# Ciliopathy

A ciliopathy is any genetic disorder that affects the cellular cilia or the cilia anchoring structures, the basal bodies, or ciliary function. Primary cilia are important in guiding the process of development, so abnormal ciliary function while an embryo is developing can lead to a set of malformations that can occur regardless of the particular genetic problem. The similarity of the clinical features of these developmental disorders means that they form a recognizable cluster of syndromes, loosely attributed to abnormal ciliary function and hence called ciliopathies. Regardless of the actual genetic cause, it is clustering of a set of characteristic physiological features which define whether a syndrome is a ciliopathy.
Although ciliopathies are usually considered to involve proteins that localize to motile and/or immotile (primary) cilia or centrosomes, it is possible for ciliopathies to be associated with unexpected proteins such as XPNPEP3, which localizes to mitochondria but is believed to affect ciliary function through proteolytic cleavage of ciliary proteins.
Significant advances in understanding the importance of cilia were made in the mid-1990s. For example, the discovery of the role of cilia in embryonic development, identification of ciliary defects in genetic disorders such as Polycystic kidney disease, Bardet–Biedl syndrome and Primary ciliary dyskinesia. However, the physiological role that this organelle plays in most tissues remains elusive. Additional studies of how ciliary dysfunction can lead to such severe disease and developmental pathologies is still a subject of current research.

## Signs and symptoms

A wide variety of symptoms are potential clinical features of ciliopathy. The signs most exclusive to a ciliopathy, in descending order of exclusivity, are:$^{:138}$
* Dandy–Walker malformation (cerebellar vermis hypoplasia, usually with hydrocephalus)
* Agenesis of the corpus callosum
* Situs inversus
* Posterior encephalocele
* Polycystic kidneys
* Postaxial polydactyly
* Liver disease
* Retinitis pigmentosa
* Intellectual disability
A case with polycystic ovary syndrome, multiple subcutaneous cysts, renal function impairment, Caroli disease and liver cirrhosis due to ciliopathy has been described.
Phenotypes sometimes associated with ciliopathies can include:
* Anencephaly
* Breathing abnormalities
* Cerebellar vermis hypoplasia
* Diabetes
* Exencephaly
* Eye movement abnormalities
* Hydrocephalus
* Hypoplasia of the corpus callosum
* Hypotonia
* Infertility
* Cognitive impairment/defects
* Obesity
* Other polydactyly
* Respiratory dysfunction
* Renal cystic disease
* Retinal degeneration
* Sensorineural deafness
* Spina bifida

## Pathophysiology

"In effect, the motile cilium is a nanomachine composed of perhaps over 600 proteins in molecular complexes, many of which also function independently as nanomachines." Cilia "function as mechano- or chemosensors and as a cellular global positioning system to detect changes in the surrounding environment." For example, ciliary signaling plays a role in the initiation of cellular replacement after cell damage.
In addition to this sensory role mediating specific signaling cues, cilia play "a secretory role in which a soluble protein is released to have an effect downstream of the fluid flow" in epithelial cells, and can of course mediate fluid flow directly in the case of motile cilia. Primary cilia in the retina play a role in transferring nourishment to the non-vascularized rod and cone cells from the pigment epithelial vascularized cells several micrometres behind the surface of the retina.
Signal transduction pathways involved include the Hedgehog signaling pathway and the Wnt signaling pathway.
Dysfunctional cilia can lead to:
* Chemosensation abnormalities, typically via ciliated epithelial cellular dysfunction.
* Defective thermosensation or mechanosensation, often via ciliated epithelial cellular dysfunction.
* Cellular motility dysfunction
* Issues with displacement of extracellular fluid
* Paracrine signal transduction abnormalities
In organisms of normal health, cilia are critical for:
* development
* homeostasis
* reproduction

