Molecular Diagnostics of Ciliopathies and Insights Into Novel Developments in Diagnosing Rare Diseases

Abstract

The definition of a rare disease in the European Union describes genetic disorders that affect less than 1 in 2,000 people per individual disease; collectively these numbers amount to millions of individuals globally, who usually manifest a rare disease early on in life. At present, there are at least 8,000 known rare conditions, of which only some are clearly molecularly defined. Over the recent years, the use of genetic diagnosis is gaining ground into informing clinical practice, particularly in the field of rare diseases, where diagnosis is difficult. To demonstrate the complexity of genetic diagnosis for rare diseases, we focus on Ciliopathies as an example of a group of rare diseases where an accurate diagnosis has proven a challenge and novel practices driven by scientists are needed to help bridge the gap between clinical and molecular diagnosis. Current diagnostic difficulties lie with the vast multitude of genes associated with Ciliopathies and trouble in distinguishing between Ciliopathies presenting with similar phenotypes. Moreover, Ciliopathies such as Autosomal Recessive Polycystic Kidney Disease (ARPKD) and Meckel-Gruber syndrome (MKS) present with early phenotypes and may require the analysis of samples from foetuses with a suspected Ciliopathy. Advancements in Next Generation Sequencing (NGS) have now enabled assessing a larger number of target genes, to ensure an accurate diagnosis. The aim of this review is to provide an overview of current diagnostic techniques relevant to Ciliopathies and discuss the applications and limitations associated with these techniques.

The hope, hype and obstacles surrounding cell therapy

“…Ciliopathy is a good example of a disease in which a mutated gene is expressed in almost all cells. 81 The first pathological changes can already be observed during embryogenesis. 82 As the organism develops and matures, these changes are both progressive and complex.…”

“…In other cases, pathophysiological changes may begin in the earliest stages of life, leading to irreversible malfunctions. Ciliopathy is a good example of a disease in which a mutated gene is expressed in almost all cells 81 . The first pathological changes can already be observed during embryogenesis 82 .…”

Single-Center Experience of Pediatric Cystic Kidney Disease and Literature Review

“…These are rare disorders caused by abnormalities in the cilia, hair-like cell surface organelles responsible for the execution of many important cellular tasks. Cilia-associated disorders, commonly originating from mutations in the genes involved in cilia structure and function, can impact multiple organs and systems, leading to conditions such as polycystic kidney disease (PKD), Bardet-Biedl syndrome (BBS), nephronophthisis complex (NPHC), and Joubert syndrome (JS), with symptoms encompassing kidney dysfunction, hepatic impairment (e.g., ARPKD), vision problems, developmental delays, intellectual disabilities, and skeletal abnormalities [5,6]. Diagnosing ciliopathies can be particularly challenging due to the significant symptom overlap within the ciliopathy spectrum, the involvement of multiple associated genes, the variation in clinical manifestation, and the unpredictable timing of these diseases' onset [6].…”

Illumination of understudied ciliary kinases

“…Some kinases are localized to cilia, while others are nuclear or located within different organelles, but still impact ciliogenesis (Wirschell et al, 2011;Christensen et al, 2012;Abraham et al, 2022). The many facets of cilia biology, including their evolution, architecture, composition, generation, localization, regulation, and subtype characterization have been extensively described by others (Hildebrandt et al, 2011;Lee and Gleeson, 2011;Christensen et al, 2012;Christensen et al, 2017;Goto et al, 2017;Reiter and Leroux, 2017;Modarage et al, 2022;Arora et al, 2023) and thus will not be the focus of this review. Dysfunctional ciliogenesis and/or aberration of other ciliary signaling pathways can result in human ciliopathies, an emerging class of more than 30 disparate, singlegene, developmental and degenerative disorders characterized by defects in ciliary structure and function (Hildebrandt et al, 2011;Lee and Gleeson, 2011;Goto et al, 2017).…”

“…They can also be pleiotropic disorders, like cerebello-oculo-renal syndrome, Primary Ciliary Dyskinesia (PCD), Bardet-Biedl syndrome, Meckel-Gruber syndrome, orofaciodigital syndrome 1, Joubert syndrome, STAR syndrome, and Jeune asphyxiating thoracic dystrophy (Zaghloul and Katsanis, 2009;Hildebrandt et al, 2011;Lee and Gleeson, 2011;Wirschell et al, 2011;Guen et al, 2016;Goto et al, 2017;Smith et al, 2022;Benmerah et al, 2023). More comprehensive reviews of ciliopathies provide additional details on their inheritance, genetics, clinical symptoms, and other features (Hildebrandt et al, 2011;Lee and Gleeson, 2011;Christensen et al, 2012;Abraham et al, 2022;Modarage et al, 2022). Advances in genomics, proteomics, nextgeneration sequencing, and transcriptomics has led to the identification of disease-causative ciliary gene mutations and allowed for a better understanding of the pathogenesis of these disorders (Lee and Gleeson, 2011;Wirschell et al, 2011;Modarage et al, 2022).…”