Meckel Syndrome and Related Disorders

Abstract

Cilia‐related disorders (ciliopathies) are characterised by great clinical and genetic heterogeneity and overlaps between different disease entities. Meckel syndrome (MKS) is generally allelic to Joubert syndrome and related disorders, and resides at the severe end of the broad phenotypic spectrum of ciliopathies. MKS is a usually autosomal recessive, multisystemic disorder of early developmental rather than degenerative nature. Classic disease manifestations comprise occipital meningoencephalocele, cystic kidneys, hepatobiliary ductal plate malformation and postaxial polydactyly, whereas several other additional features such as heart defects and cleft lip/palate have also been reported. Survival beyond birth or the neonatal period is unusual with the vast majority of cases dying in utero. Until recently and before next‐generation sequencing (NGS) have emerged, molecular genetic testing of MKS and related ciliopathies was considerably hampered by its extensive locus heterogeneity. However, NGS‐based technologies make genetic testing now possible and have revolutionised research and diagnostics. For example, specific disease panels that allow sequencing of all disease genes in parallel significantly improve genetic diagnostics and lead to reduction of turnaround times and costs.

Key Concepts:

  • Meckel syndrome (MKS) resides at the severe end of the broad phenotypic spectrum of cilia‐related disorders (ciliopathies).

  • MKS and other ciliopathies are clinically and genetically heterogeneous.

  • MKS is a usually autosomal recessive, early developmental multisystemic disorder.

  • Most patients die in utero, survival beyond birth or the neonatal period is unusual.

  • Classic disease manifestations comprise occipital meningoencephalocele, cystic kidneys, hepatobiliary ductal plate malformation and postaxial polydactyly, but additional features are common.

  • At least 10 genes are known for MKS currently, other ciliary genes are thought to be allelic; that is why more than a dozen genes have to be considered to be disease relevant in patients with MKS.

  • Efficient molecular genetic testing of MKS and related disorders have only become feasible with emerging next‐generation sequencing (NGS)‐based approaches.

  • Specific disease panels (e.g. for MKS and related disorders) allow sequencing of all disease genes in parallel and very efficiently lead to reduction of turnaround times and costs.

Keywords: Bardet–Biedl syndrome (BBS); cilia; ciliopathies; diagnostic testing; disease panels; exome sequencing; Joubert syndrome (JBTS); Meckel syndrome (MKS); next‐generation sequencing (NGS)

Figure 1.

Schematic diagram of a primary cilium and associated processes. The inner ciliary structure is defined by the axoneme composed of nine microtubule doublets derived from the basal body and the mother centriole of the centrosome (inset displays a cross‐section revealing 9+0 architecture). Along this microtubule core, the transport of proteins towards the tip of the cilium (anterograde, by kinesin‐2 with its major component KIF3A) and in the retrograde direction towards the cell body (by dynein‐2) is organised by an elaborate process called IFT. Cilia are small antennae that detect a variety of different extracellular stimuli and orchestrate multiple signalling pathways with nuclear trafficking of some molecules.

Figure 2.

Scheme of organs frequently affected in ciliopathies. Note that practically all organs can be affected.

Figure 3.

Broad clinical spectrum of ciliopathies ranging from single organ involvement to complex, early embryonic syndromic disorders in which multiple organs are usually affected.

Figure 4.

Foetus with MKS: (a) A phenotype with occipital meningoencephalocele and a massively malformed brain resembling anencephaly, (b) postaxial hexadactyly, (c) bilateral considerably enlarged kidneys interspersed with small, pinhead‐sized cysts, (d) cystic kidney with considerable interstitial fibrosis. Reproduced with permission from Frank et al.. © Human Genome Variation Society. (e) ductal plate malformation characterised by dysgenesis of the hepatic portal triad with hyperplastic biliary ducts and congenital hepatic fibrosis.

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References

Baala L , Audollent S , Martinovic J et al. (2007) Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome. American Journal of Human Genetics 81(1): 170–179.