## Genetics

"Just as different genes can contribute to similar diseases, so the same genes and families of genes can play a part in a range of different diseases." For example, in just two of the diseases caused by malfunctioning cilia, Meckel–Gruber syndrome and Bardet–Biedl syndrome, patients who carry mutations in genes associated with both diseases "have unique symptoms that are not seen in either condition alone." The genes linked to the two different conditions "interact with each other during development." Systems biologists are endeavoring to define functional modules containing multiple genes and then look at disorders whose phenotypes fit into such modules.
A particular phenotype can overlap "considerably with several conditions (ciliopathies) in which primary cilia are also implicated in pathogenicity. One emerging aspect is the wide spectrum of ciliopathy gene mutations found within different diseases."
Additionally, clinical presentations of patients with identical mutation can differ, suggesting the role of genetic modifiers.
As of 2017, 187 ciliopathy associated genes have been confirmed, while the roles of further 241 candidate genes are still being investigated.
A common way to identify ciliopathies such as ADPKD and ARPKD which have known genetic causes, is through linkage analysis direct mutation screening. Other techniques, such as gene panels and whole-exome sequencing and whole genome sequencing can also be used to provide distinct advantages. Gene panels analyse specific sets of genes and can be more comprehensive than single gene or direct mutation screening. Whole-exome/genome sequencing can screen for heterozygous carriers, and detect novel/rare variations.
Mutations in the PKD1 and PKD2 genes which encode for polycystin-1 and polycistin-2 respectively are known to be causes of ADPKD, a ciliopathy that presents with the formation and growth of cysts in the kidneys, leading to renal failure.

## List of ciliopathies

"The phenotypic parameters that define a ciliopathy may be used to both recognize the cellular basis of a number of genetic disorders and to facilitate the diagnosis and treatment of some diseases of unknown" cause.

### Known ciliopathies

| Condition | OMIM | Gene(s) | Systems/organs affected |
| Alström syndrome | 203800 | ALMS1 | |
| Asphyxiating thoracic dysplasia (Jeune syndrome) | 208500 | | |
| Bardet–Biedl syndrome | 209900 | BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12 | |
| Ellis–van Creveld syndrome | 225500 | EVC, EVC2 | |
| Joubert syndrome | 213300 | INPP5E, TMEM216, AHI1, NPHP1, CEP290, TMEM67, RPGRIP1L, ARL13B, CC2D2A, BRCC3 | Brain |
| Leber congenital amaurosis | 204000 | GUCY2D, RPE65 | |
| McKusick–Kaufman syndrome | 236700 | MKKS | |
| Meckel–Gruber syndrome | 249000 | MKS1, TMEM67, TMEM216, CEP290, RPGRIP1L, CC2D2A | Liver, heart, bone |
| Nephronophthisis | 256100 | NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, GLIS2, RPGRIP1L | Kidney |
| Orofaciodigital syndrome 1 | 311200 | OFD1 | |
| Polycystic kidney disease (ADPKD and ARPKD) | 173900 | PKD1, PKD2, PKHD1 | Kidney |
| Primary ciliary dyskinesia (Kartagener syndrome) | 244400 | DNAI1, DNAH5, TXNDC3, DNAH11, DNAI2, KTU, RSPH4A, RSPH9, LRRC50 | |
| Senior–Løken syndrome | 266900 | NPHP1, NPHP4, IQCB1, CEP290, SDCCAG8 | Eye |
| Sensenbrenner syndrome (cranioectodermal dysplasia) | 218330 | IFT122 | |
| Short rib–polydactyly syndrome | 613091 | DYNC2H1 | |
| ? | ? | IFT88 | Novel form of congenital anosmia, reported in 2012 |

### Likely ciliopathies

| Condition | OMIM | Gene(s) |
| Acrocallosal syndrome | 200990 | KIF7, GLI3 |
| Acromelic frontonasal dysostosis | 603671 | ZSWIM6 |
| Arima syndrome | 243910 | |
| Biemond syndrome | 113400 | |
| COACH syndrome | 216360 | TMEM67, CC2D2A, RPGRIP1L |
| Conorenal syndrome | 266920 | |
| Greig cephalopolysyndactyly syndrome | 175700 | GLI3 |
| Hydrolethalus syndrome | 236680 | HYLS1 |
| Johanson–Blizzard syndrome | 243800 | UBR1 |
| Mohr syndrome (oral-facial-digital syndrome type 2) | 252100 | |
| Neu–Laxova syndrome | 256520 | PHGDH, PSAT1, PSPH |
| Opitz G/BBB syndrome | 300000 | MID1 |
| Pallister–Hall syndrome | 146510 | GLI3 |
| Papillorenal syndrome | 120330 | PAX2 |
| Renal–hepatic–pancreatic dysplasia | 208540 | NPHP3 |
| Varadi–Papp syndrome (oral-facial-digital syndrome type 6) | 277170 | |

