Podocytes play an indispensable role in the formation and maintenance of the renal filtration barrier. Podocytopathies are characterized by proteinuria up to the nephrotic range caused by podocyte dysfunction. To date, more than 70 genes have been implicated as monogenic causes of hereditary nephrotic syndrome, clustering into groups that reflect diverse cellular roles, including slit diaphragm-associated genes, cytoskeletal regulators, and matrix components or receptors. Other genes are involved in mitochondrial, vesicular, or nuclear transport and signalling, offering further insights into podocyte (patho)biology. Although genetic podocytopathies frequently present in childhood, they may also manifest later in life, collectively representing a significant cause of chronic kidney disease.
Chromosomal mosaicism is a well-known phenomenon in prenatal cytogenetics and affects approximately 2 % of chorionic villus samples (CVS). The interpretation of mosaicism is challenging, and the major question is whether the abnormal cell line also affects the fetus (true fetal mosaicism, TFM). While mosaicism detected at CVS turns out to be confined to the placenta in the majority of cases, the individual risk of TFM widely varies and needs to be assessed on a case-by-case basis. This article aims to provide an overview on the different types of mosaicism in CVS, the probability of fetal involvement, the laboratory work-up, implications for genetic counselling, and potential effects upon placental function. It is emphasized that understanding placental mosaicism is crucial for the interpretation of results from non-invasive prenatal screening technologies, like NIPT for common aneuploidies, which are based on cell free placental DNA. Finally, we will discuss recent findings of genomic studies which indicate that placental mosaicism extends far beyond classic chromosome aberrations.
For a long time, a comprehensive postmortem examination has been the most important investigation in unexplained fetal and neonatal deaths. In recent years, the usefulness of autopsy has been questioned due to the availability of improved prenatal imaging techniques and genome-wide sequencing that allow an early prenatal diagnosis of an increasing number of disorders. While concordance rates of prenatal ultrasound and postmortem findings are high, fetal autopsy may provide additional information in many cases and allow more accurate counseling of parents regarding the recurrence risk and management in future pregnancies. In this article, we provide a brief outline of a systematic fetal and placental evaluation by pathology and clinical genetics. Based on selected cases, the advantages of a comprehensive postmortem evaluation will be illustrated with emphasis on its role in quality control of prenatal ultrasound after termination of pregnancy, comprehensive and deep phenotyping, the interpretation of genetic variants and its high educational value.
Monozygotic (MZ) twins sharing a placenta are known as monochorionic (MC) and account for approximately two-thirds of MZ twin pregnancies. MC twins discordant for a congenital anomaly are of particular interest as they challenge the common idea of "identical" monozygotic twins. We have performed a retrospective study including 51 monochorionic multiple pregnancies with discordant anomalies that received care at the University Hospital of Graz between 2013 and 2023, aiming to assess the accordance of the observed cases with the existing explanatory models in the literature. This study primarily identified structural discordance, while genetic insights were limited due to the rare decision of parents to undergo further genetic testing. The most frequent anomalies were hydrocephalus, neural tube defects, body-stalk anomaly and congenital heart defects. Acknowledging the limitations related to the sample size and incomplete cohort data, this study supports a growing awareness of the complexity underlying MC twin development, emphasizing the need for more longitudinal genetically and epigenetically focused studies to uncover the subtle and cumulative effects of early contributing factors that ultimately also determine phenotypic expression.
The increasing availability of chromosomal microarray (CMA), exome and genome analysis for prenatal diagnostic testing, together with concerns of potential legal consequences in cases of missed diagnoses, has contributed to substantial uncertainty in prenatal medicine. To support consistent and clinically meaningful use of genetic diagnostics in Austria, the working group for prenatal genetic diagnostics reviewed existing guidelines and recommendations and agreed on a consensus addressing eight key questions arising from clinical practice. Given the limited predictive value of genomic findings in structurally normal fetuses, the working group recommends a strictly phenotype-driven diagnostic approach with CMA, exome and genome analysis to be systematically offered in the presence of fetal pathologies.
