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1. Goldberg–Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP

Author: MacKenzie, K.C., Graaf, B.M. (Bianca) de, Syrimis, A., Zhao, Y, Brosens, E. (Erwin), Mancini, G.M.S. (Grazia), Schot, R. (Rachel), Halley, D., Wilke, M. (Martina), Vøllo, A., Flinter, F. (Frances), Green, A., Mansour, S, Pilch, J. (Jacek), Stark, Z, Zamba-Papanicolaou, E., Christophidou-Anastasiadou, V., Hofstra, R.M.W. (Robert), Jongbloed, J.D., Nicolaou, N. (Nayia), Tanteles, G.A., Brooks, A.S. (Alice), Alves, M.M. (Maria), MacKenzie, K.C., Graaf, B.M. (Bianca) de, Syrimis, A., Zhao, Y, Brosens, E. (Erwin), Mancini, G.M.S. (Grazia), Schot, R. (Rachel), Halley, D., Wilke, M. (Martina), Vøllo, A., Flinter, F. (Frances), Green, A., Mansour, S, Pilch, J. (Jacek), Stark, Z, Zamba-Papanicolaou, E., Christophidou-Anastasiadou, V., Hofstra, R.M.W. (Robert), Jongbloed, J.D., Nicolaou, N. (Nayia), Tanteles, G.A., Brooks, A.S. (Alice), and Alves, M.M. (Maria)
Abstract: Goldberg–Shprintzen syndrome (GOSHS) is caused by loss of function variants in the kinesin binding protein gene (KIFBP). However, the phenotypic range of this syndrome is wide, indicating that other factors may play a role. To date, 37 patients with GOSHS have been reported. Here, we document nine new patients with variants in KIFBP: seven with nonsense variants and two with missense variants. To our knowledge, this is the first time that missense variants have been reported in GOSHS. We functionally investigated the effect of the variants identified, in an attempt to find a genotype–phenotype correlation. We also determined whether common Hirschsprung disease (HSCR)‐associated single nucleotide polymorphisms (SNPs), could explain the presence of HSCR in GOSHS. Our results showed that the missense variants led to reduced expression of KIFBP, while the truncating variants resulted in lack of protein. However, no correlation was found between the severity of GOSHS and the location of the variants. We were also unable to find a correlation between common HSCR‐associated SNPs, and HSCR development in GOSHS. In conclusion, we show that reduced, as well as lack of KIFBP expression can lead to GOSHS, and our results suggest that a threshold expression of KIFBP may modulate phenotypic variability of the disease.
Published: 2020
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2. Definitions and classification of malformations of cortical development: Practical guidelines

Author: Severino, M., Geraldo, A.F., Utz, N., Tortora, D., Pogledic, I., Klonowski, W., Triulzi, F., Arrigoni, F., Mankad, K., Leventer, R.J. (Richard), Mancini, G.M.S. (Grazia), Barkovich, J.A., Lequin, M.H., Rossi, A. (Antonio), Severino, M., Geraldo, A.F., Utz, N., Tortora, D., Pogledic, I., Klonowski, W., Triulzi, F., Arrigoni, F., Mankad, K., Leventer, R.J. (Richard), Mancini, G.M.S. (Grazia), Barkovich, J.A., Lequin, M.H., and Rossi, A. (Antonio)
Abstract: Malformations of cortical development are a group of rare disorders commonly manifesting with developmental delay, cerebral palsy or seizures. The neurological outcome is extremely variable depending on the type, extent and severity of the malformation and the involved genetic pathways of brain development. Neuroimaging plays an essential role in the diagnosis of these malformations, but several issues regarding malformations of cortical development definitions and classification remain unclear. The purpose of this consensus statement is to provide standardized malformations of cortical development terminology and classification for neuroradiological pattern interpretation. A committee of international experts in paediatric neuroradiology prepared systematic literature reviews and formulated neuroimaging recommendations in collaboration with geneticists, paediatric neurologists and pathologists during consensus meetings in the context of the European Network Neuro-MIG initiative on Brain Malformations (https://www.neuro-mig.org/). Malformations of cortical development neuroimaging features and practical recommendations are provided to aid both expert and non-expert radiologists and neurologists who may encounter patients with malformations of cortical development in their practice, with the aim of improving malformations of cortical development diagnosis and imaging interpretation worldwide.
