Gene identification in Intellectual Disability Disorders in the era of Next Generation Sequencing: personalized genomics, phenomics and functional characterization
Projectomschrijving
In de afgelopen 15 jaar werden gedetailleerde klinische gegevens van patiënten met een verstandelijke beperking (VB) en
autisme-spectrumstoornis (ASS), die werden gezien op afdeling klinische genetica in Nijmegen, verzameld in de zogenaamde
Nijmegen Phenotype Database (NP-database). Aan het begin van het project bevatte de NP-database 7.168 patiënten met in
totaal 58.648 klinische kenmerken en tijdens het project werd deze uitgebreid tot 8.752 patiënten.
In totaal heeft dit TOP-project 37 high impact-publicaties opgeleverd. Hiermee heeft het een belangrijke bijdrage geleverd aan
ons begrip van de genetica van VB / ASS en verdere inzichten in de ontwikkeling, het fenotype-spectrum en de pathofysiologie
van deze stoornissen. Dit heeft reeds veel patiënten en hun gezinnen wereldwijd geholpen, aangezien hierdoor nu betere
begeleiding door de professionals mogelijk is en krachtige preklinische modellen beschikbaar zijn voor verdere
interventiestudies.
Producten
Titel: A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP
Auteur: Helsmoortel C, Vulto-van Silfhout AT, Coe BP, Vandeweyer G, Rooms L, van den Ende J, Schuurs-Hoeijmakers JH, Marcelis CL, Willemsen MH, Vissers LE, Yntema HG, Bakshi M, Wilson M, Witherspoon KT, Malmgren H, Nordgren A, Annerén G, Fichera M, Bosco P, Romano C, de Vries BB, Kleefstra T, Kooy RF, Eichler EE, Van der Aa N.
Magazine: Nature Genetics
Auteur: Helsmoortel C, Vulto-van Silfhout AT, Coe BP, Vandeweyer G, Rooms L, van den Ende J, Schuurs-Hoeijmakers JH, Marcelis CL, Willemsen MH, Vissers LE, Yntema HG, Bakshi M, Wilson M, Witherspoon KT, Malmgren H, Nordgren A, Annerén G, Fichera M, Bosco P, Romano C, de Vries BB, Kleefstra T, Kooy RF, Eichler EE, Van der Aa N.
Magazine: Nature Genetics
Titel: Intellectual disability and autism spectrum disorders ‘on the fly’: insights from Drosophila
Auteur: Coll-Tané, Mireia, Krebbers, Alina, Castells-Nobau, Anna, Zweier, Christiane, Schenck, Annette
Magazine: Disease Models and Mechanisms
Auteur: Coll-Tané, Mireia, Krebbers, Alina, Castells-Nobau, Anna, Zweier, Christiane, Schenck, Annette
Magazine: Disease Models and Mechanisms
Titel: Disruptive CHD8 mutations define a subtype of autism early in development.
Auteur: Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP, Penn O, Witherspoon K, Gerdts J, Baker C, Vulto-van Silfhout AT, Schuurs-Hoeijmakers JH, Fichera M, Bosco P, Buono S, Alberti A, Failla P, Peeters H, Steyaert J, Vissers LE, Francescatto L, Mefford HC, Rosenfeld JA, Bakken T, O'Roak BJ, Pawlus M, Moon R, Shendure J, Amaral DG, Lein E, Rankin J, Romano C, de Vries BB, Katsanis N, Eichler EE.
Magazine: Cell
Auteur: Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP, Penn O, Witherspoon K, Gerdts J, Baker C, Vulto-van Silfhout AT, Schuurs-Hoeijmakers JH, Fichera M, Bosco P, Buono S, Alberti A, Failla P, Peeters H, Steyaert J, Vissers LE, Francescatto L, Mefford HC, Rosenfeld JA, Bakken T, O'Roak BJ, Pawlus M, Moon R, Shendure J, Amaral DG, Lein E, Rankin J, Romano C, de Vries BB, Katsanis N, Eichler EE.
