Molecular testing strategies in the evaluation of fetal skeletal dysplasia

The aim of this study was to characterize the fetal sonographic findings and the approach utilized to obtain a definitive diagnosis through molecular testing strategies.

This is a retrospective case series of fetuses referred for consultation for prenatal findings suggestive of a skeletal dysplasia between March 1, 2014 and March 1, 2016. Ultrasound images, their timing in gestation and reported findings were reviewed and skeletal abnormalities were documented. Unique features were ascertained. The approach for molecular evaluation, and molecular results were extracted.

Nine cases were referred for evaluation secondary to prenatal sonographic features suggestive of a skeletal dysplasia. In 4 cases a skeletal dysplasia was suspected prior to 16 weeks gestation. Three of these, with mutations in CANT1, NEK1, and COL2A1 were considered lethal, while the fourth case had a non-lethal ALPL mutation. Similarly 2 of 3 cases diagnosed at 16-22 weeks gestation had lethal mutations in COL1A and DYNC2H1 while the fetus with Russell Silver survived. The final 2 cases diagnosed in the third trimester, both hypochondroplasia, were non-lethal dysplasias. A molecular diagnosis was obtained in 8/9 (88.9%) cases which encompassed eight different skeletal dysplasias. The final case declined molecular testing.

Features of specific skeletal dysplasias can be visualized in utero and guide appropriate molecular testing. Sonographic details in addition to molecular genetic results aid in prognostic counseling.