Bergmann C (2012) Educational paper: ciliopathies. European Journal of Pediatrics 171(9): 1285–1300.

Bergmann C , Fliegauf M , Brüchle NO et al. (2008) Loss of nephrocystin‐3 function can cause embryonic lethality, Meckel–Gruber–like syndrome, situs inversus, and renal–hepatic–pancreatic dysplasia. American Journal of Human Genetics 82(4): 959–970.

Delous M , Baala L , Salomon R et al. (2007) The ciliary gene RPGRIP1L is mutated in cerebello–oculo–renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nature Genetics 39(7): 875–881.

Dowdle WE , Robinson JF , Kneist A et al. (2011) Disruption of a ciliary B9 protein complex causes Meckel syndrome. American Journal of Human Genetics 89(1): 94–110.

Frank V , den Hollander AI , Brüchle NO et al. (2008) Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel–Gruber syndrome. Human Mutatation 29(1): 45–52.

Fraser FC and Lytwyn A (1981) Spectrum of anomalies in the Meckel syndrome, or: Maybe there is a malformation syndrome with at least one constant anomaly. American Journal of Medical Genetics 9: 67–73.

Hildebrandt F and Zhou W (2007) Nephronophthisis‐associated ciliopathies. Journal of the American Society of Nephrology 18(6): 1855–1871.

Hopp K , Heyer CM , Hommerding CJ et al. (2011) B9D1 is revealed as a novel Meckel syndrome (MKS) gene by targeted exon‐enriched next‐generation sequencing and deletion analysis. Human Molecular Genetics 20(13): 2524–2534.

Iannicelli M , Brancati F , Mougou‐Zerelli S et al. (2010) Novel TMEM67 mutations and genotype–phenotype correlates in meckelin‐related ciliopathies. Human Mutation 31(5): E1319–1331.

Juric‐Sekhar G , Adkins J , Doherty D and Hevner RF (2012) Joubert syndrome: brain and spinal cord malformations in genotyped cases and implications for neurodevelopmental functions of primary cilia. Acta Neuropathologica 123(5): 695–709.

Katsanis N (2006) Ciliary proteins and exencephaly. Nature Genetics 38(2): 135–136.

Kompanje EJ (2003) Features described and illustrated in 1684 suggesting Meckel–Gruber syndrome. Pediatric and Developmental Pathology 6(6): 595–598.

Kyttälä M , Tallila J , Salonen R et al. (2006) MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome. Nature Genetics 38(2): 155–157.

Leitch CC , Zaghloul NA , Davis EE et al. (2008) Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet–Biedl syndrome. Nature Genetics 40(4): 443–448.

Mecke S and Passarge E (1971) Encephalocele, polycystic kidneys, and polydactyly as an autosomal recessive trait simulating certain other disorders: the Meckel syndrome. Annales de Génétique 14: 97–103.

Ocbina PJ , Eggenschwiler JT , Moskowitz I and Anderson KV (2011) Complex interactions between genes controlling trafficking in primary cilia. Nature Genetics 43(6): 547–553.

Omran H (2008) Nephronophthisis and medullary cystic kidney disease. In: Geary DF and Schaefer F (eds) Comprehensive Pediatric Nephrology, pp 143–154. Philadelphia: Mosby Elsevier

Opitz JM and Howe JJ (1969) The Meckel–Gruber syndrome (dysencephalia splanchnocystica, the Gruber syndrome). Birth Defects 2: 167–179.

Paavola P , Salonen R , Weissenbach J and Peltonen L (1995) The locus for Meckel syndrome with multiple congenital anomalies maps to chromosome 17q21–q24. Nature Genetics 11(2): 213–215.

Ruggenenti P , Remuzzi A , Ondei P et al. (2005) Safety and efficacy of long‐acting somatostatin treatment in autosomal‐dominant polycystic kidney disease. Kidney International 68(1): 206–216.

Salonen R (1984) The Meckel syndrome: clinicopathological findings in 67 patients. American Journal of Medical Genetics 18(4): 671–689.