### Possible ciliopathies

| Condition | OMIM | Gene(s) |
| Acrofacial dysostosis | | |
| Acrofrontofacionasal dysostosis 2 | 239710 | |
| Adams–Oliver syndrome | 100300 | ARHGAP31, DOCK6, RBPJ, EOGT, NOTCH1, DLL4 |
| Asplenia with cardiovascular anomalies (Ivemark syndrome) | 208530 | |
| Autosomal recessive spastic paraplegia | | |
| Barakat syndrome (HDR syndrome) | 146255 | GATA3 |
| Basal cell nevus syndrome | 109400 | PTCH1, PTCH2, SUFU |
| Branchio‐oculo‐facial syndrome | 113620 | TFAP2A |
| C syndrome (Opitz trigonocephaly) | 211750 | CD96 |
| Carpenter syndrome | 201000 | RAB23 |
| Cephaloskeletal dysplasia (microcephalic osteodysplastic primordial dwarfism type 1) | 210710 | RNU4ATAC |
| Cerebrofaciothoracic dysplasia | 213980 | TMCO1 |
| Cerebrofrontofacial syndrome (Baraitser–Winter syndrome) | 243310 | ACTB |
| Cerebrooculonasal syndrome | 605627 | |
| Autosomal recessive spastic ataxia of Charlevoix-Saguenay | 270550 | SACS |
| Chondrodysplasia punctata 2 | 302960 | EBP |
| Choroideremia | 303100 | CHM |
| Chudley–McCullough syndrome | 604213 | GPSM2 |
| C‐like syndrome | 605039 | ASXL1 |
| Coffin–Siris syndrome | 135900 | ARID1B, SOX11, ARID2 |
| Cohen syndrome | 216550 | VPS13B |
| Craniofrontonasal dysplasia | 304110 | EFNB1 |
| Dysgnathia complex | 202650 | |
| Ectrodactyly–ectodermal dysplasia–cleft syndrome type 1 | 129900 | |
| Endocrine–cerebroosteodysplasia syndrome | 612651 | ICK |
| Focal dermal hypoplasia | 305600 | PORCN |
| Frontonasal dysplasia | 136760 | ALX3, ALX4, ALX1 |
| Fryns microphthalmia syndrome | 600776 | |
| Fryns syndrome | 229850 | |
| Genitopatellar syndrome | 606170 | KAT6B |
| Hemifacial microsomia | 164210 | |
| Hypothalamic hamartomas | 241800 | |
| Johnson neuroectodermal syndrome | 147770 | |
| Juvenile myoclonic epilepsy | 254770 | |
| Kabuki syndrome | 147920 | KMT2D, KDM6A |
| Kallmann syndrome | 308700 | ANOS1 |
| Lenz–Majewski hyperostotic dwarfism | 151050 | PTDSS1 |
| Lissencephaly 3 | 611603 | TUBA1A |
| Marden–Walker syndrome | 248700 | PIEZO2 |
| MASA syndrome | 303350 | L1CAM |
| Microhydranencephaly | 605013 | NDE1 |
| Mowat–Wilson syndrome | 235730 | ZEB2 |
| NDH syndrome | 610199 | GLIS3 |
| Oculoauriculofrontonasal syndrome | 601452 | |
| Oculocerebrocutaneous syndrome | 164180 | |
| Oculodentodigital dysplasia | 164200 | GJA1 |
| Optiz–Kaveggia syndrome | 305450 | MED12 |
| Otopalatodigital syndrome 2 | 304120 | FLNA |
| Periventricular heterotopia X‐linked | 300049 | FLNA |
| Perlman syndrome | 267000 | DIS3L2 |
| Pitt–Hopkins syndrome | 610954 | TCF4 |
| Polycystic liver disease | 174050 | |
| Proteus syndrome | 176920 | AKT1 |
| Pseudotrisomy 13 | 264480 | |
| Retinal cone dystrophy 1 | 180020 | |
| Some forms of retinitis pigmentosa | 268000 | |
| Robinow syndrome | 268310 | ROR2 |
| Rubinstein–Taybi syndrome | 180849 | CREBBP |
| Sakoda complex | 610871 | |
| Schinzel–Giedion syndrome | 269150 | SETBP1 |
| Split-hand/foot malformation 3 | 246560 | |
| Spondyloepiphyseal dysplasia congenita | 183900 | COL2A1 |
| Thanatophoric dysplasia | 187600 | FGFR3 |
| Townes–Brocks syndrome | 107480 | SALL1, DACT1 |
| Tuberous sclerosis | 191100 | TSC1, TSC2 |
| VATER association | 192350 | |
| Ven den Ende–Gupta syndrome | 600920 | SCARF2 |
| Visceral heterotaxy | 606325 | |
| Walker–Warburg syndrome | 236670 | |
| Warburg Micro syndrome | 615663 | RAB3GAP1 |
| X‐linked congenital hydrocephalus | 307000 | L1CAM |
| X‐linked lissencephaly | 300067 | DCX |
| Young–Simpson syndrome | 603736 | KAT6B |