Magazine: Cell
Titel: A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy
Auteur: Zazo Seco C*, Castells-Nobau A*, Joo SH, Schraders M, Foo JN, van der Voet M, Velan SS, Nijhof B, Oostrik J, de Vrieze E, Katana R, Mansoor A, Huynen MA, Szklarczyk R, Oti M, Tranebjærg L, van Wijk E, Scheffer-de Gooyert JM, Siddique S, Baets J, de Jonghe P, Kazmi SAR, Sadananthan SA, van de Warrenburg BP, Khor CC, Göpfert MC, Qamar R, Schenck A, Kremer H, Siddiqi S
Magazine: Disease Models and Mechanisms
Auteur: Zazo Seco C*, Castells-Nobau A*, Joo SH, Schraders M, Foo JN, van der Voet M, Velan SS, Nijhof B, Oostrik J, de Vrieze E, Katana R, Mansoor A, Huynen MA, Szklarczyk R, Oti M, Tranebjærg L, van Wijk E, Scheffer-de Gooyert JM, Siddique S, Baets J, de Jonghe P, Kazmi SAR, Sadananthan SA, van de Warrenburg BP, Khor CC, Göpfert MC, Qamar R, Schenck A, Kremer H, Siddiqi S
Magazine: Disease Models and Mechanisms
Titel: YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction.
Auteur: Gabriele M, Vulto-van Silfhout AT, Germain PL, Vitriolo A, Kumar R, Douglas E, Haan E, Kosaki K, Takenouchi T, Rauch A, Steindl K, Frengen E, Misceo D, Pedurupillay CRJ, Stromme P, Rosenfeld JA, Shao Y, Craigen WJ, Schaaf CP, Rodriguez-Buritica D, Farach L, Friedman J, Thulin P, McLean SD, Nugent KM, Morton J, Nicholl J, Andrieux J, Stray-Pedersen A, Chambon P, Patrier S, Lynch SA, Kjaergaard S, Tørring PM, Brasch-Andersen C, Ronan A, van Haeringen A, Anderson PJ, Powis Z, Brunner HG, Pfundt R,
Magazine: The American Journal of Human Genetics
Auteur: Gabriele M, Vulto-van Silfhout AT, Germain PL, Vitriolo A, Kumar R, Douglas E, Haan E, Kosaki K, Takenouchi T, Rauch A, Steindl K, Frengen E, Misceo D, Pedurupillay CRJ, Stromme P, Rosenfeld JA, Shao Y, Craigen WJ, Schaaf CP, Rodriguez-Buritica D, Farach L, Friedman J, Thulin P, McLean SD, Nugent KM, Morton J, Nicholl J, Andrieux J, Stray-Pedersen A, Chambon P, Patrier S, Lynch SA, Kjaergaard S, Tørring PM, Brasch-Andersen C, Ronan A, van Haeringen A, Anderson PJ, Powis Z, Brunner HG, Pfundt R,
Magazine: The American Journal of Human Genetics
Titel: De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions
Auteur: Fregeau B, Kim BJ, Hernández-García A, Jordan VK, Cho MT, Schnur RE, Monaghan KG, Juusola J, Rosenfeld JA, Bhoj E, Zackai EH, Sacharow S, Barañano K, Bosch DG, de Vries BB, Lindstrom K, Schroeder A, James P, Kulch P, Lalani SR, van Haelst MM, van Gassen KL, van Binsbergen E, Barkovich AJ, Scott DA, Sherr EH.
Magazine: American Journal of Human Genetics
Auteur: Fregeau B, Kim BJ, Hernández-García A, Jordan VK, Cho MT, Schnur RE, Monaghan KG, Juusola J, Rosenfeld JA, Bhoj E, Zackai EH, Sacharow S, Barañano K, Bosch DG, de Vries BB, Lindstrom K, Schroeder A, James P, Kulch P, Lalani SR, van Haelst MM, van Gassen KL, van Binsbergen E, Barkovich AJ, Scott DA, Sherr EH.
Magazine: American Journal of Human Genetics
Titel: Genome sequencing identifies major causes of severe intellectual disability.
Auteur: Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BW, Willemsen MH, Kwint M, Janssen IM, Hoischen A, Schenck A, Leach R, Klein R, Tearle R, Bo T, Pfundt R, Yntema HG, de Vries BB, Kleefstra T, Brunner HG, Vissers LE, Veltman JA.
Magazine: Nature
Auteur: Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BW, Willemsen MH, Kwint M, Janssen IM, Hoischen A, Schenck A, Leach R, Klein R, Tearle R, Bo T, Pfundt R, Yntema HG, de Vries BB, Kleefstra T, Brunner HG, Vissers LE, Veltman JA.
