In October 1848, a poor Irishman by the name of Patrick Kennedy emmigrated to Boston, USA. His descendants would become the famous Kennedy and rise to the level of Senators, Cabinet members and one even president!
The POD is simple. Patrick Kennedy dies on the trans-Atlantic voyage to the USA. Apparently the conditions on such ships were incredibly squalid, they were even sometimes referred to as 'coffin ships, it would be quite easy for Patrick to contract something fatal and die from it.
How does the history of the USA and the world change without any of the Kennedys around?