## History

In 1674–1677, the Dutch scientist Antonie van Leeuwenhoek changed humanity's perspective on the world with his discovery of "animalcules" in rainwater, along with their tiny appendages known as cilia today. It was marked as the first recorded observation of single-celled organisms and their locomotive structures.
In the late 19th century, Karl Ernst von Baer's groundbreaking work in embryonic development laid the foundation for modern developmental biology. Through meticulous observations, von Baer provided invaluable insights into tissue and organ formation during development, including the early stages of embryogenesis and the development of cilia-bearing tissues. While von Baer may not have fully appreciated the significance of cilia at the time, his observations likely included their presence in embryonic tissues. Cilia - crucial for cell signaling, tissue development, and left-right asymmetry, are now recognized as ancient organelles with essential roles in development. Von Baer's concept of embryonic recapitulation, despite refinement, underscores the evolutionary conservation of developmental processes, including ciliary function. Today, von Baer's legacy inspires ongoing research into embryology and developmental biology, particularly in understanding ciliary biology and its relevance to ciliopathies, where defects in ciliary structure or function lead to developmental disorder.
Although non-motile or primary cilia were first described in 1898, they were largely ignored by biologists. However, microscopists continued to document their presence in the cells of most vertebrate organisms. The primary cilium was long considered—with few exceptions—to be a largely useless evolutionary vestige, a vestigial organelle. Recent research has revealed that cilia are essential to many of the body's organs. These primary cilia play important roles in chemosensation, mechanosensation, and thermosensation. Cilia may thus be "viewed as sensory cellular antennae that coordinate a large number of cellular signaling pathways, sometimes coupling the signaling to ciliary motility or alternatively to cell division and differentiation."
Recent advances in mammalian genetic research have made possible the understanding of a molecular basis for a number of dysfunctional mechanisms in both motile and primary cilia structures of the cell. A number of critical developmental signaling pathways essential to cellular development have been discovered. These are principally but not exclusively found in the non-motile or primary cilia. A number of common observable characteristics of mammalian genetic disorders and diseases are caused by ciliary dysgenesis and dysfunction. Once identified, these characteristics thus describe a set of hallmarks of a ciliopathy.
Cilia have recently been implicated in a wide variety of human genetic diseases by "the discovery that numerous proteins involved in mammalian disease localize to the basal bodies and cilia." For example, in just a single area of human disease physiology, cystic renal disease, cilia-related genes and proteins have been identified to have causal effect in polycystic kidney disease, nephronophthisis, Senior–Løken syndrome type 5, orofaciodigital syndrome type 1 and Bardet–Biedl syndrome.