4.  If the default world state is the genophage is cured world state 1 just needs a description of how it happened and you are good, if the deafult is it isn;t cured you come up with a reaosn its been inflicted on them again.  The Salarians are on obvious coice, but heck the Quarians could be the ones who did it.  We just got snap shots, we have no real idea what the long term effects of synthesis is or how it works.  Maybe the Krogan started to invade on Quarian territory and the synthetic parts made making a technovirus possible so they effectively hack the synthetic parts and reinfect the Krogan.  Or the Salarians go old school or a combo of biological and synthetic hacking. Nothing indicates synthesis is unscrewable as far as I know.   It might create new vulverabiliies.  As to why anyone would do it, nothing says synthesis means old enmities went away, sure there was a moment of peace but a few years down the line the Krogan remember they are Krogan and start murderlating or other species are convinced they will. The heroes or villains depending on your perspective start a new genophage.

Does synthesis exist in the default setting?  Does it matter, that's flavor text.  You can easily say synthesis is not visible without medical scanners after X number of years of it being in your body.  If your wold set was no synthesis the improvements to your body is just described as routine cyberware, if you chose synthesis its described as synthesis.

For world state 2.  Extinct is a big guess, lots of krogan were probably off world, and it could still take a long time to take over a planet populated by krogan and all the crazy monsters that are native to their planet. How much and how far they went is up to who writes the next line of story, a snapshot isn't a complete story. They might eventually be doomed, but that assumes a lot like lack of assistance from other species.  And even if the planet is doomed there are enough Krogan off planet to leave it to dialogue, did we have to go to Tuchanka in ME1 to see the effect of the genophage or was it Wrex talking about it enough. Line of dialogue explaining we are cool, Tuchanka is thriving vs dude it sucks most Krogans are dead only the few who weren't on planet or quickly escaped survived. For ME4 its all the same you bump into 10 NPC krogan and kill a few here and there, they just give you different lines of dialogue based on what happened in your ME 1-3.  You just never visit Tuchanka because that would be harder to explain.

All these things are like this.  What is the default world state that the player will actually see.  If it matches your import awesome, if not spin a yarn about how it got there. I don't think we need a specific Geths memory, we might just need the geth for example.  Its a couple lines of dialogue that make the difference between the original Geth and new ones. If you wiped them out maybe their dialogue feels kind of like the Data reboot in Star Trek 10 or whatever. Not that many had any dialogue, they were pretty much just enemy race #5, with one specific Geth being their medium. If the Geth are not supposed to be there anymore, you killed them, they flew off into Andromeda, synthesis made them indistinguishable from a organic race whatever fits your import.  A couple lines of dialogue that get you from your world state to the new default state.  Lots of it you don't even need much organic explanation it could be the opening narrated scroll.

There aren't that many big decisions that have to be dealt with, most are small enough scale there is no reason why the next game has to even mention what happened to random character X.

That being said I still would rather they just go with MEA2, and i'd be fine with them just giving us a canon setting.  I just don't think a ME milky way sequel that doesn't ignore your import is impossible to deal with when you have professional writers spinning a tale.