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Bardet−Biedl Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Molecular genetic testing of BBS gene mutations (e.g., BBS1 p.M390R, BBS2 p.Y24X, BBS2 p.R275X, BBS10 c.91fsX5) provides a useful means of confirming the diagnosis in about 80% of cases, especially for young patients who do not show/develop sufficient symptoms to meet the diagnostic criteria [34]. For instance, although retinal degeneration (rod-cone dystrophy) occurs in 93% of cases, it does not usually appear until 8 years of age. Common genetic screening strategies for BBS include (i) SNP arrays for homozygosity mapping and gene-targeted deletion/duplication analysis for intragenic or single exon deletions or duplications (using quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification, and gene-targeted microarray), (ii) direct sequencing for BBS gene mutations (small intragenic deletions/insertions; missense, nonsense, and splice site variants), and (iii) next-generation sequencing (NGS) for screening all ciliopathy genes (e.g., BBS, nephronophthisis genes, ALMS1 gene, CCDC28B gene) and identifying the modifiers/epistatic effect of other genes [35,36]. The available data indicates that pathogenic variants responsible for BBS are mostly commonly detected in BBS1 (23.2%), BBS10 (20%), BBS2 (8.1%), BBS9 (6.0%), BBS6 (5.8%), BBS12 (5%), BBS13 (4.5%), BBS4 (2.3%), BBS7 (1.5%), and BBS8 (1.2%).
Genetics
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Jane A. Hurst, Richard H. Scott
Biallelic (recessive) loss of function mutations occurs in one of the more than 14 currently known Bardet–Biedl syndrome (BBS) genes. In some cases there is evidence of modification of the phenotype by the presence of an additional mutation in a second BBS gene. BBS is a ‘ciliopathy’ and BBS genes are important in the function of cilia.
Recording Ion Channels in Cilia Membranes
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Leo C.T. Ng, Amitabha Mukhopadhyay, Thuy N. Vien, Paul G. DeCaen
This section is a short primer on ciliopathy diseases. For those interested in a more in-depth review of ciliopathies and their disease mechanisms, we suggest reading reviews by Bisgrove and Yost26 and Oh and Katsanis.27 The importance of the primary cilia in human health is highlighted by more than 35 congenital diseases called “ciliopathies,” which impact the development of organ systems such as the kidney, brain, heart, and eye. While some defects may only affect one single organ, the majority impact multiple organs with a combination of common ciliopathic phenotypes. For example, Joubert syndrome and Joubert-related disorders are caused by variants in the genes encoding for cilia assembly components—such as centrosomal CEP120 and BBS proteins, and the ciliary GTPase ARL13B.28 These syndromic diseases primarily impact the development of the central nervous system but also have comorbidities which affect the renal and visual systems. In addition, dynein complexes are required for the coordinated and rhythmic motion of motile cilia and variants in these components result in impaired or immotile ciliary syndromes. For example, primary ciliary dyskinesis (PCD) is characterized by chronic respiratory tract infections and infertility because the cilia of airway epithelia and the sperm flagellum are immotile.29 Hydrocephalus is a common comorbidity in PCD patients. Here, the beating of motile ependymal cilia is uncoordinated, resulting in an accumulation of cerebrospinal fluid in the ventricles of the brain. Developmental defects are common among individuals with ciliopathies—such as polydactyly (extra digits on hands and toes) and situs inversus or totalis (incorrect positioning of body organs).27 However, the most common comorbidities shared by ciliopathies are polycystic kidney disease (PKD) and other renal defects but the reason for this is not known.30 The most prevalent form of PKD is the autosomal dominant form (ADPKD), a ciliopathy which is caused by gene variants in PKD1 and PKD2—which encode for two cilia-specific proteins polycystin-1 and polycystin-2, respectively.29 ADPKD a common monogenetic disorder (∼1:2000 people) characterized by kidney and liver cysts in adulthood. Embryonic knockout of both alleles of either PKD1 or PKD2 in mice causes renal disease in utero and results in embryonic death.31,32 Homozygous ablation of either gene in mature mice results in progressive kidney cyst formation and recapitulates the ADPKD phenotype found in humans.33,34 Importantly, gene variants which encode for downstream effectors of Ca2+ ciliary signaling are responsible for ciliopathies that share renal comorbidities. Thus, the significance of determining polycystin channel function and the impact of disease-causing variants will likely extend to other renal ciliopathies where localized ciliary Ca2+ dysregulation might be a shared disease-causing mechanism35,36 The ciliary patch clamp configurations discussed in Section 3.3 provides a direct measurement of cilia-localized ion channel biophysics in native and heterologous expression systems.
