Clinical and genetic heterogeneity of primary ciliopathies (Review)

Abstract

ciliopathies comprise a group of complex disorders, with involvement of the majority of organs and systems. In total, >180 causal genes have been identified and, in addition to Mendelian inheritance, oligogenicity, genetic modifications, epistatic interactions and retrotransposon insertions have all been described when defining the ciliopathic phenotype. It is remarkable how the structural and functional impairment of a single, minuscule organelle may lead to the pathogenesis of highly pleiotropic diseases. Thus, combined efforts have been made to identify the genetic substratum and to determine the pathophysiological mechanism underlying the clinical presentation, in order to diagnose and classify ciliopathies. Yet, predicting the phenotype, given the intricacy of the genetic cause and overlapping clinical characteristics, represents a major challenge. In the future, advances in proteomics, cell biology and model organisms may provide new insights that could remodel the field of ciliopathies. Contents1. Introduction 2. cilium 3. ciliopathies 4. conclusions

A multi-disciplinary, comprehensive approach to management of children with heterotaxy

“…In addition to their non-random association with HTX, these syndromes have a variety of abnormalities not typical for HTX including subtle organ laterality defects, dysmorphic features, congenital anomalies, neurodevelopmental anomalies and predispositions for endocrinologic abnormalities (see Additional file 1 ). Syndromes involving dysfunction of motile and non-motile cilia, or ciliopathies, are the most numerous and best understood of these syndromes [ 28 ]. The vast developmental, sensory and mechanical functions of cilia help explain the heterogeneous and multi-organ manifestations of ciliopathies [ 11 , 23 , 28 ].…”

“…Syndromes involving dysfunction of motile and non-motile cilia, or ciliopathies, are the most numerous and best understood of these syndromes [ 28 ]. The vast developmental, sensory and mechanical functions of cilia help explain the heterogeneous and multi-organ manifestations of ciliopathies [ 11 , 23 , 28 ].…”

“…Brain anomalies are thought to be secondary to impaired motile and non-motile ciliary function in the CNS. Indeed, hydrocephalus and other brain malformations have been reported in patients with PCD [ 101 ] and other ciliopathies [ 28 , 102 ]. In the absence of a clear understanding of the clinical relevance of these abnormalities, screening is not recommended.…”

Golgi Dysfunctions in Ciliopathies

“…Moreover, common clinical features of pathologies involving mutations in cilium-related and Golgi-related genes are observed. Surprisingly, despite a wide range of tissues affected and a high heterogeneity in clinical features, both classes of diseases, respectively referred to as ciliopathies [ 27 ] and Golgipathies [ 28 ], frequently affect the central nervous system, the retina, the skeleton and gonads ( Figure 3 ).…”

Structures and functions of cilia during vertebrate embryo development

“…Work over the last two decades in the fields of genetics, cell and molecular biology, and embryology have linked defects in the formation and/or function of cilia with several congenital multisystem disorders that are referred to as ciliopathies. Ciliopathies present with a broad spectrum of severity, partially overlapping phenotypes, and genetic heterogeneity (Focșa et al, 2021 ; Hildebrandt et al, 2011 ; Horani & Ferkol, 2021 ; Hyland & Brody, 2021 ; Waters & Beales, 2011 ). While several gene mutations that alter cilia are embryonic lethal, a window into the wide‐ranging functions for cilia during vertebrate embryonic development is provided by the breadth of multisystem birth defects associated with ciliopathies.…”