Magazine: Nature
Titel: A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency
Auteur: Jansen S, Hoischen A, Coe BP, Carvill GL, Van Esch H, Bosch DGM, Andersen UA, Baker C, Bauters M, Bernier RA, van Bon BW, Claahsen-van der Grinten HL, Gecz J, Gilissen C, Grillo L, Hackett A, Kleefstra T, Koolen D, Kvarnung M, Larsen MJ, Marcelis C, McKenzie F, Monin ML, Nava C, Schuurs-Hoeijmakers JH, Pfundt R, Steehouwer M, Stevens SJC, Stumpel CT, Vansenne F, Vinci M, van de Vorst M, Vries P, Witherspoon K, Veltman JA, Brunner HG, Mefford HC, Romano C, Vissers LELM, Eichler EE, de Vries BBA
Magazine: European Journal of Human Genetics
Auteur: Jansen S, Hoischen A, Coe BP, Carvill GL, Van Esch H, Bosch DGM, Andersen UA, Baker C, Bauters M, Bernier RA, van Bon BW, Claahsen-van der Grinten HL, Gecz J, Gilissen C, Grillo L, Hackett A, Kleefstra T, Koolen D, Kvarnung M, Larsen MJ, Marcelis C, McKenzie F, Monin ML, Nava C, Schuurs-Hoeijmakers JH, Pfundt R, Steehouwer M, Stevens SJC, Stumpel CT, Vansenne F, Vinci M, van de Vorst M, Vries P, Witherspoon K, Veltman JA, Brunner HG, Mefford HC, Romano C, Vissers LELM, Eichler EE, de Vries BBA
Magazine: European Journal of Human Genetics
Titel: Biallelicframeshift mutation in RIN2 in a patient with intellectual disability and cataract, without RIN2 syndrome.
Auteur: van Amen-Hellebrekers CJM, Jansen S, Stegmann APA, Stevens SJC, Pfundt R, de Vries BBA
Magazine: American Journal of Medical Genetics A
Auteur: van Amen-Hellebrekers CJM, Jansen S, Stegmann APA, Stevens SJC, Pfundt R, de Vries BBA
Magazine: American Journal of Medical Genetics A
Titel: Altered GPM6A/M6 Dosage Impairs Cognition and Causes Phenotypes Reversible by Cholesterol in Human and Drosophila
Auteur: Gregor A, Kramer JM, van der Voet M, Schanze M, Uebe S, Donders R, Reis A, Schenck A, Zweier C
Magazine: Human Mutation
Auteur: Gregor A, Kramer JM, van der Voet M, Schanze M, Uebe S, Donders R, Reis A, Schenck A, Zweier C
Magazine: Human Mutation
Titel: High-throughput Analysis of Locomotor Behavior in the Drosophila Island Assay
Auteur: Eidhof I, Fenckova M, Elurbe D, van de Warrenburg B, Castells Nobau A, Schenck A
Magazine: Journal of Visualized Experiments
Auteur: Eidhof I, Fenckova M, Elurbe D, van de Warrenburg B, Castells Nobau A, Schenck A
Magazine: Journal of Visualized Experiments
Titel: Targeted sequencing identifies 90 neurodevelopmental disorder risk genes with autism and developmental disability biases.
Auteur: Stessman HAF, Xiong B, Coe BP, Wang T, Hoekzema K, Fenckova M, Kvarnung M,…., Harich B, Castells-Nobau A, Xia K, Peeters H, Nordenskjöld M, Schenck A, Bernier R, Eichler EE
Magazine: Nature Genetics
Auteur: Stessman HAF, Xiong B, Coe BP, Wang T, Hoekzema K, Fenckova M, Kvarnung M,…., Harich B, Castells-Nobau A, Xia K, Peeters H, Nordenskjöld M, Schenck A, Bernier R, Eichler EE
Magazine: Nature Genetics
Titel: De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila.
Auteur: 1. Lugtenberg D, Reijnders MR, Fenckova M, Bijlsma EK, Bernier R, van Bon BW, Smeets E, Vulto-van Silfhout AT, Bosch D, Eichler EE, Mefford HC, Carvill GL, Bongers EM, Schuurs-Hoeijmakers JH, Ruivenkamp CA, Santen GW, van den Maagdenberg AM, Peeters-Scholte CM, Kuenen S, Verstreken P, Pfundt R, Yntema HG, de Vries PF, Veltman JA, Hoischen A, Gilissen C, de Vries BB, Schenck A, Kleefstra T, Vissers LE.
