Whole exome sequencing (WES) for prenatal diagnosis has a reported diagnostic yield of 6.2%-57%. Our aim was to identify patients with a high likelihood of genetic diagnosis using WES in cases with fetal ultrasound anomalies. This is a series of five selected cases for prenatal WES at our institution. Pregnant couples were initially identified due to fetal ultrasound anomalies. Candidates for WES for fetal diagnosis had a normal fetal karyotype and negative microarray with at least one of the following: parental consanguinity, large regions of homozygosity on fetal microarray, or high likelihood of single gene disorder based on ultrasound findings. All trios underwent sequencing of parental and fetal samples. WES was diagnostic in four of the five cases (80%). We identified two recessive conditions and two de novo mutations. Four couples consented to secondary findings and in one case, the father was found to have an MSH2 mutation associated with Lynch syndrome. The use of specific selection criteria for WES increased diagnostic yield to 80%. This is higher than previously reported. Wide application of our criteria can help identify those who may benefit most from this testing in prenatal diagnosis.