A novel NOTCH1 missense variant in two fetuses with a non‐syndromic conotruncal heart defect from a single family

The study describes two fetuses with conotruncal heart defects (CTDs) (persistent truncus arteriosus and pulmonary atresia/ventricular septal defect, respectively) in a Chinese family whose parents were both healthy. Testing was performed to identify any underlying genetic causes. Genomic DNA was extracted from the peripheral blood of the proband’s parents and the skeletal muscle tissue of the two aborted fetuses for genetic testing. A heterozygous likely pathogenic missense variant, c.1724G〉C, was detected in the NOTCH1 gene in the two affected fetuses but not in the parents, and the next-generation sequencing test of the proband’s father showed a normal result. It is presumed to result from germline mosaicism in the proband’s mother or, less likely, from a recurrent de novo variant in the fetuses. This is the first description of fetal non-syndromic CTD caused by a variant in NOTCH1. This report expands the gene variant spectrum of CTDs and emphasizes the importance of NOTCH1 testing when a fetal CTD is detected.