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

ciliopathy - cilia - next-generation sequencing - diagnostics - genotype-phenotype

• References

• 1 Fliegauf M, Benzing T, Omran H. When cilia go bad: cilia defects and ciliopathies. Nat Rev Mol Cell Biol 2007; 8 (11) 880-893
• 2 Satir P, Christensen ST. Overview of structure and function of mammalian cilia. Annu Rev Physiol 2007; 69: 377-400
• 3 Horani A, Ferkol TW, Dutcher SK, Brody SL. Genetics and biology of primary ciliary dyskinesia. Paediatr Respir Rev 2016; 18: 18-24
• 4 Salathe M. Regulation of mammalian ciliary beating. Annu Rev Physiol 2007; 69: 401-422
• 5 Sorokin S. Centrioles and the formation of rudimentary cilia by fibroblasts and smooth muscle cells. J Cell Biol 1962; 15: 363-377
• 6 Kim S, Dynlacht BD. Assembling a primary cilium. Curr Opin Cell Biol 2013; 25 (04) 506-511
• 7 Szymanska K, Johnson CA. The transition zone: an essential functional compartment of cilia. Cilia 2012; 1 (01) 10 . Doi: 10.1186/2046-2530-1-10
• 8 Yang TT, Su J, Wang WJ. , et al. Super resolution pattern recognition reveals the architectural map of the ciliary transition zone. Sci Rep 2015; 5: 14096 . Doi: 10.1038/srep14096
• 9 Jin H, White SR, Shida T. , et al. The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell 2010; 141 (07) 1208-1219
• 10 Kim JC, Badano JL, Sibold S. , et al. The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nat Genet 2004; 36 (05) 462-470
• 11 Malicki J, Avidor-Reiss T. From the cytoplasm into the cilium: bon voyage. Organogenesis 2014; 10 (01) 138-157
• 12 Kozminski KG, Johnson KA, Forscher P, Rosenbaum JL. A motility in the eukaryotic flagellum unrelated to flagellar beating. Proc Natl Acad Sci U S A 1993; 90 (12) 5519-5523
• 13 Rosenbaum JL, Witman GB. Intraflagellar transport. Nat Rev Mol Cell Biol 2002; 3 (11) 813-825
• 14 Pedersen LB, Rosenbaum JL. Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. Curr Top Dev Biol 2008; 85: 23-61
• 15 Powles-Glover N. Cilia and ciliopathies: classic examples linking phenotype and genotype—an overview. Reprod Toxicol 2014; 48: 98-105
• 16 Singla V, Reiter JF. The primary cilium as the cell's antenna: signaling at a sensory organelle. Science 2006; 313 (5787): 629-633
• 17 Rao Damerla R, Gabriel GC, Li Y. , et al. Role of cilia in structural birth defects: insights from ciliopathy mutant mouse models. Birth Defects Res C Embryo Today 2014; 102 (02) 115-125
• 18 Joubert M, Eisenring JJ, Robb JP, Andermann F. Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation. Neurology 1969; 19 (09) 813-825
• 19 Romani M, Micalizzi A, Valente EM. Joubert syndrome: congenital cerebellar ataxia with the molar tooth. Lancet Neurol 2013; 12 (09) 894-905
• 20 Szymanska K, Hartill VL, Johnson CA. Unraveling the genetics of Joubert and Meckel-Gruber syndromes. J Pediatr Genet 2014; 3 (02) 65-78
• 21 Parisi MA, Doherty D, Chance PF, Glass IA. Joubert syndrome (and related disorders) (OMIM 213300). Eur J Hum Genet 2007; 15 (05) 511-521
• 22 Brancati F, Dallapiccola B, Valente EM. Joubert syndrome and related disorders. Orphanet J Rare Dis 2010; 5: 20 . Doi: 10.1186/1750-1172-5-20
• 23 Salonen R, Paavola P. Meckel syndrome. J Med Genet 1998; 35 (06) 497-501
• 24 Logan CV, Abdel-Hamed Z, Johnson CA. Molecular genetics and pathogenic mechanisms for the severe ciliopathies: insights into neurodevelopment and pathogenesis of neural tube defects. Mol Neurobiol 2011; 43 (01) 12-26
• 25 Wright C, Healicon R, English C, Burn J. Meckel syndrome: what are the minimum diagnostic criteria?. J Med Genet 1994; 31 (06) 482-485
• 26 Chen CP. Meckel syndrome: genetics, perinatal findings, and differential diagnosis. Taiwan J Obstet Gynecol 2007; 46 (01) 9-14
• 27 Barisic I, Boban L, Loane M. , et al. Meckel-Gruber syndrome: a population-based study on prevalence, prenatal diagnosis, clinical features, and survival in Europe. Eur J Hum Genet 2015; 23 (06) 746-752
