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Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of chronic kidney disease that manifests in children. To date ~23 different monogenic causes have been implicated in isolated forms of human CAKUT, but the vast majority remains elusive. In a previous study, we identified a homozygous missense variant in E26 transformation‐specific (ETS) Variant Transcription Factor 4 (ETV4) causing CAKUT via dysregulation of the transcriptional function of ETV4, and a resulting abrogation of GDNF/RET/ETV4 signaling pathway. This CAKUT family remains the only family with an ETV4 variant reported so far. Here, we describe one additional CAKUT family with a homozygous truncating variant in ETV4 (p.(Lys6*)) that was identified by exome sequencing. The variant was found in an individual with isolated CAKUT displaying posterior urethral valves and renal dysplasia. The newly identified stop variant conceptually truncates the ETS_PEA3_N and ETS domains that regulate DNA‐binding transcription factor activity. The variant has never been reported homozygously in the gnomAD database. To our knowledge, we here report the first CAKUT family with a truncating variant in ETV4, potentially causing the isolated CAKUT phenotype observed in the affected individual. [ABSTRACT FROM AUTHOR]

Neurological symptoms are frequent and often a leading feature of childhood‐onset mitochondrial disorders (MD) but the exact incidence of MD in unselected neuropediatric patients is unknown. Their early detection is desirable due to a potentially rapid clinical decline and the availability of management options. In 491 children with neurological symptoms, a comprehensive diagnostic work‐up including exome sequencing was performed. The success rate in terms of a molecular genetic diagnosis within our cohort was 51%. Disease‐causing variants in a mitochondria‐associated gene were detected in 12% of solved cases. In order to facilitate the clinical identification of MDs within neuropediatric cohorts, we have created an easy‐to‐use bedside‐tool, the MDC‐NP. In our cohort, the MDC‐NP predicted disease conditions related to MDs with a sensitivity of 0.83, and a specificity of 0.96. [ABSTRACT FROM AUTHOR]

The acronym VATER/VACTERL refers to the rare nonrandom association of the following component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac anomalies (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb anomalies (L). For the clinical diagnosis, the presence of at least three CFs is required, individuals presenting with only two CFs have been categorized as VATER/VACTERL‐like. The majority of VATER/VACTERL individuals displays a renal phenotype. Hitherto, variants in FGF8, FOXF1, HOXD13, LPP, TRAP1, PTEN, and ZIC3 have been associated with the VATER/VACTERL association; however, large‐scale re‐sequencing could only confirm TRAP1 and ZIC3 as VATER/VACTERL disease genes, both associated with a renal phenotype. In this study, we performed exome sequencing in 21 individuals and their families with a renal VATER/VACTERL or VATER/VACTERL‐like phenotype to identify potentially novel genetic causes. Exome analysis identified biallelic and X‐chromosomal hemizygous potentially pathogenic variants in six individuals (29%) in B9D1, FREM1, ZNF157, SP8, ACOT9, and TTLL11, respectively. The online tool GeneMatcher revealed another individual with a variant in ZNF157. Our study suggests six biallelic and X‐chromosomal hemizygous VATER/VACTERL disease genes implicating all six genes in the expression of human renal malformations. [ABSTRACT FROM AUTHOR]

A partial life-cycle assay (PLC) with zebrafish (Danio rerio) was conducted to identify endocrine-disrupting effects of 17β-estradiol (E2) and tamoxifen (TMX) as reference for estrogen agonist and antagonist activity. Adult zebrafish were exposed for 21 d and offspring for another 42 d, allowing differentiation of gonads in control animals. The assessed end points included reproductive variables (egg production, fertilization, and hatching), gonad differentiation of juveniles, histopathology, and vitellogenin (VTG) expression. With E2, the most sensitive end points were feminization of offspring (at 0.1 nM) and increased VTG production in males (at 0.32 nM). At 1 nM, decreased F1 survival, increased F1 body length and weight, VTG-related edema and kidney lesions, and inhibited spermatogenesis were observed. Oocyte atresia occurred at even higher concentrations. Exposure to TMX resulted in specific effects at an intermediate test concentration (87 nM), including oocyte atresia with granulosa cell transformation and disturbed spermatogenesis (asynchrony within cysts). In F1, decreased hatching, survival, and body weight and length as well as decreased feminization were observed. Decreased vitellogenesis and egg production in females and clustering of Leydig cells in males occurred at higher concentrations. Toxicological profiles of estrogen agonists and antagonists are complex and specific; a valid and refined characterization of endocrine activity of field samples therefore can be obtained only by using a varied set of end points, including histology, as applied in the presented PLC. Evaluation of only a single end point can easily produce under- or overestimation of the actual hazard. [ABSTRACT FROM AUTHOR]

The importance of histology as a tool in the evaluation of endocrine disruption in fish depends on the choice and interpretation of appropriate endpoints, as is illustrated by the analysis of the effects of exposure to the estrogen 17β-estradiol (E2) and the nonaromatizable androgen 17-methyldihydrotestosterone (MDHT). The E2 led to the disappearance of vitellogenic oocytes in the ovary and an increased area of relatively large, eosinophilic cells in the testis, which were identified as spermatogonia under high-power magnification; this was a relative increase, as was shown by histomorphometry, because of a decreased size of spermatogenic cysts and a relative decrease of spermatocyte cysts. The E2 also induced an accumulation of acidophilic fluid in vessels and interstitial spaces, confirmed by immunohistochemistry as vitellogenin, and basophilia in the liver also associated with the production of vitellogenin. The MDHT induced activation of Sertoli cells in the testis and a decreased presence of vitellogenic oocytes and a reduced growth of previtellogenic oocytes in the ovary. These observations indicate the advantages of examining multiple organ systems on whole-body sections and the application of adequate magnifications. Inclusion of additional techniques such as morphometry and immunohistochemistry is valuable to further uncover insidious effects of endocrine disruptors. [ABSTRACT FROM AUTHOR]

Environmental pollution with natural or synthetic estrogens may pose a serious threat to reproduction of wildlife species. This study describes the effects of 17-α-ethynylestradiol (EE2) on fish reproductive organs in a laboratory model. Adult zebrafish were semistatically exposed to nominal concentrations of 0, 10, and 25 ng/L EE2 for 24 d and then transferred to EE2-free medium. Gonadosomatic index (GSI), plasma vitellogenin concentration (VTG), and histology of the gonads (control and 10 ng/L only) were examined as a function of time. It was found that EE2 has an adverse impact on both male and female reproductive organs. Notably in females, gonadal changes were observed through histological evaluation after 3 d of exposure to 10 ng/L EE2, and this was followed by a reduction of GSI at day 6 of exposure. In males, a reduction of GSI and altered testis histology was found after 24 d of exposure to 10 ng/L. The observed effects on the ovary after EE2 exposure, combined with complete recovery after 24 d, is considered to be triggered by feedback at the level of the pituitary. In both males and females, VTG was induced in response to EE2 and normalized during the recovery period. The observed correlation between VTG and ovarian somatic index (OSI) demonstrates that excessive VTG induction may be predictive for adverse effects of EE2 on ovarian function in female zebrafish. These results indicate that long-term stimulation by synthetic estrogens such as EE2 might impair reproductive function in zebrafish in a reversible manner. [ABSTRACT FROM AUTHOR]