"What" can be either singular or plural. "is/are" is a linking verb, so the number of the things on either side -- the subject and the predicate nominative -- should match, and then this number should match the verb.
So, for example, we say, "What IS the name of your friend?" because "name" is singular, so "what" is being used as a singular, so the verb should be singular. But we say, "What ARE the names of your friends?" because "names" is plural, etc.
In this case we have a predicate adjective rather than a predicate nominative. I think in such cases the subject "what" is always considered singular. I'm trying to think of exceptions. So in "What is/are wrong with X, Y, and Z", we should use "is". I guess you are being thrown off by the prepositional phrase "with X, Y, and Z". But such a phrase does not affect the number of the subject. A simple rule of thumb is, when trying to determine things about the subject and verb, just ignore any "extra detail" phrases.
If that doesn't make sense to your intuition, consider this sentence, "Who is/are the policeman who arrested Smith and Jones?" Clearly it should be "is", because "policeman" is singular -- we are asking for one policeman. The fact that "Smith and Jones" are two people is irrelevant. They're not the "who" here: "the policeman" is.
In the same way, the thing you are asking about in your sentence is "wrong". The fact that it is "with X, Y, and Z" has nothing to do with the number of the subject.