• 28 Salonen R, Norio R. The Meckel syndrome in Finland: epidemiologic and genetic aspects. Am J Med Genet 1984; 18 (04) 691-698
• 29 Coene KL, Roepman R, Doherty D. , et al. OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin. Am J Hum Genet 2009; 85 (04) 465-481
• 30 Abdelhamed ZA, Wheway G, Szymanska K. , et al. Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects. Hum Mol Genet 2013; 22 (07) 1358-1372
• 31 Arts H, Knoers N. Cranioectodermal Dysplasia. In: Pagon RA, Adam MP, Ardinger HH. , et al , eds. Seattle, WA: Gene Reviews(R); 1993
• 32 Schmidts M. Clinical genetics and pathobiology of ciliary chondrodysplasias. J Pediatr Genet 2014; 3 (02) 46-94
• 33 Huber C, Cormier-Daire V. Ciliary disorder of the skeleton. Am J Med Genet C Semin Med Genet 2012; 160C [phone]
• 34 Keppler-Noreuil KM, Adam MP, Welch J, Muilenburg A, Willing MC. Clinical insights gained from eight new cases and review of reported cases with Jeune syndrome (asphyxiating thoracic dystrophy). Am J Med Genet A 2011; 155A [phone]
• 35 Baujat G, Le Merrer M. Ellis-van Creveld syndrome. Orphanet J Rare Dis 2007; 2: 27 . Doi: 10.1186/1750-1172-2-27
• 36 Toriello HV. Are the oral-facial-digital syndromes ciliopathies?. Am J Med Genet A 2009; 149A [phone]
• 37 Lopez E, Thauvin-Robinet C, Reversade B. , et al. C5orf42 is the major gene responsible for OFD syndrome type VI. Hum Genet 2014; 133 (03) 367-377
• 38 Srour M, Schwartzentruber J, Hamdan FF. , et al; FORGE Canada Consortium. Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population. Am J Hum Genet 2012; 90 (04) 693-700
• 39 Thauvin-Robinet C, Lee JS, Lopez E. , et al. The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation. Nat Genet 2014; 46 (08) 905-911
• 40 Ye X, Zeng H, Ning G, Reiter JF, Liu A. C2cd3 is critical for centriolar distal appendage assembly and ciliary vesicle docking in mammals. Proc Natl Acad Sci U S A 2014; 111 (06) 2164-2169
• 41 Shalata A, Ramirez MC, Desnick RJ. , et al. Morbid obesity resulting from inactivation of the ciliary protein CEP19 in humans and mice. Am J Hum Genet 2013; 93 (06) 1061-1071
• 42 Katsanis N, Ansley SJ, Badano JL. , et al. Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder. Science 2001; 293 (5538): 2256-2259
• 43 Beales PL, Badano JL, Ross AJ. , et al. Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome. Am J Hum Genet 2003; 72 (05) 1187-1199
• 44 Forsythe E, Beales PL. Bardet-Biedl syndrome. Eur J Hum Genet 2013; 21 (01) 8-13
• 45 Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet 1999; 36 (06) 437-446
• 46 O'Dea D, Parfrey PS, Harnett JD, Hefferton D, Cramer BC, Green J. The importance of renal impairment in the natural history of Bardet-Biedl syndrome. Am J Kidney Dis 1996; 27 (06) 776-783
• 47 Marshall JD, Bronson RT, Collin GB. , et al. New Alström syndrome phenotypes based on the evaluation of 182 cases. Arch Intern Med 2005; 165 (06) 675-683
• 48 Collin GB, Marshall JD, Ikeda A. , et al. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome. Nat Genet 2002; 31 (01) 74-78
• 49 Collin GB, Marshall JD, King BL. , et al. The Alström syndrome protein, ALMS1, interacts with α-actinin and components of the endosome recycling pathway. PLoS One 2012; 7 (05) e37925 . Doi: 10.1371/journal.pone.0037925
• 50 Loktev AV, Zhang Q, Beck JS. , et al. A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev Cell 2008; 15 (06) 854-865
• 51 Liew GM, Ye F, Nager AR. , et al. The intraflagellar transport protein IFT27 promotes BBSome exit from cilia through the GTPase ARL6/BBS3. Dev Cell 2014; 31 (03) 265-278
• 52 Dell KM. The spectrum of polycystic kidney disease in children. Adv Chronic Kidney Dis 2011; 18 (05) 339-347
• 53 Bergmann C. ARPKD and early manifestations of ADPKD: the original polycystic kidney disease and phenocopies. Pediatr Nephrol 2015; 30 (01) 15-30
• 54 Guay-Woodford LM. Autosomal recessive polycystic kidney disease: the prototype of the hepato-renal fibrocystic diseases. J Pediatr Genet 2014; 3 (02) 89-101
