I believe that Symphony No. 9 fits this category perfectly. This piece was composed while Beethoven was entirely deaf. While this shows his musical genius, the depths that this piece takes is beyond breathtaking. Symphony No. 9 was written between the years of 1822 and 1824. It is the last major piece that he completed before his death.
Today, it is the most performed symphony in the world, gaining new record numbers each year in performances. I have heard this symphony many times, and it never fails to make you catch your breath. It is a shame that he had lost his hearing and never actually heard the beauty that this piece evokes.
But this symphony breaks from others in that it was written with the intention of voice added in, which breaks from his normal path in music.The many moving parts and the added scale of having this prepared for voice makes this one of the most challenging works that Beethoven put together.