It depends on how different the layout would need to be. The scenario you mentioned sounds like a multi-tenant SaaS type of system. To me, the templates would then need to be totally separate for each tenant, so the template (and layout/ design) selection would be handled at system level. If tenant X calls the site, templates from directory X would be called. If tenant Y would call the site, then templates from directory Y would be called. This would allow for the highest possible customizability.
Scott