Published: 2020
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3. The Phenotypic Spectrum of PNKP-Associated Disease and the Absence of Immunodeficiency and Cancer Predisposition in a Dutch Cohort

Author: Garrelfs, M.R., Takada, S., Kamsteeg, E.J. (Erik-Jan), Pegge, S., Mancini, G.M.S. (Grazia), Engelen, M. (Marc), van de Warrenburg, B, Rennings, A., van Gaalen, J., Peters, I., Weemaes, C., Burg, M. (Mirjam) van der, Willemsen, M.C. (M. C.), Garrelfs, M.R., Takada, S., Kamsteeg, E.J. (Erik-Jan), Pegge, S., Mancini, G.M.S. (Grazia), Engelen, M. (Marc), van de Warrenburg, B, Rennings, A., van Gaalen, J., Peters, I., Weemaes, C., Burg, M. (Mirjam) van der, and Willemsen, M.C. (M. C.)
Abstract: Background: We aimed to expand the number of currently known pathogenic PNKP mutations, to study the phenotypic spectrum, including radiological characteristics and genotype-phenotype correlations, and to assess whether immunodeficiency and increased cancer risk are part of the DNA repair disorder caused by mutations in the PNKP gene. Methods: We evaluated nine patients with PNKP mutations. A neurological history and examination was obtained. All patients had undergone neuroimaging and genetic testing as part of the prior diagnostic process. Laboratory measurements included potential biomarkers, and, in the context of a DNA repair disorder, we performed a detailed immunologic evaluation, including B cell repertoire analysis. Results: We identified three new mutations in the PNKP gene and confirm the phenotypic spectrum of PNKP-associated disease, ranging from microcephaly, seizures, and developmental delay to ataxia with oculomotor apraxia type 4. Irrespective of the phenotype, alpha-fetoprotein is a biochemical marker and increases with age and progression of the disease. On neuroimaging, (progressive) cerebellar atrophy was a universal feature. No clinical signs of immunodeficiency were present, and immunologic assessment was unremarkable. One patient developed cancer, but this was attributed to a concurrent von HippelLindau mutation. Conclusions: Immunodeficiency and cancer predisposition do not appear to be part of PNKP-associated disease, contrasting many other DNA repair disorders. Furthermore, our study illustrates that the previously described syndromes microcephaly, seizures, and developmental delay, and ataxia with oculomotor apraxia type 4, represent the extremes of an overlapping spectrum of disease. Cerebellar atrophy and elevated serum alpha-fetoprotein levels are early diagnostic findings across the entire phenotypical spectrum.
Published: 2020
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4. The potential diagnostic yield of whole exome sequencing in pregnancies complicated by fetal ultrasound anomalies

Author: Diderich, K.E.M. (Karin), Romijn, K. (Kathleen), Joosten, A-M.S (Marieke), Govaerts, L.C. (Lutgarde), Polak, M.G. (Marike), Brüggenwirth, H.T. (Hennie), Wilke, M. (Martina), Slegtenhorst, M.A. (Marjon) van, Bever, Y. (Yolande) van, Brooks, A.S. (Alice), Mancini, G.M.S. (Grazia), Laar, I.M.B.H. (Ingrid) van de, Kromosoeto, J.N.R. (Joan), Knapen, M.F.C.M. (Maarten), Go, A.T.J.I. (Attie), Van Opstal, A.R.M. (Diane), Hoefsloot, E.H. (Lies), Galjaard, R-J.H. (Robert-Jan), Srebniak, M.I. (Malgorzata), Diderich, K.E.M. (Karin), Romijn, K. (Kathleen), Joosten, A-M.S (Marieke), Govaerts, L.C. (Lutgarde), Polak, M.G. (Marike), Brüggenwirth, H.T. (Hennie), Wilke, M. (Martina), Slegtenhorst, M.A. (Marjon) van, Bever, Y. (Yolande) van, Brooks, A.S. (Alice), Mancini, G.M.S. (Grazia), Laar, I.M.B.H. (Ingrid) van de, Kromosoeto, J.N.R. (Joan), Knapen, M.F.C.M. (Maarten), Go, A.T.J.I. (Attie), Van Opstal, A.R.M. (Diane), Hoefsloot, E.H. (Lies), Galjaard, R-J.H. (Robert-Jan), and Srebniak, M.I. (Malgorzata)
