... / ... / ... / Principal Investigators / Grazia Mancini, MD, PhD

Grazia Mancini, MD, PhD

Dr. Grazia M.S. Mancini, MD, PhDGrazia Mancini

Department of Clinical Genetics
Erasmus MC
Faculty Building, Ee2026a
Wytemaweg 80

3015 CN Rotterdam 

The Netherlands

Email: g.mancini@erasmusmc.nl
Tel: +31 (0) 10 7036916




Research projects and expertise
The development of the brain cortex is a complex process, which is strictly regulated in time and space. Many genes are involved in this regulation and genetic mutations can have consequences for the intellectual development, motor skills, such as speech and walking, and behaviour leading to a broad range of intellectual disability, autism and neurological problems such as cerebral palsy and seizures.

We focus on developmental disorders of the brain, classified on radiological (MRI) pattern, such as lissencephaly, nodular heterotopia, polymicrogyria, microcephaly, megalencephaly, schizencephaly and porencephaly. All of these are very rare diseases and the knowledge about the disease mechanism is very limited.

We examine children and adults with rare developmental disorders at the Neurogenetics clinic, in close collaboration with child neurologists and neuroradiologists, to reach the appropriate diagnosis, advise about genetic tests and provide counselling to families. Some affected individuals have a developmental disorder limited to the brain, others a syndrome with additional congenital problems.

We can provide review of the MRI scans to advise on appropriate genetic testing. For MRI review please contact: g.mancini@erasmusmc.nl

After the clinical examination, classification of the disorder and appropriate genetic tests, if no diagnosis is reached, the patients can choose to participate into a research aimed at discovery of the genetic disorder.

This research is based on genome-wide DNA analysis (for example through linkage, homozygosity mapping and whole exome/genome sequencing of the affected individual(s) and/or the parents, as appropriate. Once the genetic mutation has been identified, the research also extends to investigation of the disease mechanism at biochemical and cell biological level, with focus on specific mechanisms involved in brain development, such as regulation of cell-cell interaction (e.g. formation and function of primary cilia) and regulation of cell death (apoptosis). The close collaboration with other departments at the Erasmus MC, and with national and international collaborators allows the rapid collection of information about very rare developmental disorders of the brain.

Research from our group in the last five years has led to the identification of several new genetic disorders classified within the Online McKusick catalogue of Mendelian Inheritance in Man (OMIM): SPG50, also called AP-4 syndrome (OMIM 612936); MEDS, microcephaly-epilepsy-diabetes syndrome (OMIM 614231); POREN2, familial porencephaly type 2 (OMIM 614483) and PMGYS, polymicrogyria with seizures syndrome (OMIM 614833).

Our research on periventricular nodular heterotopia has also resulted in the description of novel presentations for mutations in known genes (Oegema et al. 2010 and 2012) and in the recent identification of mutations in a novel gene called INTS8. Our research also sustains the PVNH support and awareness group (http://pvnhsupport.com/ ).

The identification of new DNA mutations in rare genetic disorders provides new diagnostic tests for the patients and accurate recurrence risk estimation to the families. Also, knowledge of the disease mechanism may lead to spin-off investigations for future therapies.

 


