Purpose: Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be... Show morePurpose: Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS), we collected clinical data from patients with a prenatal phenotype and a pathogenic variant in one of the CSS-associated genes. Methods: Clinical data was collected through an extensive web-based survey. Results: We included 44 patients with a variant in a CSS-associated gene and a prenatal phenotype; 9 of these patients have been reported before. Prenatal anomalies that were frequently observed in our cohort include hydrocephalus, agenesis of the corpus callosum, hypoplastic left heart syndrome, persistent left vena cava, diaphragmatic hernia, renal agenesis, and intrauterine growth restriction. Anal anomalies were frequently identified after birth in patients with ARID1A variants (6/14, 43%). Interestingly, pathogenic ARID1A variants were much more frequently identified in the current prenatal cohort (16/44, 36%) than in postnatal CSS cohorts (5%-9%). Conclusion: Our data shed new light on the prenatal phenotype of patients with pathogenic variants in CSS genes. (C) 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved. Show less
The embryonic development of the human cochlea (the organ of hearing) has been investigated for over one hundred years. However, little is still known about the development on a cellular and... Show moreThe embryonic development of the human cochlea (the organ of hearing) has been investigated for over one hundred years. However, little is still known about the development on a cellular and protein level, which is important to better understand etiologies and pathologies of various types of sensorineural hearing loss. Knowledge of the normal gene expression patterns and cell fate specification in the human cochlea has therefore the potential to aid in the development of gene and cell-based therapeutic strategies. For this reason, we acquired a series of human fetal cochlea of different stages of gestation and investigated several aspects of the normal development of the human cochlea such as the hair cells, the spiral ganglion neurons and the stria vascularis. Also, we investigated the neural crest stem cells residing in the hair follicle bulge. We showed that a protein (TUBB3) often used in immunochemistry to detect a neuron is also expressed both in skin and hair follicle melanocytes in humans meaning that the proposed neural crest stem cell residing in the hair follicle bulge might need revision. Show less
Congenital Human Parvovirus B19 (B19V) infection can lead to life threatening fetal complications as hydrops, fetal demise or severe fetal anaemia and thrombocytopenia. Maternal symptoms frequently... Show moreCongenital Human Parvovirus B19 (B19V) infection can lead to life threatening fetal complications as hydrops, fetal demise or severe fetal anaemia and thrombocytopenia. Maternal symptoms frequently pass unnoticed at the time of maternal infection and there was little information on the mechanism and time course of vertical transmission of B19V during gestation. Treatment consists of intrauterine fetal red blood cell and/ or platelet transfusion (IUT). The indication for treatment with IUT is set by performing fetal ultrasound screening for fetal anaemia and signs of fetal hydrops. The fetal middle cerebral artery peak systolic flow correlates well with the severity of fetal anaemia. The first two chapters of this thesis give an overview of the existing literature concerning fetal hydrops and congenital B19V infection. In the ensuing chapters we describe the course of maternal and fetal B19V infection by the B19V viral load and maternal immune response. We did not find a correlation between the fetal or maternal B19V viral load and the severity of fetal anaemia or thrombocytopenia. Thrombocytopenia is frequently encountered in congenital B19V infection, but fetal bleeding complications are not. The use of fetal platelet transfusion is therefore a matter of debate. The long- term neurodevelopment of affected fetus can be significantly delayed at a later age despite a technically correct IUT procedure. The possibility of cerebral damage due to congenital B19V infection is discussed. Parents should be counselled of these risks before the IUT procedure and long term follow -up following congenital B19V infection is advised Show less
