We have developed a fully integrated WGS process for clinical diagnosis: from sequence generation through to interpretation and reporting, including follow-up and counselling tailored specifically to WGS testing. Our initial pilot program has been extended to a Children's Hospital of Wisconsin clinic providing dedicated genetics staff. This required development of a series of CAP/ CLIA compliant protocols and pipelines for dealing with samples and returning reports, and has spurred ongoing development of tools including a platform for electronic health record (EHR) data extraction. Clinically validated WGS analysis tools were also developed to support determination of whether the variant is: (1) a likely error, (2) known to be causally linked with human disease, (3) of a type likely to lead to altered function thereby giving rise to a phenotypic change, and/or (4) within a gene with a function associated or relevant to the patient phenotype (including identification of causative disease genes). They support consideration of variant and functional information simultaneously, as required for interpretation and reporting. Development of this clinic also required formation of institutional review bodies, definition of a structure for counselling, and development of criteria for appropriate reporting and return of WGS-based findings.