DNA Copy Number Variations in Patients with Persistent Cloaca

Purpose: Persistent cloaca is a devastating female anomaly associated with renal insufficiency/failure, urinary and fecal incontinence and mullerian dysfunction. Genetically engineered murine models of persistent cloaca suggest that this anomaly could have a genetic component in humans. Genomic copy number variations account for previously unexplained genetic diseases by identifying candidate genes in various disorders. We assessed whether novel copy number variations are present in patients with persistent cloaca. Materials and Methods: With institutional review board approval we performed a retrospective chart review to identify patients with persistent cloaca. Lymphocyte DNA was prospectively tested by whole genome array comparative genomic hybridization. HHAT was Sanger sequenced from genomic DNA. Results: At study recruitment mean age was 12 years (range 0.5 to 23) in 17 females with cloaca. Seven females (41%) had a solitary functioning kidney and 2 each had renal insufficiency and renal replacement therapy. The common cloaca channel was 1.5 to 6 cm long in 6 newborns. Six patients (35%) had vaginal duplication and 4 had spinal anomalies. Array comparative genomic hybridization revealed copy number variations in 7 patients (41%), including 5 gains and 2 losses. Two copy number variations were novel, including a paternally inherited duplication on 16p13.2 and a de novo deletion on 1q32.1q32.3. Subsequent sequencing of the candidate gene HHAT identified no causal mutations. Conclusions: Persistent cloaca is a rare but morbid birth defect. Copy number variations are common in these females but HHAT mutations are not common. Further investigation of these genomic rearrangements may lead to the identification of genetic causes of persistent cloaca.