Ciliopathies: Genetics in Pediatric Medicine

Abstract

Ciliary disorders, which are also referred to as ciliopathies, are a group of hereditary disorders that result from dysfunctional cilia. The latter are cellular organelles that stick up from the apical plasma membrane. Cilia have important roles in signal transduction and facilitate communications between cells and their surroundings. Ciliary disruption can result in a wide variety of clinically and genetically heterogeneous disorders with overlapping phenotypes. Because cilia occur widespread in our bodies many organs and sensory systems can be affected when they are dysfunctional. Ciliary disorders may be isolated or syndromic, and common features are cystic liver and/or kidney disease, blindness, neural tube defects, brain anomalies and intellectual disability, skeletal abnormalities ranging from polydactyly to abnormally short ribs and limbs, ectodermal defects, obesity, situs inversus, infertility, and recurrent respiratory tract infections. In this review, we summarize the features, frequency, morbidity, and mortality of each of the different ciliopathies that occur in pediatrics. The importance of genetics and the occurrence of genotype-phenotype correlations are indicated, and advances in gene identification are discussed. The use of next-generation sequencing by which a gene panel or all genes can be screened in a single experiment is highlighted as this technology significantly lowered costs and time of the mutation detection process in the past. We discuss the challenges of this new technology and briefly touch upon the use of whole-exome sequencing as a diagnostic test for ciliary disorders. Finally, a perspective on the future of genetics in the context of ciliary disorders is provided.

Keywords: cilia; ciliopathy; diagnostics; genotype-phenotype; next-generation sequencing.

Fig. 1

Schematic structure of motile and immotile cilia. Cilia are composed of a basal body and a ciliary axoneme that protrudes from the apical plasma membrane. These two structures are linked via the transition zone (TZ) that consists of three compartments, that is, a base and two compartments filling the space between the microtubules and the axonemal membrane, which are thought to act as a diffusion barrier for regulation of ciliogenesis and signaling. Cilia contain microtubule skeletons that are composed of nine microtubule doublets that organize in a ring. A central microtubule pair is usually also present in motile cilia but not in immotile cilia. Inner and outer dynein arms, radial spokes, and nexin links are also solely present in motile cilia and actively regulate ciliary movement. During this process, dynein heavy chains of one doublet slide against microtubules of a neighboring doublet, thereby orchestrating the beating of the cilium in an ATP-dependent fashion. In both cilium types, the ciliary microtubules also function as rails for intraflagellar transport (IFT) trains that control bidirectional ciliary transport. During this process, IFT-B particles are associated with kinesin-2 motors and regulate transportation of cargo from the ciliary base to the tip, while IFT-A particles and ciliary dynein motors transport cargo in the opposite direction.

Fig. 2

Phenotypic features of ciliopathies. The following features are commonly seen in ciliopathies. ( A ) Distinctive cerebellar and brain stem malformation that is known as the “molar tooth sign” in a JBTS patient. Open and filled arrowheads point out a deepened interpeduncular fossa and elongated superior cerebellar peduncles, respectively. ( B–D ) MKS fetus at the 14th week of gestation showing swollen stomach due to enlarged kidneys (B), occipital encephalocele (C), and polydactyly of hands (B) and feet (D). ( E ) Radiograph of an SRTD fetus displaying a short and narrow thorax, horizontally oriented ribs, short tubular bones with smooth ends, short and ovoid tibiae, and postaxial polysyndactyly. ( F ) The patient with CED showing a narrow thorax, pectus excavatum, and rhizomelic shortening of limbs. ( G ) Narrow thorax in a JATD patient. (H, L) Images of an EVC patient with a long narrow chest and shortness of the limbs (H), and hypodontia, that is, absence of upper and lower conical incisors (L). ( I ) BBS patient with truncal obesity, micropenis, and apathetic facial features. ( J ) Cystic kidneys of a patient with infantile NPHP. ( K ) Postaxial polydactyly of the right hand in a patient with OFDS. Reprinted from Brancati et al. Joubert syndrome and related disorders. Orphanet J Rare Dis 2010 Jul 8;5:20, Copyright (2010), with permission from BioMed Central Ltd. (A); Tallila et al. Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle. Am J Hum Genet 2008 Jun;82(6):1361–1367, Copyright (2008) with permission from Elsevier (B–D); El Hokayem et al. NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases. J Med Genet 2012 Apr;49(4):227–233, Copyright (2012) with permission from BMJ Publishing Group Ltd. (E); Gilissen et al. Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome. Am J Hum Genet 2010 Sep 10;87(3):418–423, Copyright (2010) with permission from Elsevier (F); Schmidts. Clinical genetics and pathobiology of ciliary chondrodysplasias. J Pediatr Genet 2014 Nov;3(2):46–94, Copyright (2014) Thieme Publishers (G); Baujat and Le Merrer. Ellis-van Creveld syndrome. Orphanet J Rare Dis 2007 Jun; 4;2:27, Copyright (2007) with permission from Central Ltd. (H, L); Sahin et al. Two brothers with Bardet-Biedl syndrome presenting with chronic renal failure. Case Rep Nephrol 2015 Apr 3;2015:764973, Copyright (2015) (I); Oud et al. Early presentation of cystic kidneys in a family with a homozygous INVS mutation. Am J Med Genet A 2014 Jul;164A(7):1627–1634, Copyright (2014) with permission from John Wiley and Sons Inc. (J); Poretti et al. Delineation and diagnostic criteria of oral-facial-digital syndrome type VI. Orphanet J Rare Dis 2012 Jan 11;7:4, Copyright (2012) with permission from BioMed Central Ltd (K).