I run a multisite with the secondary blogs pointing to subdomains. After updating my network sites became unavailable with a 404 error. I thought it was related to some host issues at Hostgator first. Tech support couldn't fix it, they recommended installing a backup of my entire site, which I did, static files only. Database was left intact. That did not fix the issue.
After fiddling with some settings in Cpanel, I got it to work again. I had to get rid of all my subdomains and add them again, make sure they pointed to the root where WordPress was installed.
Everything was working fine, but the site restore took me back to just before the Jetpack upgrade. As soon as I upgraded Jetpack, the network sites became unavailable again! I tried deactivating the plugin, but that still didn't help. Fortunately, removing my subdomains and adding them again did the trick.