Theme 3: Plasticity and Memory

Genomic profiling in intellectual disability

Intellectual disability (ID) is defined by an IQ level below 70 and can be divided into mild (70-50), moderate (50-30) and severe (<30) level. It occurs in 2-3 % of newborns, and affects almost ½ million people in The Netherlands. Because of lifelong severity and poor curability the impact of ID is great, and there is great need for better basic knowledge. In clinical practice only ~50% of ID patients have received a proper diagnosis in The Netherlands. Any intervention or prevention in ID will require a much better insight into its underlying causes.

Patients with intellectual disability can be divided into non-syndromic and syndromic based upon the absence or presence of additional clinical features. Genetic anomalies especially chromosome aberrations are a major cause of ID. Microscopically detectable anomalies are mostly sporadic and usually cause ID in conjunction with physical malformations (=syndromic), because they lead to relatively large genetic imbalances (duplication/deletion of many genes). Three other genetic causes of ID exist. Single gene disorders can be transmitted through the germ line either as X-linked ID, which is largely limited to males, as dominant ID, which mostly occurs in a sporadic form, and recessive ID, which mostly affects sib-pairs. Despite significant progress, however, the genetic causes of ID remain largely unknown.

Objectives

This research project aims:

to carefully phenotype a large cohort of patients with intellectual disability
to identify genomic disorders and genes causing dominant and recessive forms of intellectual disability
to unravel genetic networks underlying intellectual disability

Approach

Within the current project phenotypically well-characterized patients are studied with various novel strategies in order to achieve a better understanding of the genetic networks underlying intellectual disability.

Clinical collection and detailed phenotyping on a large scale
Different assay systems are used to identify the various genomic aberrations underlying intellectual disability:
-Genome-wide deletion mapping
-Genome-wide exome sequencing
Bioinformatics: towards genetic networks in intellectual disability

Contact
Name:	Dr. Bert de Vries
Telephone:	024-3653678
Email:	Bert.deVries@radboudumc.nl
Visiting address:	Department of Human Genetics Radboud University Nijmegen Medical Center Geert Grooteplein 10, route 836 6525 GA Nijmegen The Netherlands
Postal address:	Department of Human Genetics Radboud University Nijmegen Medical Center P.O. Box 9101 / 836 6500 HB Nijmegen The Netherlands

Key Publications

Rivière JB, van Bon BW, Hoischen A, Kholmanskikh SS, O'Roak BJ, Gilissen C, Gijsen S, Sullivan CT, Christian SL, Abdul-Rahman OA, Atkin JF, Chassaing N, Drouin-Garraud V, Fry AE, Fryns JP, Gripp KW, Kempers M, Kleefstra T, Mancini GM, Nowaczyk MJ, van Ravenswaaij-Arts CM, Roscioli T, Marble M, Rosenfeld JA, Siu VM, de Vries BB, Shendure J, Verloes A, Veltman JA, Brunner HG, Ross ME, Pilz DT, Dobyns WB. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat Genet. 2012 Feb 26;44(4):440-4
Koolen DA, Kramer JM, Neveling K, Nillesen WM, Moore-Barton HL, Elmslie FV, Toutain A, Amiel J, Malan V, Tsai AC, Cheung SW, Gilissen C, Verwiel ET, Martens S, Feuth T, Bongers EM, de Vries P, Scheffer H, Vissers LE, de Brouwer AP, Brunner HG, Veltman JA, Schenck A, Yntema HG, de Vries BB. Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nat Genet. 2012 Apr 29;44(6):639-41
van Bon BW, Gilissen C, Grange DK, Hennekam RC, Kayserili H, Engels H, Reutter H, Ostergaard JR, Morava E, Tsiakas K, Isidor B, Le Merrer M, Eser M, Wieskamp N, de Vries P, Steehouwer M, Veltman JA, Robertson SP, Brunner HG, de Vries BB, Hoischen A. Cantú Syndrome Is Caused by Mutations in ABCC9. Am J Hum Genet. 2012 June 8;90:1094-1101
Koolen DA, Vissers LELM, Pfundt R, de Leeuw N, Knight SJL, Regan R, Kooy FR, Reyniers E, Romano C, Fichera M, Schinzel A, Baumer A, Anderlid BM, Schoumans J, Knoers NV, Geurts van Kessel A, Sistermans EA, Veltman JA, Brunner HG, de Vries BBA.
A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism.
Nat Genet. 38: 999-1001, 2006.
Kleefstra T, Brunner HG, Amiel J, Oudakker AR, Nillesen WM, Magee A, Genevieve D, Cormier-Daire V, van Esch H, Fryns JP, Hamel BC, Sistermans EA, de Vries BB, van Bokhoven H.
Loss-of-Function Mutations in Euchromatin Histone Methyl Transferase 1 (EHMT1) Cause the 9q34 Subtelomeric Deletion Syndrome.
Am J Hum Genet. 79:370-377, 2006
Koolen DA, Pfundt R, de Leeuw N, Hehir-Kwa JY, Nillesen WM, Neefs I, Scheltinga I, Sistermans E, Smeets D, Brunner HG, van Kessel AG, Veltman JA, de Vries BB.
Genomic microarrays in mental retardation: a practical workflow for diagnostic applications
Hum Mutat. 30:283-292, 2009.

For a list of all publications see Pubmed

Links

These studies are financially supported by:

The Dutch Brain Foundation
The Netherlands Organization for Health Research and Development (ZonMW)

Back to:
Theme 3:
Plasticity and Memory

Research Group
Genomic Profiling in Intellectual Disability

Principal Investigator
Dr. L.B.A. de Vries

Group members