A 34-year-old pregnant woman who was at 23 weeks' gestation was referred to our prenatal diagnosis clinic, as fetal skeletal and cardiac abnormalities were diagnosed by another hospital. Her family history and past health were unremarkable. Fetal ultrasonography demonstrated shortness of the radius and ulna, especially the radius (Figure 1A). Both hands had the inability to supinate (Figures 1B,C), and the right thumb was missing in ultrasound imaging (Figure 1D). Fetal echocardiography detected fetal cardiac tissues with ventricular septal defect (VSD), which exhibited an ~0.21-cm interruption of continuity in the ventricular septal membrane, and the signals of trans-septal blood flow were detected at the VSD (Figures 2A,B). Based on this ultrasonic diagnosis, a tentative diagnosis of HOS was made. Next, whole-exome sequencing (WES) was performed for further confirmation. Fetal amniotic fluid cells were collected by amniocentesis for WES; and WES was also performed on family members. Further verification of false-positive text by Sanger sequencing was performed to exclude false-positive variants.
The fetus was the second child of non-consanguineous Chinese parents. The fetal brother (same parents) had cubitus valgus, thumb adduction, short radius and ulna, and VSD, while the father had short radius and ulna and VSD only. But the mother did not have any signs of limb or heart abnormalities. The WES revealed a heterozygous mutation in the fetus (Figure 3A). The variant, c.510+1G>A (RefSep NM_000192: c.510+1G>A), was inherited from the father, and mother is normal (Figures 3B,C). The variant in TBX5 gene was also found in the brother (Figure 3D), but not in grandfather and grandmother (Figures 3E,F). The variant occurs at splice donor. Further analysis by Human Splicing Finder system version 3.1 (HSF3.1) demonstrated that the mutation most probably influenced splicing, with the variation in the mutated sequence estimated to be 61.14, and variation for the wild-type sequence being 87.97 (DeltaCV: -30.5%). According to clinical phenotype and genetic analysis, the case was diagnosed with HOS. However, follow-up data on the fetus were not available, because the pregnancy was terminated by labor induction.