Magazine: European Journal of Human Genetics
Auteur: 1. Lugtenberg D, Reijnders MR, Fenckova M, Bijlsma EK, Bernier R, van Bon BW, Smeets E, Vulto-van Silfhout AT, Bosch D, Eichler EE, Mefford HC, Carvill GL, Bongers EM, Schuurs-Hoeijmakers JH, Ruivenkamp CA, Santen GW, van den Maagdenberg AM, Peeters-Scholte CM, Kuenen S, Verstreken P, Pfundt R, Yntema HG, de Vries PF, Veltman JA, Hoischen A, Gilissen C, de Vries BB, Schenck A, Kleefstra T, Vissers LE.
Magazine: European Journal of Human Genetics
Titel: A Drosophila Mitochondrial Complex I Phenotype Array
Auteur: Foriel S, Renkema GH, Lasarzewski Y, Berkhout J, Rodenburg RJ, Smeitink JAM, Beyrath J, Schenck A
Magazine: frontiers in genetics
Auteur: Foriel S, Renkema GH, Lasarzewski Y, Berkhout J, Rodenburg RJ, Smeitink JAM, Beyrath J, Schenck A
Magazine: frontiers in genetics
Titel: De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome
Auteur: Kim JH, Shinde DN, Reijnders MR, Hauser NS, Belmonte RL, Wilson GR, Bosch DG, Bubulya PA, Shashi V, Petrovski S, Stone JK, Park EY, Veltman JA, Sinnema M, Stumpel CT, Draaisma JM, Nicolai J; University of Washington Center for Mendelian Genomics, Yntema HG, Lindstrom K, de Vries BB, Jewett T, Santoro SL, Vogt J; Deciphering Developmental Disorders Study, Bachman KK, Seeley AH, Krokosky A, Turner C, Rohena L, Hempel M, Kortüm F, Lessel D, Neu A, Strom TM, Wieczorek D, Bramswig N, Laccone FA, Beh
Magazine: American Journal of Human Genetics
Auteur: Kim JH, Shinde DN, Reijnders MR, Hauser NS, Belmonte RL, Wilson GR, Bosch DG, Bubulya PA, Shashi V, Petrovski S, Stone JK, Park EY, Veltman JA, Sinnema M, Stumpel CT, Draaisma JM, Nicolai J; University of Washington Center for Mendelian Genomics, Yntema HG, Lindstrom K, de Vries BB, Jewett T, Santoro SL, Vogt J; Deciphering Developmental Disorders Study, Bachman KK, Seeley AH, Krokosky A, Turner C, Rohena L, Hempel M, Kortüm F, Lessel D, Neu A, Strom TM, Wieczorek D, Bramswig N, Laccone FA, Beh
Magazine: American Journal of Human Genetics
Titel: Gene networks underlying convergent and pleiotropic phenotypes in a large and systematically-phenotyped cohort with heterogeneous developmental disorders.
Auteur: Andrews T, Meader S, Vulto-van Silfhout A, Taylor A, Steinberg J, Hehir-Kwa J, Pfundt R, de Leeuw N, de Vries BB, Webber C.
Magazine: PLoS Genetics
Auteur: Andrews T, Meader S, Vulto-van Silfhout A, Taylor A, Steinberg J, Hehir-Kwa J, Pfundt R, de Leeuw N, de Vries BB, Webber C.
Magazine: PLoS Genetics
Titel: Novel genetic causes of cerebral visual impairment.
Auteur: Bosch D.G., Boonstra, F.N., de Leeuw, N., Pfundt, R., Nillesen, W.M., de Ligt, J., Gilissen, C., Jhangiani, S., Vissers, L.E., Lupski, J.R., et al.
Magazine: European Journal of Human Genetics
Auteur: Bosch D.G., Boonstra, F.N., de Leeuw, N., Pfundt, R., Nillesen, W.M., de Ligt, J., Gilissen, C., Jhangiani, S., Vissers, L.E., Lupski, J.R., et al.
Magazine: European Journal of Human Genetics
Titel: Drosophila models of early onset cognitive disorders and their clinical applications.
Auteur: van der Voet M*, Nijhof B*, Oortveld MAW and Schenck A.
