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Recent Advances in the Genetic Etiology of Brain Malformations

  • Genetics (V Bonifati, Section Editor)
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Abstract

In the past few years, the increasing accessibility of next-generation sequencing technology has translated to a number of significant advances in our understanding of brain malformations. Genes causing brain malformations, previously intractable due to their complex presentation, rarity, sporadic occurrence, or molecular mechanism, are being identified at an unprecedented rate and are revealing important insights into central nervous system development. Recent discoveries highlight new associations of biological processes with human disease including the PI3K-AKT-mTOR pathway in brain overgrowth syndromes, the trafficking of cellular proteins in microcephaly-capillary malformation syndrome, and the role of the exosome in the etiology of pontocerebellar hypoplasia. Several other gene discoveries expand our understanding of the role of mitosis in the primary microcephaly syndromes and post-translational modification of dystroglycan in lissencephaly. Insights into polymicrogyria and heterotopias show us that these 2 malformations are complex in their etiology, while recent work in holoprosencephaly and Dandy-Walker malformation suggest that, at least in some instances, the development of these malformations requires “multiple-hits” in the sonic hedgehog pathway. The discovery of additional genes for primary microcephaly, pontocerebellar hypoplasia, and spinocerebellar ataxia continue to impress upon us the significant degree of genetic heterogeneity associated with many brain malformations. It is becoming increasingly evident that next-generation sequencing is emerging as a tool to facilitate rapid and cost-effective molecular diagnoses that will be translated into routine clinical care for these rare conditions in the near future.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Nüsslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature. 1980;287(5785):795–801.

    Article  PubMed  Google Scholar 

  2. Belloni E, Muenke M, Roessler E, et al. Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nat Genet. 1996;14(3):353–6.

    Article  CAS  PubMed  Google Scholar 

  3. Komada M. Sonic hedgehog signaling coordinates the proliferation and differentiation of neural stem/progenitor cells by regulating cell cycle kinetics during development of the neocortex. Congenit Anom (Kyoto). 2012;52(2):72–7.

    Article  Google Scholar 

  4. Schinzel A. Cyclopia and cebocephaly in two newborn infants with unbalanced segregation of a familial translocation rcp (1;7)(q32;q34). Am J Med Genet. 1984;18(1):153–61.

    Article  CAS  PubMed  Google Scholar 

  5. Hatziioannou AG, Krauss CM, Lewis MB, Halazonetis TD. Familial holoprosencephaly associated with a translocation breakpoint at chromosomal position 7q36. Am J Med Genet. 1991;40(2):201–5.

    Article  CAS  PubMed  Google Scholar 

  6. Bamshad MJ, Ng SB, Bigham AW, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011;12(11):745–55.

    Article  CAS  PubMed  Google Scholar 

  7. Thornton GK, Woods CG. Primary microcephaly: do all roads lead to Rome? Trends Genet. 2009;25(11):501–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Woods CG, Bond J, Enard W. Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am J Hum Genet. 2005;76(5):717–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. • Yu TW, Mochida GH, Tischfield DJ, et al. Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat Genet. 2010;42(11):1015–20. See reference 10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. • Bilgüvar K, Oztürk AK, Louvi A, et al. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature. 2010;467(7312):207–10. References 9 and 10 describe the identification of mutations in WDR62 in individuals with brain malformations. In Reference 9, the researchers perfomed a linkage study, followed by targeted NGS in 2 individuals to identify WDR62 as a cause of primary microcephaly. In Reference 10, the researchers used WES in a single individual to identify WDR62 as the gene responsible for a complex brain malformation including microcephaly, pachygyria, lissencephaly, and polymicrogyria. Both studies highlighted the emerging utility of NGS for identifying genes causing brain malformations.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Wollnik B. A common mechanism for microcephaly. Nat Genet. 2010;42(11):923–4.

    Article  CAS  PubMed  Google Scholar 

  12. Genin A, Desir J, Lambert N, et al. Kinetochore KMN network gene CASC5 mutated in primary microcephaly. Hum Mol Genet. 2012;21(24):5306–17.

    Article  CAS  PubMed  Google Scholar 

  13. Hussain MS, Baig SM, Neumann S, et al. A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function. Am J Hum Genet. 2012;90(5):871–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kitagawa D, Kohlmaier G, Keller D, et al. Spindle positioning in human cells relies on proper centriole formation and on the microcephaly proteins CPAP and STIL. J Cell Sci. 2011;124(Pt 22):3884–93.