Salonen R , Kestilä M and Bergmann C (2011) Clinical utility gene card for: Meckel syndrome. European Journal of Human Genetics 19(7). Doi: 10.1038/ejhg.2010.255.

Sang L , Miller JJ , Corbit KC et al. (2011) Mapping the NPHP–JBTS–MKS protein network reveals ciliopathy disease genes and pathways. Cell 145(4): 513–528.

Satir P , Pedersen LB and Christensen ST (2010) The primary cilium at a glance. Journal of Cell Science 123(Pt 4): 499–503.

Sayer JA , Otto EA , O'Toole JF et al. (2006) The centrosomal protein nephrocystin‐6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nature Genetics 38(6): 674–681.

Sepulveda W , Sebire NJ , Souka A , Snijders RJ and Nicolaides KH (1997) Diagnosis of the Meckel‐Gruber syndrome at eleven to fourteen weeks' gestation. American Journal of Obstetrics & Gynecology 176(2): 316–319.

Shaheen R , Faqeih E , Seidahmed MZ et al. (2011) A TCTN2 mutation defines a novel Meckel Gruber syndrome locus. Human Mutation 32(6): 573–578.

Smith UM , Consugar M , Tee LJ et al. (2006) The transmembrane protein meckelin (MKS3) is mutated in Meckel–Gruber syndrome and the wpk rat. Nature Genetics 38(2): 191–196.

Stenson PD , Mort M , Ball EV et al. (2009) The human gene mutation database: 2008 update. Genome Medicine 1(1): 13.

Tallila J , Jakkula E , Peltonen L et al. (2008) Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle. American Journal of Human Genetics 82(6): 1361–1367.

Valente EM , Logan CV , Mougou‐Zerelli S et al. (2010) Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nature Genetics 42(7): 619–625.

de Vries J , Yntema JL , van Die CE et al. (2010) Jeune syndrome: description of 13 cases and a proposal for follow‐up protocol. European Journal of Pediatrics 169(1): 77–88.

Further Reading

Alexiev BA , Lin X , Sun CC and Brenner DS (2006) Meckel–Gruber syndrome: Pathologic manifestations, minimal diagnostic criteria, and differential diagnosis. Archives of Pathology & Laboratory Medicine 130(8): 1236–1238.

Badano JL , Mitsuma N , Beales PL and Katsanis N (2006) The ciliopathies: an emerging class of human genetic disorders. Annual Review of Genomics and Human Genetics 7: 125–148.

Fliegauf M , Benzing T , Omran H (2007) When cilia go bad: cilia defects and ciliopathies. Nature Reviews Molecular Cell Biology 8(11): 880–893.

Hildebrandt F , Benzing T and Katsanis N (2011) Ciliopathies. New England Journal of Medicine 364(16): 1533–1543.

Parisi MA (2009) Clinical and molecular features of Joubert syndrome and related disorders. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 151C(4): 326–340.

Salomon R , Saunier S and Niaudet P (2009) Nephronophthisis. Pediatric Nephrology 24(12): 2333–2344.

Salonen R and Paavola P (1998) Meckel syndrome. Journal of Medical Genetics 35(6): 497–501.

Shah AS , Farmen SL , Moninger TO et al. (2008) Loss of Bardet–Biedl syndrome proteins alters the morphology and function of motile cilia in airway epithelia. Proceedings of the National Academy of Sciences of the USA 105(9): 3380–3385.

Valente EM , Brancati F and Dallapiccola B (2008) Genotypes and phenotypes of Joubert syndrome and related disorders. European Journal of Human Genetics 51(1): 1–23.

Zaghloul NA and Katsanis N (2009) Mechanistic insights into Bardet–Biedl syndrome, a model ciliopathy. Journal of Clinical Investigation 119(3): 428–437.

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Frank, Valeska, and Bergmann, Carsten(Nov 2013) Meckel Syndrome and Related Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024286]