Discovery, Diagnosis, and Etiology of Craniofacial Ciliopathies
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Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Discovery, Diagnosis, and Etiology of Craniofacial Ciliopathies Elizabeth N. Schock and Samantha A. Brugmann Division of Plastic Surgery, Department of Surgery, and Division of Developmental Biology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229 Correspondence: [email protected] Seventy-five percent of congenital disorders present with some form of craniofacial malfor- mation. The frequency and severity of these malformations makes understanding the etio- logical basis crucial for diagnosis and treatment. A significant link between craniofacial malformations and primary cilia arose several years ago with the determination that 30% of ciliopathies could be primarily defined by their craniofacial phenotype. The link between the cilium and the face has proven significant, as several new “craniofacial cili- opathies” have recently been diagnosed. Herein, we reevaluate public disease databases, report several new craniofacial ciliopathies, and propose several “predicted” craniofacial ciliopathies. Furthermore, we discuss why the craniofacial complex is so sensitive to cilio- pathic dysfunction, addressing tissue-specific functions of the cilium as well as its role in signal transduction relevant to craniofacial development. As a whole, these analyses suggest a characteristic facial phenotype associated with craniofacial ciliopathies that can perhaps be used for rapid discovery and diagnosis of similar disorders in the future. n 2009, Baker and Beales published a review niofacial phenotype, which included cleft lip/ Icharacterizing human ciliopathies. This work palate, increased/decreased midfacial width detailed known, likely, and possible ciliopathies (hyper-/hypotelorism), small lower jaw (mi- based on the presentation of nine core pheno- crognathia), and prematurely fused cranial su- typic features: retinitis pigmentosa, polydactyly, tures (craniosynostosis) (Zaghloul and Brug- situs inversus, mental retardation, agenesis of mann 2011). the corpus callosum, Dandy–Walker malfor- Much has been learned about ciliopathies in mation, posterior encephalocele, renal cystic the last 5 years. In this review, we reexamine disease, and hepatic disease. Using these core what is known regarding craniofacial ciliopa- characteristics, they identified 15 known cilio- thies, those ciliopathies defined by their cranio- pathies and 88 potential ciliopathies (Baker and facial phenotype. To do so, we modified the Beales 2009). Two years later, we analyzed the original search methods used by Baker and ciliopathies put forth by Baker and Beales and Beales. We searched the Online Mendelian In- determined that 30% of known or proposed heritance in Man (OMIM) database for any dis- ciliopathies were primarily defined by their cra- ease that met two requirements: presentation of Editors: Wallace Marshall and Renata Basto Additional Perspectives on Cilia available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a028258 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a028258 1 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press E.N. Schock and S.A. Brugmann one of the ciliopathic craniofacial phenotypes by phenotypes associated with the brain: agen- (cleft lip/palate, hyper-/hypotelorism, micro- esis of the corpus callosum, Dandy–Walker gnathia, or craniosynostosis) and presentation malformation, posterior encephalocele, and of two core ciliopathic phenotypes (excluding mental retardation. renal cystic disease and hepatic disease) (Table In addition to our list of “known” craniofa- 1). We excluded searches for “cleft lip/palate cial ciliopathies, we also used our analyses to AND mental retardation” and “hypertelorism generate a list of “predicted” craniofacial cili- AND mental retardation” because these search- opathies, disorders that meet the phenotypic es resulted in exceedingly large lists that are like- criteria, yet do not have a known genetic cause ly not specific to ciliopathies. In total, we iden- linked to the structure or function of the prima- tified more than 400 possible ciliopathies using ry cilia. We identified 25 predicted craniofacial this unbiased method. We then manually in- ciliopathies (Table 3). Of the 25 disorders, 13 spected this list of diseases and excluded any were previously predicted (Baker and Beales syndrome caused by large-scale chromosomal 2009), whereas the remaining 12 were newly duplication, deletion, or rearrangements, as a classified as predicted craniofacial ciliopathies. specific