Molecular diagnoses in fetuses with megacystis/LUTO by prenatal ultrasound

Failure of bladder emptying, with or without lower urinary tract obstruction (LUTO), is associated with severe perinatal morbidity. Molecular diagnoses of single gene disorders are becoming apparent for many prenatal conditions, including megacystis/LUTO, and may provide diagnostic clarity and predict recurrence. Our objective was to describe the prenatal diagnostic experience and elucidate genotype-phenotype correlations in cases with a sonographic appearance of LUTO. A retrospective case series of pregnancies affected by megacystis/LUTO with a molecular diagnosis was collected from multiple centers in the Fetal Sequencing Consortium. Demographics, sonograms, genetic test results, and delivery outcomes were abstracted for each case. All sonograms were performed at a tertiary care referral center and interpreted by a Maternal-Fetal-Medicine specialist. Genetic testing was performed via chromosomal microarray and/or exome sequencing (ES). We identified 5 cases of prenatally diagnosed megacystis/LUTO with a molecular diagnosis. All 5 cases had megacystis, 3/5 cases had oligohydramnios, and 4/5 cases had echogenic kidneys, cortical cystic changes, or hydronephrosis. Extrarenal anomalies were seen in 3 cases, and the most common extrarenal anomaly was clubfoot. No case underwent fetal shunting and one case underwent serial amnioinfusions. One case had a positive family history of genitourinary anomalies and 1 case had a history of 4 stillbirths (all with megacystis). Variants in MYOCD (2), ACTG2 (1), and MYH11 (1) were classified as likely pathogenic or pathogenic by ACMG guidelines, while the variant in ATRX (1) was classified as a VUS. Our data suggests that ES is important to consider in the workup of megacystis/LUTO to identify causative genes including MYOCD, ACTG2, and MYH11. Our series demonstrates the potential utility of molecular testing in the setting of isolated LUTO without extrarenal anomalies, especially in cases with a positive family history, such as patient 2 in our series.View Large Image Figure ViewerDownload Hi-res image Download (PPT)