• 55 Ward CJ, Hogan MC, Rossetti S. , et al. The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet 2002; 30 (03) 259-269
• 56 Hildebrandt F, Attanasio M, Otto E. Nephronophthisis: disease mechanisms of a ciliopathy. J Am Soc Nephrol 2009; 20 (01) 23-35
• 57 Salomon R, Saunier S, Niaudet P. Nephronophthisis. Pediatr Nephrol 2009; 24 (12) 2333-2344
• 58 Saunier S, Salomon R, Antignac C. Nephronophthisis. Curr Opin Genet Dev 2005; 15 (03) 324-331
• 59 Wolf MT. Nephronophthisis and related syndromes. Curr Opin Pediatr 2015; 27 (02) 201-211
• 60 Afzelius BA. A human syndrome caused by immotile cilia. Science 1976; 193 (4250): 317-319
• 61 Paff T, Daniels JMA, Pals G, Haarman EG. Primary ciliary dyskinesia: from diagnosis to molecular mechanisms. J Pediatr Genet 2014; 3 (02) 115-127
• 62 Halbritter J, Porath JD, Diaz KA. , et al; GPN Study Group. Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. Hum Genet 2013; 132 (08) 865-884
• 63 Bachmann-Gagescu R, Dempsey JC, Phelps IG. , et al; University of Washington Center for Mendelian Genomics. Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity. J Med Genet 2015; 52 (08) 514-522
• 64 Collins SA, Walker WT, Lucas JS. Genetic testing in the diagnosis of primary ciliary dyskinesia: state-of-the-art and future perspectives. J Clin Med 2014; 3 (02) 491-503
• 65 Maguire AM, High KA, Auricchio A. , et al. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet 2009; 374 (9701): 1597-1605
• 66 Testa F, Maguire AM, Rossi S. , et al. Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital Amaurosis type 2. Ophthalmology 2013; 120 (06) 1283-1291
• 67 Brimble MA, Reiss UM, Nathwani AC, Davidoff AM. New and improved AAVenues: current status of hemophilia B gene therapy. Expert Opin Biol Ther 2016; 16 (01) 79-92
• 68 Hawkes N. Gene therapy trial for cystic fibrosis shows modest benefits. BMJ 2015; 351: h3608 . Doi: 10.1136/bmj.h3608
• 69 Estrada-Cuzcano A, Roepman R, Cremers FP, den Hollander AI, Mans DA. Non-syndromic retinal ciliopathies: translating gene discovery into therapy. Hum Mol Genet 2012; 21 (R1): R111-R124
• 70 Simons DL, Boye SL, Hauswirth WW, Wu SM. Gene therapy prevents photoreceptor death and preserves retinal function in a Bardet-Biedl syndrome mouse model. Proc Natl Acad Sci U S A 2011; 108 (15) 6276-6281
• 71 McIntyre JC, Williams CL, Martens JR. Smelling the roses and seeing the light: gene therapy for ciliopathies. Trends Biotechnol 2013; 31 (06) 355-363
• 72 Chhin B, Negre D, Merrot O. , et al. Ciliary beating recovery in deficient human airway epithelial cells after lentivirus ex vivo gene therapy. PLoS Genet 2009; 5 (03) e1000422 . Doi: 10.1371/journal.pgen.1000422
• 73 The European Polycystic Kidney Disease Consortium. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell 1994; 77 (06) 881-894
• 74 Mykytyn K, Braun T, Carmi R. , et al. Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. Nat Genet 2001; 28 (02) 188-191
• 75 Mykytyn K, Nishimura DY, Searby CC. , et al. Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. Nat Genet 2002; 31 (04) 435-438
• 76 Gilissen C, Arts HH, Hoischen A. , et al. Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome. Am J Hum Genet 2010; 87 (03) 418-423
• 77 Huang L, Szymanska K, Jensen VL. , et al. TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone. Am J Hum Genet 2011; 89 (06) 713-730
• 78 Otto EA, Hurd TW, Airik R. , et al. Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nat Genet 2010; 42 (10) 840-850
• 79 Srour M, Hamdan FF, McKnight D. , et al; Care4Rare Canada Consortium. Joubert syndrome in French Canadians and identification of mutations in CEP104. Am J Hum Genet 2015; 97 (05) 744-753
• 80 Delous M, Baala L, Salomon R. , et al. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet 2007; 39 (07) 875-881