genetic etiology would be difficult to Many of these diseases share a striking pheno- determine. The genetic cause of the remaining typic resemblance with known craniofacial cil- diseases, if known, was examined and lists of iopathies, presenting with severe micrognathia, known and predicted ciliopathies were generat- hypertelorism, and cleft lip/palate. ed based on gene function (Tables 2 and 3). Unlike Baker and Beales, who included tran- scription factors thought to be downstream tar- Why Is the Craniofacial Complex So Sensitive gets of ciliary signaling, we did not include to Ciliary Dysfunction? these, as ciliary function is not dependent on these genes. Primary cilia are ubiquitous organelles that Our search identified 26 known ciliopathies are present on almost every cell type through- defined by craniofacial phenotypes (Table 2). out development, yet the phenotypes of cili- Weconfirmed 20 previously known craniofacial opathies are not identical and can be confined ciliopathies and reclassified five craniofacial cil- to individual organ systems. The craniofacial iopathies formerly categorized by Baker and complex is the primary organ system affected Beales as “likely” ciliopathies. Furthermore, in almost 30% of ciliopathies. This metric our analysis identified one new craniofacial cili- begs the question—what makes the face so opathy, Hydrolethalus syndrome 2, not previ- sensitive to ciliary dysfunction? There are per- ously reported in any search. Within our updat- haps two main reasons the face is so sensitive ed list of known ciliopathies, we found that cleft to defects in the primary cilium. First, the lip/palate was the most common craniofacial face is formed by intricate tissue–tissue inter- phenotype (Fig. 1A,B), followed by hypertelor- actions between cranial neural crest cells ism (Fig. 1C), micrognathia (Fig. 1D), cranio- (CNCCs), neuroectoderm, facial ectoderm, synostosis (Fig. 1E), and hypotelorism (Fig. and pharyngeal endoderm. Thus, if any one 1C). Interestingly, the most prevalent craniofa- of these tissues requires ciliary function for cial phenotypes were directly associated either proper development, the face, as a whole, widening or deficiencies of the midface (cleft will be negatively impacted. Second, several lip/palate, hypertelorism, micrognathia). Fi- of the signaling pathways essential for proper nally, we cross-referenced our list of 26 known craniofacial patterning require the cilium for craniofacial ciliopathies against the seven core signal transduction. In the following sections, ciliopathic phenotypes. This analysis revealed we will explain the tissues and signaling path- that, within craniofacial ciliopathies, polydacty- ways required for craniofacial development. ly most commonly presented in combination Furthermore, we will comment on how ciliary with craniofacial phenotypes (Fig. 1F), followed defects can impact facial development. 2 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a028258 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Craniofacial Ciliopathies Table 1. Pairwise combinations of phenotypes Cleft lip and/or palate Hypertelorism Hypotelorism Micrognathia Craniosynostosis Retinitis pigmentosa þ 12 34 5 polydactyly Retinitis pigmentosa þ mental 6a 7a 8910 retardation Retinitis pigmentosa þ situs 11 12 13 14 15 inversus Retinitis pigmentosa þ 16 17 18 19 20 agenesis of corpus callosum Retinitis pigmentosa þ 21 22 23 24 25 Dandy–Walker malformation Retinitis pigmentosa þ 26 27 28 29 30 posterior encephalocele Polydactyly þ mental 31a 32a 33 34 35 retardation Polydactyly þ situs inversus 36 37 38 39 40 Polydactyly þ agenesis of 41 42 43 44 45 corpus callosum Polydactyly þ Dandy–Walker 46 47 48 49 50 malformation Polydactyly þ posterior 51 52 53 54 55 encephalocele Mental retardation þ situs 56a 57a 58 59 60 inversus Mental retardation þ agenesis 61a 62a 63 64 64 of corpus callosum Mental retardation þ Dandy– 66a 67a 68 69 70 Walker malformation Mental retardation þ 71a 72a 73 74 75 posterior encephalocele Situs inversus þ agenesis of 76 77 78 79 80 corpus callosum Situs inversus þ Dandy– 81 82 83 84 85 Walker malformation Situs inversus þ posterior 86 87 88 89 90 encephalocele Agenesis of corpus callosum þ 91 92 93 94 95 Dandy–Walker malformation Agenesis of corpus callosum þ 96 97 98 99 100 posterior encephalocele Dandy–Walker malformation 101 102 103 104 105 þ posterior encephalocele aThese comparisons could not be evaluated because initial searches for “cleft lip and/or palate AND mental retardation” and “hypertelorism AND mental retardation” were not completed. 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