Magazine: Neuroscience & Biobehavioral Reviews
Auteur: van der Voet M*, Nijhof B*, Oortveld MAW and Schenck A.
Magazine: Neuroscience & Biobehavioral Reviews
Titel: ADHD-associated dopamine transporter, latrophilin and neurofibromin share a dopamine-related locomotor signature in Drosophila
Auteur: van der Voet M, Harich B, Franke B, Schenck A
Magazine: Molecular Psychiatry
Auteur: van der Voet M, Harich B, Franke B, Schenck A
Magazine: Molecular Psychiatry
Titel: De novo variants in CDK13 associated with syndromic ID/DD: Molecular and clinical delineation of 15 individuals and a further review.
Auteur: van den Akker WMR, Brummelman I, Martis LM, Timmermans RN, Pfundt R, Kleefstra T, Willemsen MH, Gerkes EH, Herkert JC, van Essen AJ, Rump P, Vansenne F, Terhal PA, van Haelst MM, Cristian I, Turner CE, Cho MT, Begtrup A, Willaert R, Fassi E, van Gassen KLI, Stegmann APA, de Vries BBA, Schuurs-Hoeijmakers JHM
Magazine: Clinical Genetics
Auteur: van den Akker WMR, Brummelman I, Martis LM, Timmermans RN, Pfundt R, Kleefstra T, Willemsen MH, Gerkes EH, Herkert JC, van Essen AJ, Rump P, Vansenne F, Terhal PA, van Haelst MM, Cristian I, Turner CE, Cho MT, Begtrup A, Willaert R, Fassi E, van Gassen KLI, Stegmann APA, de Vries BBA, Schuurs-Hoeijmakers JHM
Magazine: Clinical Genetics
Titel: Functional convergence of histone methyltransferases EHMT1 and KMT2C involved in Intellectual Disability and Autism
Auteur: Koemans TS, Kleefstra T, Stone MH, Chubak MC, Reijnders MRF, de Munnik S, Willemsen M, Fenckova M, Stumpel C, Bok LA, Sifuentes Saenz M, Byerly K, Baughn LB, Stegmann S, Pfundt R,van Bokhoven H, Schenck A$, Kramer JM
Magazine: PLoS Genetics
Auteur: Koemans TS, Kleefstra T, Stone MH, Chubak MC, Reijnders MRF, de Munnik S, Willemsen M, Fenckova M, Stumpel C, Bok LA, Sifuentes Saenz M, Byerly K, Baughn LB, Stegmann S, Pfundt R,van Bokhoven H, Schenck A$, Kramer JM
Magazine: PLoS Genetics
Titel: Cerebral visual impairment and intellectual disability caused by PGAP1 variants.
Auteur: Bosch D.G., Boonstra, F.N., Kinoshita, T., Jhangiani, S, de Ligt, J., Cremers,F.P., Lupski, J.R., Murakami, Y., de Vries, B.B.
Magazine: European Journal of Human Genetics
Auteur: Bosch D.G., Boonstra, F.N., Kinoshita, T., Jhangiani, S, de Ligt, J., Cremers,F.P., Lupski, J.R., Murakami, Y., de Vries, B.B.
Magazine: European Journal of Human Genetics
Titel: Low vision due to cerebral visual impairment: differentiating between acquired and genetic causes.
Auteur: Bosch, D.G., Boonstra, F.N., Willemsen, M.A., Cremers, F.P., and de Vries, B.B.
Magazine: BMC Ophthalmology
Auteur: Bosch, D.G., Boonstra, F.N., Willemsen, M.A., Cremers, F.P., and de Vries, B.B.
Magazine: BMC Ophthalmology
Titel: De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome.
Auteur: Jansen S, Geuer S, Pfundt R, Brough R, Ghongane P, Herkert JC, Marco EJ, Willemsen MH, Kleefstra T, Hannibal M, Shieh JT, Lynch SA, Flinter F, FitzPatrick DR, Gardham A, Bernhard B, Ragge N, Newbury-Ecob R, Bernier R, Kvarnung M, Magnusson EA, Wessels MW, van Slegtenhorst MA, Monaghan KG, de Vries P, Veltman JA; Deciphering Developmental Disorders Study, Lord CJ, Vissers LE, de Vries BB.
