Prenatal diagnosis of Holt-Oram syndrome through ultrasonography and molecular analysis. S. M. Weiss, C. L. Yates Northwestern University, Chicago, IL.

   Holt-Oram syndrome (HOS) is an autosomal dominant disorder characterized by upper-extremity malformations, a personal or family history of congenital heart defects, and an increased risk for cardiac conduction disease. Upper-extremity malformations involve the radial, thenar or carpal bone(s). Most common cardiac defects include atrial and ventricular septal defects. Approximately 70% of individuals who present with clinical criteria have an identifiable mutation in the TBX5 gene [12q24.1]. TBX5 encodes for a transcription factor that plays a role in cardiac septation and limb development. Approximately 85% of TBX5 gene mutations are de novo. Prenatal diagnosis of low risk pregnancies is difficult due to the variable expressivity of the gene mutations and the overlap of clinical features with numerous other conditions. We report on an affected fetus ascertained through routine ultrasound in a G2P1001 woman with an unremarkable family history. Unilateral absence of the radius and a possible heart defect were identified on level II ultrasound at 19w2d. Subsequent fetal echocardiogram suggested atrial septal defect (ASD). Amniocentesis revealed a normal 46, XX karyotype. Testing on amniocytes for a mutation in the TBX5 gene revealed a heterozygous G>T nucleotide substitution in exon 4 (D111Y), resulting in the replacement of an aspartic acid with a tyrosine at amino acid position 111 of the TBX5 protein product. Prompt diagnosis through TBX5 gene mutation analysis allowed for accurate genetic counseling and expectant management.