• 81 Hopp K, Heyer CM, Hommerding CJ. , et al. B9D1 is revealed as a novel Meckel syndrome (MKS) gene by targeted exon-enriched next-generation sequencing and deletion analysis. Hum Mol Genet 2011; 20 (13) 2524-2534
• 82 Redin C, Le Gras S, Mhamdi O. , et al. Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alström syndromes. J Med Genet 2012; 49 (08) 502-512
• 83 Onoufriadis A, Shoemark A, Schmidts M. , et al; UK10K. Targeted NGS gene panel identifies mutations in RSPH1 causing primary ciliary dyskinesia and a common mechanism for ciliary central pair agenesis due to radial spoke defects. Hum Mol Genet 2014; 23 (13) 3362-3374
• 84 Failler M, Gee HY, Krug P. , et al. Mutations of CEP83 cause infantile nephronophthisis and intellectual disability. Am J Hum Genet 2014; 94 (06) 905-914
• 85 Schmidts M, Frank V, Eisenberger T. , et al. Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney disease. Hum Mutat 2013; 34 (05) 714-724
• 86 Knopp C, Rudnik-Schöneborn S, Eggermann T. , et al. Syndromic ciliopathies: from single gene to multi gene analysis by SNP arrays and next generation sequencing. Mol Cell Probes 2015; 29 (05) 299-307
• 87 Lambacher NJ, Bruel AL, van Dam TJ. , et al. TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome. Nat Cell Biol 2016; 18 (01) 122-131
• 88 Lin AE, Traum AZ, Sahai I. , et al. Sensenbrenner syndrome (cranioectodermal dysplasia): clinical and molecular analyses of 39 patients including two new patients. Am J Med Genet A 2013; 161A (11) 2762-2776
• 89 D'Asdia MC, Torrente I, Consoli F. , et al. Novel and recurrent EVC and EVC2 mutations in Ellis-van Creveld syndrome and Weyers acrofacial dyostosis. Eur J Med Genet 2013; 56 (02) 80-87
• 90 Schueler M, Halbritter J, Phelps IG. , et al. Large-scale targeted sequencing comparison highlights extreme genetic heterogeneity in nephronophthisis-related ciliopathies. J Med Genet 2016; 53 (03) 208-214
• 91 Djakow J, Kramná L, Dušátková L. , et al. An effective combination of sanger and next generation sequencing in diagnostics of primary ciliary dyskinesia. Pediatr Pulmonol 2016; 51 (05) 498-509
• 92 Saudi Mendeliome G. ; Saudi Mendeliome Group. Comprehensive gene panels provide advantages over clinical exome sequencing for Mendelian diseases. Genome Biol 2015; 16: 134 . Doi: 10.1186/s13059-015-0693-2
• 93 de Koning TJ, Jongbloed JD, Sikkema-Raddatz B, Sinke RJ. Targeted next-generation sequencing panels for monogenetic disorders in clinical diagnostics: the opportunities and challenges. Expert Rev Mol Diagn 2015; 15 (01) 61-70
• 94 Renkema KY, Stokman MF, Giles RH, Knoers NV. Next-generation sequencing for research and diagnostics in kidney disease. Nat Rev Nephrol 2014; 10 (08) 433-444
• 95 Sawyer SL, Hartley T, Dyment DA. , et al; FORGE Canada Consortium; Care4Rare Canada Consortium. Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care. Clin Genet 2016; 89 (03) 275-284
• 96 Neveling K, Feenstra I, Gilissen C. , et al. A post-hoc comparison of the utility of sanger sequencing and exome sequencing for the diagnosis of heterogeneous diseases. Hum Mutat 2013; 34 (12) 1721-1726
• 97 Valencia CA, Husami A, Holle J. , et al. Clinical impact and cost-effectiveness of whole exome sequencing as a diagnostic tool: a pediatric center's experience. Front Pediatr 2015; 3: 67 . Doi: 10.3389/fped.2015.00067
• 98 Soden SE, Saunders CJ, Willig LK. , et al. Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med 2014; 6 (265) 265ra168 . Doi: 10.1126/scitranslmed.3010076
• 99 Yang Y, Muzny DM, Reid JG. , et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 2013; 369 (16) 1502-1511
• 100 Yang Y, Muzny DM, Xia F. , et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 2014; 312 (18) 1870-1879
• 101 Lee H, Deignan JL, Dorrani N. , et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA 2014; 312 (18) 1880-1887
• 102 Li F, Cao Y, Han L. , et al. Gene expression signature: an R package for discovering functional connections using gene expression signatures. OMICS 2013; 17 (02) 116-118