    Article  CAS  PubMed  Google Scholar 

  15. • McDonell LM, Mirzaa GM, Alcantara D, et al. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome. Nat Genet. 2013;45(5):556–62. The researchers used NGS to identify mutations in STAMBP in patients with microcephaly-capillary malformation syndrome. The gene is a deubiquitinating enzyme responsible for proper trafficking of proteins from the endosome to the lysosome, implicating a novel mechanism of disease for this brain malformation.

  16. Mirzaa GM, Conway RL, Gripp KW, et al. Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis. Am J Med Genet. 2012;158A(2):269–91.

    Article  PubMed  Google Scholar 

  17. • Rivière JB, Mirzaa GM, O'Roak BJ, et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet. 2012;44(8):934–40. The researchers identified several mutations in genes (AKT3, PIK3R2, and PIK3C) in the PI3K-AKT-mTOR pathway as responsible for 2 brain overgrowth syndromes; MCAP and MPPH. Many patients had postzygotic mutations at low levels of mosaicism and the authors highlight this type of mutation as tractable to discovery using NGS.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. • Lee JH, Huynh M, Silhavy JL, et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet. 2012;44(8):941–5. The researchers identified somatic mutations in PIK3CA, AKT3, and MTOR by using NGS in samples from both brain and blood in 5 individuals with hemimegalencephaly. By pairing WES in affected and unaffected tissue samples from each patient the researchers present a powerful method to detect somatic mutations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cabrera-López C, Martí T, Catalá V, et al. Assessing the effectiveness of rapamycin on angiomyolipoma in tuberous sclerosis: a two year trial. Orphanet J Rare Dis. 2012;7:87.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Devisme L, Bouchet C, Gonzalès M, et al. Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies. Brain. 2012;135(Pt 2):469–82.

    Article  PubMed  Google Scholar 

  21. Vuillaumier-Barrot S, Bouchet-Seraphin C, Chelbi M, et al. Intragenic rearrangements in LARGE and POMGNT1 genes in severe dystroglycanopathies. Neuromuscul Disord. 2011;21(11):782–90.

    Article  CAS  PubMed  Google Scholar 

  22. Wright KM, Lyon KA, Leung H, et al. Dystroglycan organizes axon guidance cue localization and axonal pathfinding. Neuron. 2012;76(5):931–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. • Roscioli T, Kamsteeg EJ, Buysse K, et al. Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of α-dystroglycan. Nat Genet. 2012;44(5):581–5. References 23, 24, and 25 identified ISPD as a gene causing WWS. In Reference 23, the researchers used WES in a single individual to identify ISPD as a cause of WWS and then show that ISPD is the second most common cause of WWS. They also elucidate a role for ISPD in the glycosylation of alpha-dystroglycan and the maintenance of sarcolemma integrity. In Reference 24, the researchers first minimized genetic heterogeneity of their study cohort with a cellular assay and then performed linkage analysis and targeted NGS to identify mutations in ISPD. In Reference 25, the researchers performed WES in siblings with WWS to identify ISPD and TMEM5 mutations. The authors report arriving at a molecular diagnosis in over 60% of their severe, fetal lissencephaly cases using screening of the 8 genes known to cause WWS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. • Willer T, Lee H, Lommel M, et al. ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome. Nat Genet. 2012;44(5):575–80. See reference 23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. • Vuillaumier-Barrot S, Bouchet-Séraphin C, Chelbi M, et al. Identification of mutations in TMEM5 and ISPD as a cause of severe cobblestone lissencephaly. Am J Hum Genet. 2012;91(6):1135–43. See reference 23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Buysse K, Riemersma M, Powell G, et al. Missense mutations in β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker-Warburg syndrome. Hum Mol Genet. 2013;22(9):1746–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Manzini MC, Tambunan DE, Hill RS, et al. Exome sequencing and functional validation in zebrafish identify GTDC2 mutations as a cause of Walker-Warburg syndrome. Am J Hum Genet. 2012;91(3):541–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cirak S, Foley AR, Herrmann R, et al. ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies. Brain. 2013;136(Pt 1):269–81.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Moore CJ, Winder SJ. The inside and out of dystroglycan post-translational modification. Neuromuscul Disord. 2012;22(11):959–65.

    Article  PubMed  Google Scholar 

  30. Leventer RJ, Jansen A, Pilz DT, et al. Clinical and imaging heterogeneity of polymicrogyria: a study of 328 patients. Brain. 2010;133(Pt 5):1415–27.

