Whole Exome Sequencing in Fetal Cardiac Rhabdomyoma Detected by Ultrasonography: An Analysis of 12 Cases

Background Most of fetal cardiac rhabdomyomas (CRs) are associated with tuberous sclerosis (TSC), an autosomal dominant inherited disorder caused by mutations in the TSC1 or TSC2 genes. In this study, we conducted a comprehensive analysis integrating prenatal echocardiographic findings, parental phenotypic characteristics, and genetic profiles of fetuses with CR. Methods 12 fetuses with sonographically identified CR were included. Karyotype and SNP-array/CNV-seq were performed simultaneously with Trio-WES. Results All CRs were observed in the ventricle, interventricular septum, and the atrium, while the left ventricle were the most common areas. All subjects did not detect arrhythmia during pregnancy. Beside CRs, irregular low echo in the brain was detected in Case 12. TSC1 and TSC2 variants were identified in all 12 fetuses (100%). Mutants of TSC1 account for 25% (3/12) and TSC2 account for 75%(9/12). Two-thirds of these variants were de novo . The P/LP variant spectrum in TSC1 / TSC2 includes 4 (34%) nonsense, 4 (33%) missense, 2 (17%) frameshift, 1 (8%) splice and 1 (8%) small deletion. A 780kb deletion in 9q34.13 (arr[hg19] 9q34.13 (132286422–133062068)×1) encompassing the entire of TSC1 gene, and the other two de novo mutants of c.1687G > C and c.1106delT in TSC2 gene had not been reported previously. Conclusion Combination of ultrasound and genetic testing can effectively diagnose the prenatal cases of TSC. Three novel mutations in TSC genes enlarge the mutation spectrum of TSC .