Magazine: The American Journal of Human Genetics
Auteur: Jansen S, Geuer S, Pfundt R, Brough R, Ghongane P, Herkert JC, Marco EJ, Willemsen MH, Kleefstra T, Hannibal M, Shieh JT, Lynch SA, Flinter F, FitzPatrick DR, Gardham A, Bernhard B, Ragge N, Newbury-Ecob R, Bernier R, Kvarnung M, Magnusson EA, Wessels MW, van Slegtenhorst MA, Monaghan KG, de Vries P, Veltman JA; Deciphering Developmental Disorders Study, Lord CJ, Vissers LE, de Vries BB.
Magazine: The American Journal of Human Genetics
Titel: Duplications of SLC1A3: Associated with ADHD and autism.
Auteur: van Amen-Hellebrekers CJ, Jansen S, Pfundt R, Schuurs-Hoeijmakers JH, Koolen DA, Marcelis CL, de Leeuw N, de Vries BB
Magazine: European Journal of Medical Genetics
Auteur: van Amen-Hellebrekers CJ, Jansen S, Pfundt R, Schuurs-Hoeijmakers JH, Koolen DA, Marcelis CL, de Leeuw N, de Vries BB
Magazine: European Journal of Medical Genetics
Titel: De novo loss-of-function mutations in X-linked SMC1A cause severe ID and therapy resistant epilepsy in females: expanding the phenotypic spectrum.
Auteur: Jansen S, Kleefstra T, Willemsen MH, de Vries P, Pfundt R, Hehir-Kwa JY, Gilissen C, Veltman JA, de Vries BB, Vissers LE.
Magazine: Clinical Genetics
Auteur: Jansen S, Kleefstra T, Willemsen MH, de Vries P, Pfundt R, Hehir-Kwa JY, Gilissen C, Veltman JA, de Vries BB, Vissers LE.
Magazine: Clinical Genetics
Titel: TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function
Auteur: Ba W, Yan Y, Reijnders MR, Schuurs-Hoeijmakers JH, Feenstra I, Bongers EM, Bosch DG, De Leeuw N, Pfundt R, Gilissen C, De Vries PF, Veltman JA, Hoischen A, Mefford HC, Eichler EE, Vissers LE, Nadif Kasri N, De Vries BB.
Magazine: Human Molecular Genetics
Auteur: Ba W, Yan Y, Reijnders MR, Schuurs-Hoeijmakers JH, Feenstra I, Bongers EM, Bosch DG, De Leeuw N, Pfundt R, Gilissen C, De Vries PF, Veltman JA, Hoischen A, Mefford HC, Eichler EE, Vissers LE, Nadif Kasri N, De Vries BB.
Magazine: Human Molecular Genetics
Titel: Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules
Auteur: Kochinke K*, Zweier C*, Nijhof B, Fenckova M, Cizek P, Honti F, Keerthikumar S, Oortveld MAW, Kleefstra T, Kramer JM, Webber C, Huynen MA, and Schenck A
Magazine: American Journal of Human Genetics
Auteur: Kochinke K*, Zweier C*, Nijhof B, Fenckova M, Cizek P, Honti F, Keerthikumar S, Oortveld MAW, Kleefstra T, Kramer JM, Webber C, Huynen MA, and Schenck A
Magazine: American Journal of Human Genetics
Titel: Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.
Auteur: Lelieveld SH, Reijnders MR, Pfundt R, Yntema HG, Kamsteeg EJ, de Vries P, de Vries BB, Willemsen MH, Kleefstra T, Löhner K, Vreeburg M, Stevens SJ, van der Burgt I, Bongers EM, Stegmann AP, Rump P, Rinne T, Nelen MR, Veltman JA, Vissers LE, Brunner HG, Gilissen C.
Magazine: Nature Neuroscience
Auteur: Lelieveld SH, Reijnders MR, Pfundt R, Yntema HG, Kamsteeg EJ, de Vries P, de Vries BB, Willemsen MH, Kleefstra T, Löhner K, Vreeburg M, Stevens SJ, van der Burgt I, Bongers EM, Stegmann AP, Rump P, Rinne T, Nelen MR, Veltman JA, Vissers LE, Brunner HG, Gilissen C.
Magazine: Nature Neuroscience
Titel: ADHD-associated dopamine transporter, latrophilin and neurofibromin share a dopamine-related locomotor signature in Drosophila
Auteur: van der Voet M, Harich B, Franke B, Schenck A
Magazine: Molecular Psychiatry
Auteur: van der Voet M, Harich B, Franke B, Schenck A
Magazine: Molecular Psychiatry
Titel: Chromosomal aberrations in cerebral visual impairment.
