This was confirmed by Edmund McMillen during a YouTube stream.
This is in reference of Mount Moriah, the place where Abraham takes his son Isaac to be sacrificed, in the Book of Genesis. Isaac's natural hair color is strawberry blonde. Which could be a reference to the Nazarite Vow in Numbers 6:1–21. Isaac is bald because his mother shaved his head. Contrary to previous theories made about Isaac, he does not have a sister. Isaac's mother could have forced him to learn things the "righty" way for fear of him being "evil." 
This could be a reference to the Catholic bias against left-handedness, stemming from Matthew 25:33 proclaiming that God will put those deserving to ascend to Heaven on his right-hand side and put those deserving to descend to Hell on his left-hand side. Edmund has stated that Isaac is left-handed, but in the opening cutscene, Isaac is holding a pencil with his right hand. In a response to TBoI Youtuber Sinvicta of whether there was any concept art of what Isaac's original design was, Edmund McMillen confirmed that Isaac's design was originally one of an Octorock while showing very similar features of how the gameplay would be modeled by posting an old concept art. Sacrifice him there as a burnt offering on a mountain I will show you.'" (Genesis 22:2) "Then God said, 'Take your son, your only son, whom you love - Isaac - and go to the region of Moriah. 
Isaac is a reference to the biblical story of the binding of Isaac, in which Abraham is commanded by God to sacrifice his only son, Isaac, to prove his loyalty and love.
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