Cardiovascular Defects as the Initial Presentation in Two Prenatal Cases of De Novo Heterozygous PBX1 Variants.

PBX1-associated congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED) is a highly pleiotropic, autosomal dominant developmental disorder. The disease spectrum is broad, and only a limited number of prenatal cases have been reported to date. We report two well-documented prenatal cases of CAKUTHED presenting with cardiovascular defects as the initial manifestation in the second trimester. Trio exome sequencing identified two de novo variants in PBX1 (c.192-3C>A and c.869G>A), confirming the genetic diagnosis of CAKUTHED in the two fetuses. In Case 1, minigene assays validated that the c.192-3C>A variant interfered with RNA splicing. The individual predominantly manifested tetralogy of Fallot and renal hypoplasia. In Case 2, the c.869G>A missense variant was identified, with more complex clinical features. Cardiac malformations included coarctation of the aorta, pulmonary artery stenosis, coronary sinus dilatation, and persistent left superior vena cava. Moreover, the fetus exhibited severe growth restriction, polyhydramnios, and marked thoracic and pulmonary defects, with no significant structural abnormalities of the urinary system detected. Both pregnancies were subsequently terminated. Our report, by detailing the previously rarely reported prenatal clinical features and novel genetic variants, helps to expand the known phenotypic and genotypic spectrum of PBX1-related disorders.