Selected recent publications

  1. van Binsbergen E, Ellis RJ, Abdelmalik N, Jarvis J, Randhawa K, Wyatt-Ashmead J, Canham N, Thorpe-Beeston JG, Mancini GM, Van Haelst MM.A fetus with de novo 2q33.2q35 deletion including MAP2 with brain anomalies, esophageal atresia, and laryngeal stenosis. Am J Med Genet A. 2014 Jan;164A(1):194-8.
  2. G. Mirzaa, D A Parry, A E Fry, K A Giamanco, J Schwartzentruber , M Vanstone, C V Logan, N Roberts, C A Johnson, S Singh, S S Kholmanskikh, C Adams, R D. Hodge, R F. Hevner, D T Bonthron, K P.J. Braun, L Faivre, J-B Rivière, J St-Onge, K W Gripp, G MS Mancini, Ki Pang, E Sweeney, H van Esch, N Verbeek, D Wieczorek, M Steinraths, J Majewski, FORGE Canada Consortium, K M Boycot, D T. Pilz, M. E Ross, W B. Dobyns, E G. Sheridan De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. Nature Genetics 2014, in press. IF 35
  3. Banka S, Lederer D, Benoit V, Jenkins E, Howard E, Bunstone S, Kerr B, McKee S, Lloyd IC, Shears D, Stewart H, White SM, Savarirayan R, Mancini GM, Beysen D, Cohn RD, Grisart B, Maystadt I, Donnai D. Novel KDM6A (UTX) mutations and a clinical and molecular review of the X-linked Kabuki syndrome (KS2). Clin Genet. 2014 Feb 14. doi: 10.1111/cge.12363.
  4. van de Kamp J, Errami A, Howidi M, Anselm I, Winter S, Phalin-Roque J, Osaka H, van Dooren S, Mancini G, Steinberg S, Salomons G. Genotype-phenotype correlation of contiguous gene deletions of SLC6A8, BCAP31 and ABCD1. Clin Genet. 2014 Mar 5. doi: 10.1111/cge.12355. [Epub ahead of print] IF 3.0
  5. Oegema R, Hulst JM, Theuns-Valks SD, van Unen LM, Schot R, Mancini GM, Schipper ME, de Wit MC, Sibbles BJ, de Coo IF, Nanninga V, Hofstra RM, Halley DJ, Brooks AS.Novel no-stop FLNA mutation causes multi-organ involvement in males. Am J Med Genet A. 2013 Sep;161(9):2376-84. IF 2.3
  6. Renske Oegema* , Cathryn J Poulton*, and Grazia Mancini. Reply To: Review Article “A single Strand that links multiple neuropathologies in human disease”. Letter to the Editor. Brain. 2014 Apr;137(Pt 4):e266. IF 9.9
  7. van de Kamp JM, Betsalel OT, Mercimek-Mahmutoglu S, Abulhoul L, Grünewald S, Anselm I, Azzouz H, Bratkovic D, de Brouwer A, Hamel B, Kleefstra T, Yntema H, Campistol J, Vilaseca MA, Cheillan D, D'Hooghe M, Diogo L, Garcia P, Valongo C, Fonseca M, Frints S, Wilcken B, von der Haar S, Meijers-Heijboer HE, Hofstede F, Johnson D, Kant SG, Lion-Francois L, Pitelet G, Longo N, Maat-Kievit JA, Monteiro JP, Munnich A, Muntau AC, Nassogne MC, Osaka H, Ounap K, Pinard JM, Quijano-Roy S, Poggenburg I, Poplawski N, Abdul-Rahman O, Ribes A, Arias A, Yaplito-Lee J, Schulze A, Schwartz CE, Schwenger S, Soares G, Sznajer Y, Valayannopoulos V, Van Esch H, Waltz S, Wamelink MM, Pouwels PJ, Errami A, van der Knaap MS, Jakobs C, Mancini GM, Salomons GS. Phenotype and genotype in 101 males with X-linked creatine transporter deficiency. J Med Genet. 2013 Jul;50(7):463-72. IF 5.7
  8. Poulton C*, Oegema* R, Heijsman D, Hoogeboom J, Schot R, Stroink H, Willemsen MA, Verheijen FW, van de Spek P, Kremer A, Mancini GM. Progressive cerebellar atrophy and polyneuropathy: expanding the spectrum of PNKP mutations. Neurogenetics. 2013 Feb;14(1):43-51. IF 3.5
  9. Kheradmand Kia S, Verbeek E, Engelen E, Schot R, Poot RA, de Coo IF, Lequin MH, Poulton CJ, Pourfarzad F, Grosveld FG, Brehm A, de Wit MC, Oegema R, Dobyns WB, Verheijen FW, Mancini GM. RTTN mutations link primary cilia function to organization of the human cerebral cortex. Am J Hum Genet. 2012 Sep 7;91(3):533-40. IF 11.
  10. Verbeek E, Meuwissen ME, Verheijen FW, Govaert PP, Licht DJ, Kuo DS, Poulton CJ, Schot R, Lequin MH, Dudink J, Halley DJ, de Coo RI, den Hollander JC, Oegema R, Gould DB, Mancini GM. COL4A2 mutation associated with familial porencephaly and small-vessel disease. Eur J Hum Genet. 2012 Aug;20(8):844-51. IF 4.4