Effectively combining prenatal ultrasound and foetal MRI maximizes the diagnostic possibilities in foetal medicine. Foetal MRI offers excellent soft tissue contrast and detailed assessment of the brain, body, and placenta. It is particularly valuable for evaluating CNS anomalies, complex syndromes, pulmonary hypoplasia, and structural abnormalities of the gastrointestinal and urogenital tracts. MRI phenotyping-performed in expert centres-enables detailed structural characterization, supporting genotype-phenotype correlations and refining risk assessment. Foetal MRI is considered safe from 18 weeks of gestation, with emerging research exploring its use earlier in pregnancy. When combined with genetic testing and expert ultrasound, foetal MRI enables a personalised, deep phenotypic evaluation. This integrated approach is essential for accurate prenatal diagnosis, risk stratification, and counselling in the context of complex congenital disorders. Rather than confirming or refuting sonographic diagnoses, MRI can be used more efficiently. Following the motto 'the deeper you go, the more you know', 'MR phenotyping' can be regarded as an important concept in future prenatal medicine.
Prenatal testing for genetic disorders is part of routine clinical practice. Trisomy 21 can now be detected with high sensitivity using non-invasive tests on maternal blood. In cases with other suspected genetic anomalies or structural malformations, invasive testing is required and can be performed with low risk of complications. Genetic analyses such as microarray and trio whole exome sequencing have led to improved diagnostic yield but can also cause uncertainty and difficult counselling situations. Prenatal testing for genetic disorders in the foetus raises ethical and legal questions: Some couples may wish to exercise their 'right not to know', while others might take legal action if a genetic abnormality that could have been diagnosed prenatally and would have justified termination of the pregnancy for the couple is only detected after birth. More recent approaches explore prenatal drug therapies based on specific disease-causing variants.
Autosomal dominant tubulointerstitial kidney disease (ADTKD) constitutes a spectrum of rare, but underdiagnosed renal disorders. ADTKD presents with a bland urinary sediment (no hematuria and little to no proteinuria), usually has no extrarenal manifestations (with the exception of HNF1B-associated disease), and results in a slowly progressive chronic kidney disease. Renal failure typically occurs in the fourth to fifth decade of life. Despite a uniform clinical picture, there is substantial interfamilial- and intrafamilial diversity in progression of CKD sometimes ranging from before the third to beyond the sixth decade of life.ADTKD shows modest genetic heterogeneity, with four main types (UMOD, MUC1, HNF1B, and REN) accounting for the vast majority of cases. However, sometimes ADTKD is used as an umbrella term for a broader number of isolated or syndromal conditions that may present with an ADTKD phenotype. The two most common ADTKD types caused by pathogenic variants in the glycoproteins uromodulin (UMOD), mucin 1 (MUC1), and the enzyme renin (REN) show striking similarities in their molecular pathophysiology and are considered toxic proteinopathies.From a spectrum of kidney disease virtually unknown to the public and to large parts of the medical community before the identification of UMOD as the first identified cause of ADTKD (then termed MCKD2) in 2002, ADTKD is increasingly recognized as a leading genetic cause of kidney disease in adults. The identification of MUC1 as the cause for the second main type has greatly stimulated research on all aspects of ADTKD and unveiled important molecular insights into its underlying pathophsiology. Our molecular knowledge on common ADTKD forms has passed the critical threshold required for developing targeted therapeutic strategies and personalized treatment approaches can be expected in the near future.
Congenital anomalies of the kidney and urinary tract (CAKUT) represent a heterogeneous group of developmental disorders and are the leading cause of pediatric chronic kidney disease worldwide. The phenotypic spectrum is broad, encompassing kidney agenesis, hypodysplasia, multicystic dysplastic kidneys, vesicoureteral reflux, obstructive uropathies, and other malformations affecting the kidneys, ureters, and urethra. Advances in genetics have begun to unravel the molecular pathways underlying these diverse phenotypes, yet the complexity of CAKUT reflects contributions from both monogenic variants and multifactorial causes. This review provides an overview of the current understanding of the genetic causes of CAKUT, beginning with fundamental principles of kidney and urinary tract development, and then focusing on major discoveries in the past ten years. We aim to summarize key genetic findings, with an emphasis on genotype-phenotype correlations and developmental pathways, highlight emerging mechanisms, and discuss their implications for diagnosis, counseling, and clinical management.
Genetic metabolic kidney diseases arise from (likely) pathogenic variants affecting kidney metabolism, causing progressive kidney dysfunction. Symptoms include but are not restricted to nephrolithiasis, proteinuria, kidney failure, and extrarenal manifestations. Genetic testing in combination with metabolic profiling aids early diagnosis and personalized management strategies, which may include enzyme replacement, dietary changes, and kidney-related therapies. Advances in gene therapy and precision medicine offer hope for better outcomes. Early diagnosis and intervention are key to improving prognosis and quality of life, emphasizing the importance of advancing combined metabolic/genetic testing and treatment approaches.
