Translation:She is always late. What's the matter?
First of all, I'd say there are several stable phrases with this meaning: В чём дело?, Что случилось?, Ну, что? The difference is in formality, emotional state. I have a feeling that "Что случилось" is the most polite, "Ну, что" the least polite and "В чём дело" is somewhat in the middle, but they are all widely used.
The key word дело can be translated as matter, point, concern, business: ближе к делу = come to the point, get down to business, говорить по делу = to speak on business, дело не в этом = that's not the point.
It is an idiomatic expression, you can think of it as the matter consists of something. So the question is What does it consist of?. One can even ask В чём состоит дело?, which is the longer version and gives a hint. The answer follows the same pattern: Дело в том, что я беременна = The problem is that I'm pregnant [The problem consists of the fact that I'm pregnant]
Hope this helps, probably it would be easier just to memorize the whole phrase. =)
Yes, one should say Дело в <предложный падеж>:
всё дело в машине [им: машина] = it's the car, дело в твоём поведении [им: поведение] = it's about your behavior.
You can always use this form, longer but grammatically simpler: дело в том, что <предложение без изменений>:
дело в том, что я хочу кушать = the problem is that I'm hungry.
Duo accepts "What's up with that?" for В чём дело" here - I guess it will only do it on exercises where there is a sentence to give the "that" context. But I was really pleased it was accepted because it works and is semi-polite given it's the lateness that is an issue rather than her. It's my preferred translation in this case.
I wouldn't say so. What's the matter? is the closest translation here. This phrase can be easily said by the boss or the colleague, so the context is like "Does she know about discipline?".
If I wanted to say "What's the big deal?", I would say Ну и что такого?, or А ты не знал? for "Is it a surprise?"