There is clearly something happening with Serena’s father and Chuck’s mother being written into storylines and my theory is that their parents hooked up and this is why they are both being brought back to the show. This also explains why Chuck and Serena have never hooked up in the show’s history.
When executive producer Stephanie Savage said that the Chuck mother storyline would lead to a lot of questions, this might be in reference to a possible brother/sister relationship between Serena and Chuck.
They are not blood-related although they are step-siblings now (since Lilly married Bart), but this would make them related by blood.