The role of sonographic phenotyping in delivering an efficient noninvasive prenatal diagnosis service for FGFR3-related skeletal dysplasias

Objectives To evaluate the diagnostic yield of noninvasive prenatal diagnosis (NIPD) for FGFR3-related skeletal dysplasias and assess the accuracy of referrals based on sonographic findings to inform guidelines for referral. Methods We retrospectively reviewed laboratory and referral records from 2012 to 2018 to ascertain all NIPD tests performed using our next generation sequencing panel to detect FGFR3 mutations. We calculated the diagnostic yield of the test overall and when sub-divided according to the phenotypic features identified on ultrasound before testing. Pregnancy outcomes were ascertained wherever possible from referring centers. Results Of 335 tests, 261 were referred because of sonographic findings, of which 80 (31.3%) had a mutation. The diagnostic yield when short limbs were the only abnormal sonographic feature reported was 17.9% (30/168), increasing to 48.9% (23/47) in the presence of one, and 82.6% (19/23) in the presence of two or more characteristic features in addition to short limbs. Conclusions Accurate sonographic phenotyping can maximise the diagnostic yield of NIPD in fetuses suspected to have FGFR3-related skeletal dysplasias. We suggest that clear guidelines for referral are necessary to increase benefits, decrease costs by preventing unnecessary NIPD, and potentially allow first-line broader spectrum testing for fetuses where the aetiology may be more heterogeneous.