    Article  PubMed  PubMed Central  Google Scholar 

  31. • Barkovich AJ, Guerrini R, Kuzniecky RI, Jackson GD, Dobyns WB. A developmental and genetic classification for malformations of cortical development: update 2012. Brain. 2012;135(Pt 5):1348–69. An important review article updating the genetic classification for brain malformations. A rigorous and accurate diagnosis of complex malformations will be necessary when interpreting the thousands of variants detected by NGS in the research as well as the clinical settings.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB. Classification system for malformations of cortical development: update 2001. Neurology. 2001;57(12):2168–78.

    Article  CAS  PubMed  Google Scholar 

  33. Jansen A, Andermann E. Genetics of the polymicrogyria syndromes. J Med Genet. 2005;42(5):369–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Piao X, Hill RS, Bodell A, et al. G protein-coupled receptor-dependent development of human frontal cortex. Science. 2004;303(5666):2033–6.

    Article  CAS  PubMed  Google Scholar 

  35. Doherty D, Chudley AE, Coghlan G, et al. GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome. Am J Hum Genet. 2012;90(6):1088–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Konno D, Shioi G, Shitamukai A, et al. Neuroepithelial progenitors undergo LGN-dependent planar divisions to maintain self-renewability during mammalian neurogenesis. Nat Cell Biol. 2008;10(1):93–101.

    Article  CAS  PubMed  Google Scholar 

  37. Walsh T, Shahin H, Elkan-Miller T, et al. Whole exome sequencing and homozygosity mapping identify mutation in the cell polarity protein GPSM2 as the cause of nonsyndromic hearing loss DFNB82. Am J Hum Genet. 2010;87(1):90–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Liu JS. Molecular genetics of neuronal migration disorders. Curr Neurol Neurosci Rep. 2011;11(2):171–8.

    Article  CAS  PubMed  Google Scholar 

  39. Guerrini R, Parrini E. Neuronal migration disorders. Neurobiol Dis. 2010;38(2):154–66.

    Article  CAS  PubMed  Google Scholar 

  40. Chardon JW, Mignot C, Aradhya S, et al. Deletion of filamin A in two female patients with periventricular nodular heterotopia. Am J Med Genet. 2012;158A(6):1512–6.

    Article  PubMed  CAS  Google Scholar 

  41. de Wit MC, Kros JM, Halley DJ, et al. Filamin A mutation, a common cause for periventricular heterotopia, aneurysms and cardiac defects. J Neurol Neurosur PS. 2009;80(4):426–8.

    Article  Google Scholar 

  42. Okumura A, Hayashi M, Shimojima K, et al. Whole-exome sequencing of a unique brain malformation with periventricular heterotopia, cingulate polymicrogyria and midbrain tectal hyperplasia. Neuropathology. 2012;[Epub ahead of print].

  43. Sheen VL, Feng Y, Graham D, et al. Filamin A and Filamin B are co-expressed within neurons during periods of neuronal migration and can physically interact. Hum Molec Genet. 2002;11(23):2845–54.

    Article  CAS  PubMed  Google Scholar 

  44. Leoncini E, Baranello G, Orioli IM, et al. Frequency of holoprosencephaly in the International Clearinghouse Birth Defects Surveillance Systems: searching for population variations. Birth Defects Res A Clin Mol Teratol. 2008;82(8):585–91.

    Article  CAS  PubMed  Google Scholar 

  45. Roessler E, Muenke M. The molecular genetics of holoprosencephaly. Am J Med Genet; C Semin Med Genet. 2010;154C(1):52–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mercier S, Dubourg C, Garcelon N, et al. New findings for phenotype-genotype correlations in a large European series of holoprosencephaly cases. J Med Genet. 2011;48(11):752–60.

    Article  CAS  PubMed  Google Scholar 

  47. Parisi MA, Dobyns WB. Human malformations of the midbrain and hindbrain: review and proposed classification scheme. Mol Genet Metab. 2003;80(1–2):36–53.

    Article  CAS  PubMed  Google Scholar 

  48. Barkovich AJ, Kjos BO, Norman D, Edwards MS. Revised classification of posterior fossa cysts and cystlike malformations based on the results of multiplanar MR imaging. Am J Roentgenol. 1989;153(6):1289–300.

    Article  CAS  Google Scholar 

  49. Garel C, Fallet-Bianco C, Guibaud L. The fetal cerebellum: development and common malformations. J Child Neurol. 2011;26(12):1483–92.

