Abstract
Lower urinary tract obstruction (LUTO) is, in most cases, caused by anatomical blockage of the bladder outlet. The most common form are posterior urethral valves (PUVs), a male-limited phenotype. Here, we surveyed the genome of 155 LUTO patients to identify disease-causing CNVs. Raw intensity data were collected for CNVs detected in LUTO patients and 4.392 healthy controls using CNVPartition, QuantiSNP and PennCNV. Overlapping CNVs between patients and controls were discarded. Additional filtering implicated CNV frequency in the database of genomic variants, gene content and final visual inspection detecting 37 ultra-rare CNVs. After, prioritization qPCR analysis confirmed 3 microduplications, all detected in PUV patients. One microduplication (5q23.2) occurred de novo in the two remaining microduplications found on chromosome 1p36.21 and 10q23.31. Parental DNA was not available for segregation analysis. All three duplications comprised 11 coding genes: four human specific lncRNA and one microRNA. Three coding genes (FBLIM1, SLC16A12, SNCAIP) and the microRNA MIR107 have previously been shown to be expressed in the developing urinary tract of mouse embryos. We propose that duplications, rare or de novo, contribute to PUV formation, a male-limited phenotype.
Highlights
Congenital lower urinary tract obstructions (LUTO) are a heterogeneous group of pathologies caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding
We identified a de novo 852,734 bp microduplication at 5q23.2 in a male posterior urethral valves (PUVs) patient
The oligohydramnios, the facial appearance resembling that of a child with Potter sequence, and the pulmonary hypoplasia accompanied by bilateral hydronephrosis highly suggest that their index patient had some form of anatomical Lower urinary tract obstruction (LUTO), this was not described by the authors
Summary
Congenital lower urinary tract obstructions (LUTO) are a heterogeneous group of pathologies caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding. The most common form of LUTO are posterior urethral valves (PUV), a male-limited phenotype [1,2] This phenotype presents in 63% of patients with LUTO [2]. The reduced urinary excretion into the amniotic cavity results in oligo- or anhydramnios with consecutive pulmonary hypoplasia and joint contractures, and can potentially lead to all of the features of the Potter sequence [3]. These secondary problems can be prevented in some patients by vesico-amniotic shunting, relieving the urinary retention and ensuring a sufficient amount of amniotic fluid. While for LUTO patients, possible potential causative CNVs could only be described in individual patients up until now [9], previous studies identified an enrichment for rare duplications
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