Diagnostic genetics within the United Kingdom National Health Service (NHS) has undergone many stepwise improvements in technology since the completion of the human genome project in 2003. Although Sanger sequencing has remained a cornerstone of the diagnostic sequencing arena, the human genome reference sequence has enabled next-generation sequencing (more accurately named 'second-generation sequencing'), to rapidly surpass it in scale and potential. This mini review discusses such developments from the viewpoint of the Stickler's higher specialist service, detailing the considerations and improvements to diagnostic sequencing implemented since 2003.