Application of targeted exome capture in identifying fetal skeletal malformation mutations

Objective To investigate the feasibility of targeted exome capture with high throughput sequencing in gene mutations related to fetal skeletal dysplasia. Methods From July 2009 to July 2014, ten fetuses with skeletal dysplasia were identified by ultrasound screening at 18-24 and/or 30-32 gestational weeks in the Chinese PLA General Hospital. Amniotic fluid or cord blood was collected for karyotyping. Amniotic fluid or cord blood, fetal tissues after labor induction, and blood samples from neonates and parents were collected and analyzed for 248 genes associated with fetal skeletal dysplasia using targeted exome capture with high throughput sequencing. Detected gene mutations were confirmed by direct Sanger sequencing reactions. Results No abnormal karyotypes were found in the ten fetuses. Three fetuses carried collagen, typeⅠ, alpha-1 (COLIA1) gene mutations of c.3307G>A, c.1706G>C and c.2101G>A, respectively. No mutations were found in their parents, which were confirmed by direct Sanger sequencing reactions. Another three fetuses carried fibroblast growth factor 3 (FGFR3) gene mutations of c.1138G>A and c.1118A>G, respectively. One fetus carried compound heterozygous Ellis-van Creveld syndrome (EVC) gene mutations of c.884C>G and c.982C>T from her parents and were confirmed by direct Sanger sequencing reactions. No causative mutations were found in the remaining three cases. Conclusion Targeted exome capture with high throughput sequencing is a new approach for identifying causative gene mutations in fetal skeletal dysplasia. Key words: Bone diseases, developmental; Limb deformities, congenital; Exons; High-throughput nucleotide sequencin; Genetic testing; Ultrasonography, prenatal