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.

Figure 1

Pedigrees and genotypes of the families with pathogenic SNVs in genes known to cause CAKUT and a novel CAKUT gene (Family 38, FOXP1). * denotes individuals for whom WES were performed. NT means not tested. Family 1. Solid black fill shows renal dysplasia and solid grey fill means proteinuria. CG/CG is normal and CG/C- denotes heterozygous deletion of G (c.70delG) in PAX2. Family 2. Proband has cystic renal dysplasia. C/C is normal and C/CC is heterozygous duplication of C (c.1132dupC) in HNF1B. Family 3. Proband has vesicoureteral reflux and multicystic dysplastic kidney (MCDK). G/G is normal and G/A denotes heterozygous splice site variant (c.867+5G>A) in EYA1. Family 38. Proband has unilateral renal agenesis and hydrocephaly. G/G is normal and G/T denotes heterozygous de novo FOXP1 p.P225T SNV.