We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10(-11)). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10(-58)). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay.

Ciliogenesis in developing and post-natal human kidneys appears to influence cell proliferation and differentiation, apico-basal cell polarity, and tubular lumen formation. We have analyzed the appearance of primary cilia and differentiation of kidney cells in ten human conceptuses aged 6-22 weeks and in one 5-year-old kidney, using a double immunofluorescence labeling technique for α-tubulin, γ-tubulin, Oct-4, and Ki-67 and by electron microscopy. Immature forms of nephrons and ampullae were characterized by intense cell proliferation, which subsequently decreased during development. Primary cilia appeared on the surfaces of non-proliferating cells in developing nephrons, gradually increasing in length from 0.59 μm in renal vesicles to 0.81 μm in the S-forms of nephrons, ultimately reaching 3.04 μm in length in mature fetal and post-natal nephrons. Ciliary length increased from 0.59 μm in ampullae to 1.28 μm in post-natal collecting tubules. Mesenchymal to epithelial transformation of kidney cells coincided with the appearance of apico-basal polarity, both gap and tight junctions, and lumen formation. Up-regulation of Oct-4 expression correlated with the onset of kidney cell differentiation. Our results demonstrate the importance of proper primary cilia lengthening and Oct-4 expression for the normal development of fetal and post-natal kidneys and of apico-basal polarity for normal tubular lumen formation. Disturbances in these processes are associated with ciliopathies.

BackgroundUltrasonographic (US) screening of the urinary tract (UT) in infants was used to determine if there is a connection between the frequency of pyelocaliceal dilation (PCD) in asymptomatic infants with normal antenatal US screening and occurrence of congenital anomalies of kidney and urinary tract (CAKUT) and urinary tract infections (UTI).Material/MethodsUS screening of the UT was performed on 1000 healthy infants, 7 days to 6 months old. Two subgroups of kidneys were described: subgroup 1 contained kidneys with anterior posterior pelvic diameter (APPD) of 5–9.9 mm, and subgroup 2 with APPD over 10 mm. US examinations and methods for detection of UTI and CAKUT were used.Results PCD was found in 74 infants (7.4%): 1.9% of infants had CAKUT, and 8.4% had UTI. In subgroup 1, CAKUT was found in 4 (6.3%) and UTI in 9 (14.3%) infants. In subgroup 2, CAKUT was found in 6 (54.5%), and UTI in 4 (36.4%) infants.ConclusionsMild PCD significantly increases the risk for CAKUT but not for UTI. Moderate to severe PCD significantly increases risk for both CAKUT and UTI. The postnatal US screening of UT is recommended for improved detection of PCD and associated CAKUT. Indirectly, postnatal US screening of UT can help in detecting people at risk for UTI in the first year of life, and therefore help prevent possible kidney damage.

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