As of the Afterbirth+ DLC, one of the in-between levels nightmare loading screens Isaac has while crying in his signature fetal position reveals that The Lost is the voice Isaac's mother was hearing. The Lost is (presumably, if we think about this) Isaac's ghost after passing away, but Isaac was still alive when Mom heard the voice from above. It is of common knowledge that the whole God asking Mom to sacrifice Isaac thing never really happened but still... How can this be? Is The Lost not Isaac? Is he a completely different entity?
We've never actually seen what other people in Isaac's art style would look like as ghosts. So it's very well possible that this nightmare is actually depicting Mom hearing a random ghost haunting their attic, not The Lost.