• 103 Eisenberger T, Decker C, Hiersche M. , et al. An efficient and comprehensive strategy for genetic diagnostics of polycystic kidney disease. PLoS One 2015; 10 (02) e0116680 . Doi: 10.1371/journal.pone.0116680
• 104 Tan AY, Michaeel A, Liu G. , et al. Molecular diagnosis of autosomal dominant polycystic kidney disease using next-generation sequencing. J Mol Diagn 2014; 16 (02) 216-228
• 105 Rossetti S, Hopp K, Sikkink RA. , et al. Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing. J Am Soc Nephrol 2012; 23 (05) 915-933
• 106 Trujillano D, Bullich G, Ossowski S. , et al. Diagnosis of autosomal dominant polycystic kidney disease using efficient PKD1 and PKD2 targeted next-generation sequencing. Mol Genet Genomic Med 2014; 2 (05) 412-421
• 107 Kirby A, Gnirke A, Jaffe DB. , et al. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing. Nat Genet 2013; 45 (03) 299-303
• 108 Acuna-Hidalgo R, Bo T, Kwint MP. , et al. Post-zygotic point mutations are an underrecognized source of de novo genomic variation. Am J Hum Genet 2015; 97 (01) 67-74
• 109 de Ligt J, Boone PM, Pfundt R. , et al. Platform comparison of detecting copy number variants with microarrays and whole-exome sequencing. Genom Data 2014; 2: 144-146
• 110 Wang J, Liao J, Zhang J. , et al. ClinLabGeneticist: a tool for clinical management of genetic variants from whole exome sequencing in clinical genetic laboratories. Genome Med 2015; 7 (01) 77 . Doi: 10.1186/s13073-015-0207-6
• 111 Ajzenberg H, Slaats GG, Stokman MF. , et al. Non-invasive sources of cells with primary cilia from pediatric and adult patients. Cilia 2015; 4: 8 . Doi: 10.1186/s13630-015-0017-x
• 112 Arts HH, Bongers EM, Mans DA. , et al. C14ORF179 encoding IFT43 is mutated in Sensenbrenner syndrome. J Med Genet 2011; 48 (06) 390-395
• 113 Davis EE, Zhang Q, Liu Q. , et al; NISC Comparative Sequencing Program. TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet 2011; 43 (03) 189-196
• 114 Roberson EC, Dowdle WE, Ozanturk A. , et al. TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone. J Cell Biol 2015; 209 (01) 129-142
• 115 Diggle CP, Moore DJ, Mali G. , et al. HEATR2 plays a conserved role in assembly of the ciliary motile apparatus. PLoS Genet 2014; 10 (09) e1004577 . Doi: 0.1371/journal.pgen.1004577
• 116 Gilissen C, Hehir-Kwa JY, Thung DT. , et al. Genome sequencing identifies major causes of severe intellectual disability. Nature 2014; 511 (7509): 344-347
• 117 Kundaje A, Meuleman W, Ernst J. , et al; Roadmap Epigenomics Consortium. Integrative analysis of 111 reference human epigenomes. Nature 2015; 518 (7539): 317-330
• 118 Miller NA, Farrow EG, Gibson M. , et al. A 26-hour system of highly sensitive whole genome sequencing for emergency management of genetic diseases. Genome Med 2015; 7 (01) 100 . Doi: 10.1186/s13073-015-0221-8
• 119 Saunders CJ, Miller NA, Soden SE. , et al. Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Sci Transl Med 2012; 4 (154) 154ra135 . Doi: 10.1126/scitranslmed.3004041
• 120 Jones D, Fiozzo F, Waters B, McKnight D, Brown S. First-trimester diagnosis of Meckel-Gruber syndrome by fetal ultrasound with molecular identification of CC2D2A mutations by next-generation sequencing. Ultrasound Obstet Gynecol 2014; 44 (06) 719-721
• 121 Stokowski R, Wang E, White K. , et al. Clinical performance of non-invasive prenatal testing (NIPT) using targeted cell-free DNA analysis in maternal plasma with microarrays or next generation sequencing (NGS) is consistent across multiple controlled clinical studies. Prenat Diagn 2015; 35 (12) 1243-1246
• 122 Thung DT, Beulen L, Hehir-Kwa J, Faas BH. Implementation of whole genome massively parallel sequencing for noninvasive prenatal testing in laboratories. Expert Rev Mol Diagn 2015; 15 (01) 111-124
• 123 Amor DJ. Future of whole genome sequencing. J Paediatr Child Health 2015; 51 (03) 251-254