  11. L.S. de Vries and G.M.S. Mancini. Intracerebral haemorrhage, COL4A1 and COL4A2 mutations, from fetal life into adulthood. Editorial. Ann Neurol 2012 Apr;71(4):439-41. IF 11
  12. Poulton CJ, Schot R, Kia SK, Jones M, Verheijen FW, Venselaar H, de Wit MC, de Graaff E, Bertoli-Avella AM, Mancini GM. Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors. Am J Hum Genet. 2011 Aug 12;89(2):265-76. IF 11
  13. R. Oegema, A. Maat-Kievit, M.H. Lequin, R. Schot, V.M.H. Nanninga- van den Neste, M.E. Doornbos, M.C.Y. de Wit, D.J. Halley, G.M.S. Mancini. Asymmetric Polymicrogyria and Periventricular Nodular Heterotopia due to Mutation in ARX . Am J Med Genet 2012. 158A(6):1472-6 IF 2.3
  14. Rivière JB, Mirzaa GM, O'Roak BJ, Beddaoui M, Alcantara D, Conway RL, St-Onge J, Schwartzentruber JA, Gripp KW, Nikkel SM, Worthylake T, Sullivan CT, Ward TR, Butler HE, Kramer NA, Albrecht B, Armour CM, Armstrong L, Caluseriu O, Cytrynbaum C, Drolet BA, Innes AM, Lauzon JL, Lin AE, Mancini GM, Meschino WS, Reggin JD, Saggar AK, Lerman-Sagie T, Uyanik G, Weksberg R, Zirn B, Beaulieu CL; Finding of Rare Disease Genes (FORGE) Canada Consortium, Majewski J, Bulman DE, O'Driscoll M, Shendure J, Graham JM Jr, Boycott KM, Dobyns WB. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet. 2012 Jun 24;44(8):934-40. IF 35.
  15. Roscioli T, Kamsteeg EJ, Buysse K, Maystadt I, van Reeuwijk J, van den Elzen C, van Beusekom E, Riemersma M, Pfundt R, Vissers LE, Schraders M, Altunoglu U, Buckley MF, Brunner HG, Grisart B, Zhou H, Veltman JA, Gilissen C, Mancini GM, Delrée P, Willemsen MA, Ramadža DP, Chitayat D, Bennett C, Sheridan E, Peeters EA, Tan-Sindhunata GM, de Die-Smulders CE, Devriendt K, Kayserili H, El-Hashash OA, Stemple DL, Lefeber DJ, Lin YY, van Bokhoven H.Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of α-dystroglycan. Nat Genet. 2012 May;44(5):581-5. IF 35
  16. Meuwissen ME, de Vries LS, Verbeek HA, Lequin MH, Govaert PP, Schot R, Cowan FM, Hennekam R, Rizzu P, Verheijen FW, Wessels MW, Mancini GM. Neurology. 2011 Mar 1;76(9):844-6. IF 8
  17. Oegema R, Schot R, deWit MCY, Lequin MH, Oosterbrink R., deCoo IFM, Mancini GM. KBG syndrome associated with periventricular nodular heterotopia. Clin Dysmorphol. 2010 Jul;19(3):164-
  18. R. Oegema, A.de Klein, A.J. Verkerk, Rachel Schot , Belinda Dumee, Hannie Douben, Marie-Claire Y. de Wit, Bert Eussen, Lorette Dubbel, Pino J. Poddighe, , Ingrid van der Laar, William B. Dobyns, Peter J. van der Spek, Maarten H. Lequin, Irenaeus F.M. de Coo, ,Marja W. Wessels and Grazia M.S. Mancini. Distinctive Phenotypic Abnormalities associated with Submicroscopic 21q22 Deletion including DYRK1A. Molecular Syndromology, 2010, 1:113-120
  19. Verkerk AJ, Schot R, Dumee B, Schellekens K, Swagemakers S, Bertoli-Avella AM, Lequin MH, Dudink J, Govaert P, van Zwol AL, Hirst J, Wessels MW, Catsman-Berrevoets C, Verheijen FW, de Graaff E, de Coo IF, Kros JM, Willemsen R, Willems PJ, van der Spek PJ, Mancini GM. Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. Am J Hum Genet. 2009 Jul;85(1):40-52. IF 11
  20. Verkerk AJ, Schot R, van Waterschoot L, Douben H, Poddighe PJ, Lequin MH, de Vries LS, Terhal P, Hahnemann JM, de Coo IF, de Wit MC, Wafelman LS, Garavelli L, Dobyns WB, Van der Spek PJ, de Klein A, Mancini GM. Unbalanced der(5)t(5;20) translocation associated with megalencephaly, perisylvian polymicrogyria, polydactyly and hydrocephalus. Am J MedGenet A. 2010 Jun;152A(6):1488-97. IF2.3

Recent grant allocations:

2014-2018 ErasmusMC Mrace Grant (PI): Cilia-related defects in Brain Developmental Disorders

2013-2014 Ohra-Nuts fonds (PI) :ROSEN, Rotterdam Onderzoek naar Stroke en Erfelijkheid bij Neonaten, project nr. 1203-030.

2010-2011 International Pediatric Research foundation fellowship (PI): Search for autosomal recessive mutation in 4 families with congenital microcephaly and infantile diabetes.


News

  1. Monitor 2014 - Classificatie zeldzame hersenafwijkingen (pdf)