I would disallow skills the character could not ever have in the first place (sorcery or conjuring skills for a non-mage, resonance skills for a non-technomancer), as well as the more esoteric ones such as orbital launch weaponry.
For other skills, two things to keep in mind, as far as making it a disadvantage, are - 1) it gives you a point of Notoriety, and 2) you are treated as unaware in that skill.
I agree with farothel that excessive cheesiness can be self-defeating. If you have a moderate allergy to silver, then once in a blue moon you will run into someone wearing silver jewelry or shooting silver bullets. If you have a moderate allergy to dinosaur poop, then Aztechnology's cloned pterodactyl experiments will escape to the skies of Seattle, where the pollution, combined with a greasy diet of pigeons, devil rats and the occasional squatter, will give them bad diarrhea, and your character will continually find himself, literally, dumped on.