    Article  PubMed  Google Scholar 

  50. Blank MC, Grinberg I, Aryee E, et al. Multiple developmental programs are altered by loss of Zic1 and Zic4 to cause Dandy-Walker malformation cerebellar pathogenesis. Development. 2011;138(6):1207–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ming JE, Muenke M. Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am J Hum Genet. 2002;71(5):1017–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wannasilp N, Solomon BD, Warren-Mora N, et al. Holoprosencephaly in a family segregating novel variants in ZIC2 and GLI2. Am J Med Genet. 2011;155A(4):860–4.

    Article  PubMed  CAS  Google Scholar 

  53. Namavar Y, Barth PG, Poll-The BT, Baas F. Classification, diagnosis and potential mechanisms in pontocerebellar hypoplasia. Orphanet J Rare Dis. 2011;6:50.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Namavar Y, Barth PG, Kasher PR, et al. Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia. Brain. 2011;134(Pt 1):143–56.

    Article  PubMed  Google Scholar 

  55. • Wan J, Yourshaw M, Mamsa H, et al. Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration. Nat Genet. 2012;44(6):704–8. NGS was utilized in a single family to identify EXOSC3 mutations in siblings affected by pontocerebellar hypoplasia. This is the first example of dysfunction of the RNA exosome causing a human disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rudnik-Schöneborn S, Senderek J, Jen JC, et al. Pontocerebellar hypoplasia type 1: clinical spectrum and relevance of EXOSC3 mutations. Neurology. 2013;80(5):438–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Verbeek DS, van de Warrenburg BP. Genetics of the dominant ataxias. Semin Neurol. 2011;31(5):461–9.

    Article  PubMed  Google Scholar 

  58. Anheim M, Tranchant C, Koenig M. The autosomal recessive cerebellar ataxias. N Engl J Med. 2012;366(7):636–46.

    Article  CAS  PubMed  Google Scholar 

  59. Trott A, Houenou LJ. Mini-review: spinocerebellar ataxias: an update of SCA genes. Recent Pat DNA Gene Seq. 2012;6(2):115–21.

    Article  CAS  PubMed  Google Scholar 

  60. Huang L, Chardon JW, Carter MT, et al. Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia. Orphanet J Rare Dis. 2012;7:67.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Wang JL, Yang X, Xia K, et al. TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing. Brain. 2010;133(Pt 12):3510–8.

    Article  PubMed  Google Scholar 

  62. Tomiwa K, Baraitser M, Wilson J. Dominantly inherited congenital cerebellar ataxia with atrophy of the vermis. Pediatr Neurol. 1987;3(6):360–2.

    Article  CAS  PubMed  Google Scholar 

  63. Dudding TE, Friend K, Schofield PW, et al. Autosomal dominant congenital non-progressive ataxia overlaps with the SCA15 locus. Neurology. 2004;63(12):2288–92.

    Article  CAS  PubMed  Google Scholar 

  64. Hadjivassiliou M, Aeschlimann P, Strigun A, et al. Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann Neurol. 2008;64(3):332–43.

    Article  CAS  PubMed  Google Scholar 

  65. • Goetz SC, Liem KF, Anderson KV. The spinocerebellar ataxia-associated gene Tau tubulin kinase 2 controls the initiation of ciliogenesis. Cell. 2012;151(4):847–58. The investigators performed a mutation screen in mice to identify malformations that are likely to be secondary to abnormal ciliogenesis. They identified Ttbk2 as one such gene. In humans, TTBK2 causes SCA11 and thus, this work shows the importance of ciliogenesis for the long-term integrity of the cerebellum.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Houlden H, Johnson J, Gardner-Thorpe C, et al. Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nat Genet. 2007;39(12):1434–6.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

D.A. Dyment and K. M. Boycott are supported by Clinical Investigatorship Awards from the Canadian Institutes of Health Research, Institute of Genetics. S. L. Sawyer and J. W. Chardon are supported by CHAMO Fellowships from the Children’s Hospital of Eastern Ontario and J. W. Chardon is further supported by a University of Ottawa Canadian Fellowship for New Faculty. We would like to thank Mrs. Megan Vanstone for her assistance in preparing this manuscript.

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  1. Department of Genetics, Children’s Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, Canada, K1H 8L1

    David A. Dyment, Sarah L. Sawyer, Jodi Warman-Chardon & Kym M. Boycott

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David A. Dyment declares that he has no conflict of interest.

Sarah L. Sawyer declares that she has no conflict of interest.

Jodi Warman-Chardon declares that she has no conflict of interest.

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Dyment, D.A., Sawyer, S.L., Warman-Chardon, J. et al. Recent Advances in the Genetic Etiology of Brain Malformations. Curr Neurol Neurosci Rep 13, 364 (2013). https://doi.org/10.1007/s11910-013-0364-1

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