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Whole-exome Sequencing in the Molecular Diagnosis of Individuals with Congenital Anomalies of the Kidney and Urinary Tract and Identification of a New Causative Gene

Abstract

Purpose: To investigate the utility of whole-exome sequencing (WES) to define a molecular diagnosis for patients clinically diagnosed with congenital anomalies of kidney and urinary tract (CAKUT).

Methods: WES was performed in 62 families with CAKUT. WES data were analyzed for single-nucleotide variants (SNVs) in 35 known CAKUT genes, putatively deleterious sequence changes in new candidate genes, and potentially disease-associated copy-number variants (CNVs).

Results: In approximately 5% of families, pathogenic SNVs were identified in PAX2, HNF1B, and EYA1. Observed phenotypes in these families expand the current understanding about the role of these genes in CAKUT. Four pathogenic CNVs were also identified using two CNV detection tools. In addition, we found one deleterious de novo SNV in FOXP1 among the 62 families with CAKUT. The clinical database of the Baylor Miraca Genetics laboratory was queried and seven additional unrelated individuals with novel de novo SNVs in FOXP1 were identified. Six of these eight individuals with FOXP1 SNVs have syndromic urinary tract defects, implicating this gene in urinary tract development.

Conclusion: We conclude that WES can be used to identify molecular etiology (SNVs, CNVs) in a subset of individuals with CAKUT. WES can also help identify novel CAKUT genes.Genet Med 19 4, 412-420.

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References
1.
Sollis E, Graham S, Vino A, Froehlich H, Vreeburg M, Dimitropoulou D . Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder. Hum Mol Genet. 2015; 25(3):546-57. DOI: 10.1093/hmg/ddv495. View

2.
Karaca E, Harel T, Pehlivan D, Jhangiani S, Gambin T, Akdemir Z . Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. Neuron. 2015; 88(3):499-513. PMC: 4824012. DOI: 10.1016/j.neuron.2015.09.048. View

3.
Vivante A, Kohl S, Hwang D, Dworschak G, Hildebrandt F . Single-gene causes of congenital anomalies of the kidney and urinary tract (CAKUT) in humans. Pediatr Nephrol. 2014; 29(4):695-704. PMC: 4676405. DOI: 10.1007/s00467-013-2684-4. View

4.
Hwang D, Dworschak G, Kohl S, Saisawat P, Vivante A, Hilger A . Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract. Kidney Int. 2014; 85(6):1429-33. PMC: 4040148. DOI: 10.1038/ki.2013.508. View

5.
Krumm N, Sudmant P, Ko A, ORoak B, Malig M, Coe B . Copy number variation detection and genotyping from exome sequence data. Genome Res. 2012; 22(8):1525-32. PMC: 3409265. DOI: 10.1101/gr.138115.112. View