Renal ciliopathies: promising drug targets and prospects for clinical trials
Published in Expert Opinion on Therapeutic Targets, 2023
Laura Devlin, Praveen Dhondurao Sudhindar, John A. Sayer
Primary ciliopathies are a group of rare genetic multi-system syndromes, caused by defects in the maintenance, biogenesis or functioning of the primary cilium. Primary ciliopathies are classified further into disease syndromes with defined clinical presentations, but they often have genetic and phenotypic overlaps. There are over 35 ciliopathy syndromes with an estimated grouped incidence of 1 in 1,000 people, with over 180 known primary ciliopathy genes, but approximately 50% of ciliopathy cases remain genetically unsolved [1,35,37–39]. Also, primary ciliopathy genes have high pleiotropy, making it difficult for clear diagnosis, prognosis, and appropriate disease management based upon genotype alone. It might be that as the number of ciliary genes increases and syndromes overlap further, ciliopathies will become a continuum of disorders rather than the current system of discrete syndromes [38].
A Stargardt disease-like phenotype in GAS8-related primary ciliary dyskinesia
Published in Ophthalmic Genetics, 2022
Although the features of non-motile ciliopathy and primary ciliary dyskinesia are typically distinct, there is evidence for overlap. In this case of GAS8-related primary ciliary dyskinesia (and in another similar case (6)), retinal dystrophy resembling Stargardt disease occurred. Patients with CEP290-related early-onset retinal dystrophy, a non-motile ciliopathy, can have defective respiratory cilia. (10) Patients with autosomal dominant polycystic kidney disease, a non-motile ciliopathy, can show radiographic bronchiectasis. (11) Some patients with RPGR-related retinal dystrophy, a non-motile ciliopathy, also show a primary ciliary dyskinesia phenotype. (12) Careful phenotyping and longer follow-ups may reveal additional examples of feature overlap between non-motile ciliopathy and primary ciliary dyskinesia.
Short-rib polydactyly syndrome presenting with recurrent severe first-trimester phenotypes: the utility of exome sequencing in deciphering variants of DYNC2H1 gene
Published in Journal of Obstetrics and Gynaecology, 2020
Yi He, Yu-Juan Li, Li-Li Xu, Dong-Zhi Li
Ciliopathies form a group of heterogeneous congenital disorders mechanistically caused by an underlying dysfunction of the primary cilium. The number of reported ciliopathies is increasing, as is the number of established and candidate ciliopathy-associated genes (Reiter and Leroux 2017). Among the skeletal ciliopathies, the short-rib polydactyly syndrome (SPRS) subtypes are the most severe and are incompatible with postnatal life. In addition to skeletal abnormalities including a small rib cage, shortening of the long bones and polydactyly, SPRS may also manifest extraskeletal phenotypes including polycystic kidney disease, retinal degeneration, and cardiac, liver and brain anomalies. SPRS can be diagnosed prenatally by ultrasound. However, most diagnoses are made during the second-trimester ultrasound (Yamada et al. 2011). In this study, the authors report a family with recurrent SPRS identified by first trimester ultrasound and confirmed by exome sequencing (ES).