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Am J Med Genet A. 2016 Mar;170(3):622-33. doi: 10.1002/ajmg.a.37493. Epub 2015 Dec 14.

Rare copy number variants implicated in posterior urethral valves.

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Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina.
Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
Department of Health, Division of Genetics, Wadsworth Center, Albany, New York.
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota.
Department of Health, Congenital Malformations Registry, Albany, New York.
University at Albany School of Public Health, Rensselaer, New York.
Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, Iowa.
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.


The cause of posterior urethral valves (PUV) is unknown, but genetic factors are suspected given their familial occurrence. We examined cases of isolated PUV to identify novel copy number variants (CNVs). We identified 56 cases of isolated PUV from all live-births in New York State (1998-2005). Samples were genotyped using Illumina HumanOmni2.5 microarrays. Autosomal and sex-linked CNVs were identified using PennCNV and cnvPartition software. CNVs were prioritized for follow-up if they were absent from in-house controls, contained ≥ 10 consecutive probes, were ≥ 20 Kb in size, had ≤ 20% overlap with variants detected in other birth defect phenotypes screened in our lab, and were rare in population reference controls. We identified 47 rare candidate PUV-associated CNVs in 32 cases; one case had a 3.9 Mb deletion encompassing BMP7. Mutations in BMP7 have been associated with severe anomalies in the mouse urethra. Other interesting CNVs, each detected in a single PUV case included: a deletion of PIK3R3 and TSPAN1, duplication/triplication in FGF12, duplication of FAT1--a gene essential for normal growth and development, a large deletion (>2 Mb) on chromosome 17q that involves TBX2 and TBX4, and large duplications (>1 Mb) on chromosomes 3q and 6q. Our finding of previously unreported novel CNVs in PUV suggests that genetic factors may play a larger role than previously understood. Our data show a potential role of CNVs in up to 57% of cases examined. Investigation of genes in these CNVs may provide further insights into genetic variants that contribute to PUV.


congenital urinary tract obstruction; copy number variant; posterior urethral valve; urethra; urinary tract malformation

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