Screening of renal anomalies in first-degree relatives of children diagnosed with non-syndromic congenital anomalies of kidney and urinary tract

Viswanathan, Aarthi; Sharawat, Indar Kumar; Tiewsoh, Karalanglin; Saxena, Akshay Kumar; Dutta, Sourabh; Suri, Deepti

doi:10.1007/s10157-020-01977-7

Cited by 7 publications

(2 citation statements)

References 27 publications

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“…Family members with the same genetic defects can even have urinary phenotypes ranging from asymptomatic to advanced renal failure [ 45 ]. For example, among the harmful variants or deletions identified in TOM1L2, the majority of patients inherited mutations from their asymptomatic parents, except for a few de novo variants [ 46 ], which can be considered a concrete manifestation of incomplete explicit characteristics. In addition to the dominant role of genetic factors, environmental factors and epigenetic factors (such as DNA methylation) are involved in CAKUT pathogenesis [ 39 ], which should be explored in the future.…”

Section: Discussionmentioning

confidence: 99%

GEN1 as a risk factor for human congenital anomalies of the kidney and urinary tract

Du,

Wang,

Liu

et al. 2024

Hum Genomics

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Background Congenital anomalies of the kidney and urinary tract (CAKUT) are prevalent birth defects. Although pathogenic CAKUT genes are known, they are insufficient to reveal the causes for all patients. Our previous studies indicated GEN1 as a pathogenic gene of CAKUT in mice, and this study further investigated the correlation between GEN1 and human CAKUT. Methods In this study, DNA from 910 individuals with CAKUT was collected; 26 GEN1 rare variants were identified, and two GEN1 (missense) variants in a non-CAKUT group were found. Mainly due to the stability results of the predicted mutant on the website, in vitro, 10 variants (eight CAKUT, two non-CAKUT) were selected to verify mutant protein stability. In addition, mainly based on the division of the mutation site located in the functional region of the GEN1 protein, 8 variants (six CAKUT, two non-CAKUT) were selected to verify enzymatic hydrolysis, and the splice variant GEN1 (c.1071 + 3(IVS10) A > G) was selected to verify shear ability. Based on the results of in vitro experiments and higher frequency, three sites with the most significant functional change were selected to build mouse models. Results Protein stability changed in six variants in the CAKUT group. Based on electrophoretic mobility shift assay of eight variants (six CAKUT, two non-CAKUT), the enzymatic hydrolysis and DNA-binding abilities of mutant proteins were impaired in the CAKUT group. The most serious functional damage was observed in the Gen1 variant that produced a truncated protein. A mini-gene splicing assay showed that the variant GEN1 (c.1071 + 3(IVS10) A > G) in the CAKUT group significantly affected splicing function. An abnormal exon10 was detected in the mini-gene splicing assay. Point-mutant mouse strains were constructed (Gen1: c.1068 + 3 A > G, p.R400X, and p.T105R) based on the variant frequency in the CAKUT group and functional impairment in vitro study and CAKUT phenotypes were replicated in each. Conclusion Overall, our findings indicated GEN1 as a risk factor for human CAKUT.

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Section: Discussionmentioning

confidence: 99%

GEN1 as a risk factor for human congenital anomalies of the kidney and urinary tract

Du,

Wang,

Liu

et al. 2024

Hum Genomics

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“…For example, in first‐degree relatives of children with non‐syndromic CAKUT, the incidence of CAKUT is 6% (9 out of 149 family members), which is significantly higher than the risk in the general population. Interestingly, most of the CAKUT phenotypes detected in biologically related individuals were discordant to the index case (88.8%) (Viswanathan et al, 2021). In another study, the familial occurrence of CAKUT was noted in 7.9% of the 138 families using either renal ultrasonogram, radionuclide diuretic renogram, or micturating cystourethrogram in family members of the index case (Manoharan, Krishnamurthy, Sivamurukan, Ananthakrishnan, & Jindal, 2020).…”

Section: Screening For Cakutmentioning

confidence: 99%

Disease mechanisms of monogenic congenital anomalies of the kidney and urinary tract

Connaughton

Hildebrandt

2022

American J of Med Genetics Pt C

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Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is a developmental disorder of the kidney and/or genito‐urinary tract that results in end stage kidney disease (ESKD) in up to 50% of children. Despite the congenital nature of the disease, CAKUT accounts for almost 10% of adult onset ESKD. Multiple lines of evidence suggest that CAKUT is a Mendelian disorder, including the observation of familial clustering of CAKUT. Pathogenesis in CAKUT is embryonic in origin, with disturbances of kidney and urinary tract development resulting in a heterogeneous range of disease phenotypes. Despite polygenic and environmental factors being implicated, a significant proportion of CAKUT is monogenic in origin, with studies demonstrating single gene defects in 10%–20% of patients with CAKUT. Here, we review monogenic disease causation with emphasis on the etiological role of gene developmental pathways in CAKUT.

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The genetic basis of congenital anomalies of the kidney and urinary tract

2022

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Screening of renal anomalies in first-degree relatives of children diagnosed with non-syndromic congenital anomalies of kidney and urinary tract

Cited by 7 publications

References 27 publications

GEN1 as a risk factor for human congenital anomalies of the kidney and urinary tract

GEN1 as a risk factor for human congenital anomalies of the kidney and urinary tract

Disease mechanisms of monogenic congenital anomalies of the kidney and urinary tract

The genetic basis of congenital anomalies of the kidney and urinary tract

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