Auteur: Bosch, D.G., Boonstra, F.N., Reijnders, M.R., Pfundt, R., Cremers, F.P., and de Vries, B.B.
Magazine: European Journal of Pediatric Neurology
Auteur: Bosch, D.G., Boonstra, F.N., Reijnders, M.R., Pfundt, R., Cremers, F.P., and de Vries, B.B.
Magazine: European Journal of Pediatric Neurology
Titel: NR2F1 mutations cause optic atrophy with intellectual disability.
Auteur: Bosch, D.G.*, Boonstra, F.N.*, Gonzaga-Jauregui, C.*, Xu, M., de Ligt, J., Jhangiani, S., Wiszniewski, W., Muzny, D.M., Yntema, H.G., Pfundt, R., et al.
Magazine: American Journal of Human Genetics
Auteur: Bosch, D.G.*, Boonstra, F.N.*, Gonzaga-Jauregui, C.*, Xu, M., de Ligt, J., Jhangiani, S., Wiszniewski, W., Muzny, D.M., Yntema, H.G., Pfundt, R., et al.
Magazine: American Journal of Human Genetics
Titel: Two Algorithms for High-throughput and Multi-parametric Quantification of Drosophila Neuromuscular Junction Morphology.
Auteur: Castells-Nobau A*, Nijhof B*, Eidhof, I, Wolf L, de Gooyert-Scheffer JM, Monedero I, Toroja L, Coromina L, van der Laak, JAWM and Schenck A
Magazine: Journal of Visualized Experiments
Auteur: Castells-Nobau A*, Nijhof B*, Eidhof, I, Wolf L, de Gooyert-Scheffer JM, Monedero I, Toroja L, Coromina L, van der Laak, JAWM and Schenck A
Magazine: Journal of Visualized Experiments
Titel: Human Intellectual Disability genes form conserved functional modules in Drosophila.
Auteur: Oortveld MAV, Keerthikumar S, Oti M, Nijhof B, Fernandes AC, Kochinke K, van Engelen E, Ellenkamp T, Eshuis L, Galy A, van Bokhoven H, Habermann B, Brunner H, Zweier C, Verstreken P, Huynen MA and Schenck A
Magazine: PLoS Genetics
Auteur: Oortveld MAV, Keerthikumar S, Oti M, Nijhof B, Fernandes AC, Kochinke K, van Engelen E, Ellenkamp T, Eshuis L, Galy A, van Bokhoven H, Habermann B, Brunner H, Zweier C, Verstreken P, Huynen MA and Schenck A
Magazine: PLoS Genetics
Titel: Novel genetic causes for cerebral visual impairment.
Auteur: Bosch DG, Boonstra FN, de Leeuw N, Pfundt R, Nillesen WM, de Ligt J, Gilissen C, Jhangiani S, Lupski JR, Cremers FP, de Vries BB.
Magazine: European Journal of Human Genetics
Auteur: Bosch DG, Boonstra FN, de Leeuw N, Pfundt R, Nillesen WM, de Ligt J, Gilissen C, Jhangiani S, Lupski JR, Cremers FP, de Vries BB.
Magazine: European Journal of Human Genetics
Titel: Conserved regulation of neurodevelopmental processes and behavior by FoxP in Drosophila
Auteur: Castells-Nobau, Anna, Eidhof, Ilse, Fenckova, Michaela, Brenman-Suttner, Dova B., Scheffer-de Gooyert, Jolanda M., Christine, Sheren, Schellevis, Rosa L., van der Laan, Kiran, Quentin, Christine, van Ninhuijs, Lisa, Hofmann, Falko, Ejsmont, Radoslaw, Fisher, Simon E., Kramer, Jamie M., Sigrist, Stephan J., Simon, Anne F., Schenck, Annette
Magazine: PLoS Biology
Auteur: Castells-Nobau, Anna, Eidhof, Ilse, Fenckova, Michaela, Brenman-Suttner, Dova B., Scheffer-de Gooyert, Jolanda M., Christine, Sheren, Schellevis, Rosa L., van der Laan, Kiran, Quentin, Christine, van Ninhuijs, Lisa, Hofmann, Falko, Ejsmont, Radoslaw, Fisher, Simon E., Kramer, Jamie M., Sigrist, Stephan J., Simon, Anne F., Schenck, Annette
Magazine: PLoS Biology
Titel: Cerebral visual impairment, autism, and pancreatitis associated with a 9 Mbp deletion on 10p12
Auteur: Bosch, D.G., Boonstra, F.N., Pfundt, R., Cremers, F.P., and de Vries, B.B.
