Ciliopathies in Children: Clinical and Translational Insights

Abstract

The Joubert syndrome (JS), Meckel syndrome (MKS), Bardet-Biedl syndrome (BBS), Alström syndrome (AS), and nephronophthisis (NPH) ciliopathy spectrum could represent one of the major examples for progresses and challenges in pediatric genetics and neurosciences during the last three decades. In fact, advancing in our understanding of these pediatric neurological diseases illustrates many central notions of human genetics. The JS phenotype itself is caused by mutations in at least 40 genes, all encoding critical components associated with the primary cilium. Primary cilia are microtubule-based organelles that play crucial roles in the development and homeostasis of different tissues and organs, within both the central nervous system and also in nearly all other systems. Protruding from the cells, these cellular antennae sense different signals and mediate Hedgehog as well as other important signaling pathways relevant to brain and different organs development and function, such as the Wnt signaling. Importantly, ciliary dysfunction causes several human genetic diseases known as “ciliopathies,” which encompass infantileand childhood-onset syndromes associated with multiple congenital anomalies and broad neurodevelopmental impairment as well as later onset conditions characterized by single-organ failure and less prominent neurological features. Progress of scientific research in the field of the JSMKS-BBS-AS-NPH phenotypic spectrum and its associated molecular mechanisms stimulated extensive functional (cellular and animal) studies that explored the overall crucial role of primary cilia in both humandevelopment and disease. This research shed a new light on the genetic mechanisms underlying the JS-MKS-BBS-AS-NPH spectrum in affected individuals carrying pathogenic mutations in central ciliarelated genes. This also allowed the identification of potentially promising etiologically targeted therapies across the different genetic causes, as well as the generation of a ranges of precision medicine approaches in the field of pediatric ciliopathies. In this special issue, clinicians and scientists from different universities and teaching hospitals contributed a number of original articles and in-depth reviews covering many aspects of the clinical assessment, associated genetic and molecular mechanisms, therapeutic management, and prevention and treatment of ciliopathies and ciliarelated neurodevelopmental conditions in children. In fact, a multidisciplinary approach to ciliopathies across different medical specialties is now essential. Pediatricians, neurologists, geneticists, nephrologists, and ophthalmologists all have valuable roles in clinically assessing and managing children diagnosed with ciliopathies and associated developmental diseases. In the last three decades, the primary cilium was considered to be a vestigial organelle, and ciliopathies were not considered as a coherent group of phenotypically and genetically distinct diseases. Thus, important progresses in Mendelian human genomics, imaging, and basic science (based on cell and developmental biology) all have a great impact on our understanding of the JS-MKS-BBS-AS-NPH spectrum. This allows us now to provide a precise diagnosis to most affected children, thus improving both prognosis and prevention based on carrier testing as well as prenatal diagnosis. Thus, advances in magnetic resonance imaging and nextgeneration sequencing(NGS) technologies are at the forefront in enabling more effective and timely diagnoses of