Magazine: Clinical Dysmorphology
Auteur: Bosch, D.G., Boonstra, F.N., Pfundt, R., Cremers, F.P., and de Vries, B.B.
Magazine: Clinical Dysmorphology
Titel: Converging evidence does not support GIT1 as an ADHD risk gene
Auteur: Klein M*, van der Voet M*, Harich B, van Hulzen K, Onnink M, Hoogman M, Guadalupe T, Zwiers M, Groothuismink J Verberkt A, Nijhof B, Castells-Nobau A, Psychiatric Genomics Consortium ADHD Working Group, Faraone SV, Buitelaar JK, Schenck A, Arias-Vasquez A, Franke B
Magazine: American Journal of Medical Genetics
Auteur: Klein M*, van der Voet M*, Harich B, van Hulzen K, Onnink M, Hoogman M, Guadalupe T, Zwiers M, Groothuismink J Verberkt A, Nijhof B, Castells-Nobau A, Psychiatric Genomics Consortium ADHD Working Group, Faraone SV, Buitelaar JK, Schenck A, Arias-Vasquez A, Franke B
Magazine: American Journal of Medical Genetics
Titel: Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration
Auteur: Dubos A, Castells-Nobau A, Meziane H, Oortveld MAW, Houbaert X, Iacono G, Martin C, Mittelhaeuser C, Lalanne V, Kramer JM, Messaddeq N, Quentin C, Slabbert J, Verstreken P, Sigrist SJ, Birling MC, Selloum M, Rosahl T, Mudget J, Stunnenberg HG, Humeau J, Schenck A# and Herault Y#
Magazine: Human Molecular Genetics
Auteur: Dubos A, Castells-Nobau A, Meziane H, Oortveld MAW, Houbaert X, Iacono G, Martin C, Mittelhaeuser C, Lalanne V, Kramer JM, Messaddeq N, Quentin C, Slabbert J, Verstreken P, Sigrist SJ, Birling MC, Selloum M, Rosahl T, Mudget J, Stunnenberg HG, Humeau J, Schenck A# and Herault Y#
Magazine: Human Molecular Genetics
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Samenvatting van de aanvraag
Intellectual Disability (ID) is a leading medical and socio-economic problem with a strong genetic component affecting approximately 1% of the population. So far, no more than a handful of autosomal genes have been well established as ID genes for which we understand the pathogenic nature of the mutations. The main reasons for this are that (a) ID is a genetically heterogeneous disease, and (b) the unavailability of affected tissue from patients, complicating functional validation. As a consequence, the majority of patients remains undiagnosed and there are virtually no targets for therapy. Absence of accurate and timely molecular diagnostics and therapeutics for this large group of rare diseases has a strong negative effect on the health management and lives of patients and relatives.
Whole genome or exome sequencing approaches have recently emerged as excellent discovery tools. De novo mutations in candidate ID genes are readily detected using a patient-parent sequencing approach, but the clinical relevance of these candidate ID genes remains to be established. In this project we propose to move 100 candidate ID genes from the discovery to the clinical and functional validation phase. For this we will use a 4-step systematic approach:
1. Select 100 candidate ID genes from diagnostic exome sequencing studies and literature, and establish the clinical characteristics seen in each patient
2. Interrogate phenotypically similar patients selected from large cohorts (n=10,000) of clinically well-characterised ID patients for recurrence of mutated genes
3. Apply disease-relevant high-throughput phenotyping in a highly efficient animal model, Drosophila, and
4. Establish causality of ID genes by combining human and fly phenotype data
We expect to find recurrent mutations in 30 to 40 validated ID genes, for which detailed clinical studies in patients and functional studies in Drosophila will provide crucial insight into the underlying clinical, molecular and cellular (neuro)pathologies. This will improve clinical and molecular diagnostics.
Our unconventional, interdisciplinary research aims to meet a major challenge in genome research and diagnostics, applied to one of the most frequent and complex class of disorders.