Abstract: Introduction: The aim of this retrospective cohort study was to determine the potential diagnostic yield of prenatal whole exome sequencing in fetuses with structural anomalies on expert ultrasound scans and normal chromosomal microarray results. Material and methods: In the period 2013-2016, 391 pregnant women with fetal ultrasound anomalies who received normal chromosomal microarray results, were referred for additional genetic counseling and opted for additional molecular testing pre- and/or postnatally. Most of the couples received only a targeted molecular test and in 159 cases (40.7%) whole exome sequencing (broad gene panels or open exome) was performed. The results of these molecular tests were evaluated retrospectively, regardless of the time of the genetic diagnosis (prenatal or postnatal). Results: In 76 of 391 fetuses (19.4%, 95% CI 15.8%-23.6%) molecular testing provided a genetic diagnosis with identification of (likely) pathogenic variants. In the majority of cases (91.1%, 73/76) the (likely) pathogenic variant would be detected by prenatal whole exome sequencing analysis. Conclusions: Our retrospective cohort study shows that prenatal whole exome sequencing, if offered by a clinical geneticist, in addition to chromosomal microarray, would notably increa
Published: 2020
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5. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Author: Bryant, L. (Laura), Li, D. (Dong), Cox, S.G. (Samuel G.), Marchione, D. (Dylan), Joiner, E.F. (Evan F.), Wilson, K. (Khadija), Janssen, K. (Kevin), Lee, P. (Pearl), March, K. (Keith), Nair, D. (Divya), Sherr, E. (Elliott), Fregeau, B. (Brieana), Wierenga, K.J. (Klaas J.), Wadley, A. (Alexandrea), Mancini, G.M.S. (Grazia), Powell-Hamilton, N. (Nina), Kamp, J.J.P. (Jacques) van de, Grebe, T. (Theresa), Dean, J. (John), Ross, A.J. (Alison), Crawford, H.P. (Heather P.), Powis, Z. (Zoe), Cho, M.T. (Megan T.), Willing, M.C. (Marcia C.), Manwaring, L. (Linda), Schot, R. (Rachel), Nava, C. (Caroline), Afenjar, A. (Alexandra), Lessel, D. (Davor), Wagner, M. (Matias), Klopstock, T. (Thomas), Winkelmann, B., Catarino, C.B. (Claudia B.), Retterer, K. (Kyle), Schuette, J.L. (Jane L.), Innis, J.W. (Jeffrey), Pizzino, A. (Amy), Lüttgen, S. (Sabine), Denecke, J. (Jonas), Strom, T.M. (Tim), Monaghan, K.G. (Kristin G.), Yuan, Z.-F. (Zuo-Fei), Dubbs, H. (Holly), Bend, R. (Renee), Lee, J.A. (Jennifer A.), Lyons, M.J. (Michael J.), Hoefele, J. (Julia), Günthner, R. (Roman), Reutter, H. (Heiko), Keren, B. (Boris), Radtke, K. (Kelly), Sherbini, O. (Omar), Mrokse, C. (Cameron), Helbig, K.L. (Katherine L.), Odent, S. (Sylvie), Cogne, B. (Benjamin), Mercier, S. (Sandra), Bezieau, S. (Stephane), Besnard, T. (Thomas), Kury, S. (Sebastien), Redon, R. (Richard), Reinson, K. (Karit), Wojcik, M.H. (Monica H.), Õunap, K. (Katrin), Ilves, P. (Pilvi), Innes, A.M. (A Micheil), Kernohan, K.D. (Kristin), Costain, G. (Gregory), Meyn, M.S. (M Stephen), Chitayat, D. (David), Zackai, E. (Elaine), Lehman, A. (Anna), Kitson, H. (Hilary), Martin, M.G. (Martin G.), Martinez-Agosto, J.A. (Julian A.), Nelson, S.F. (Stan F.), Palmer, C.G.S. (Christina G S), Papp, J.C. (Jeanette C.), Parker, N.H. (Neil H.), Sinsheimer, J.S. (Janet S.), Vilain, E. (Eric), Wan, J. (Jijun), Yoon, A.J. (Amanda J.), Zheng, A. (Allison), Brimble, E. (Elise), Ferrero, G.B. (Giovanni Battista), Radio, F.C. (Francesca Clementina), Carli, D. (Diana), Barresi, S. (Sabina), Brusco, A. (Alfredo), Tartaglia, M. (Marco), Thomas, J.M. (Jennifer Muncy), Umana, L. (Luis), Weiss, M.M. (Marjan M.), Gotway, G. (Garrett), Stuurman, K.E. (Kyra), Thompson, M.L. (Michelle L.), McWalter, K. (Kirsty), Stumpel, C.T.R.M. (Constance T R M), Stevens, S.J.C. (Servi J C), Stegmann, A.P.A. (Alexander P A), Tveten, K. (Kristian), Vøllo, A. (Arve), Prescott, T. (Trine), Fagerberg, C. (Christina), Laulund, L.W. (Lone Walentin), Larsen, M.J. (Martin J.), Byler, M. (Melissa), Lebel, R.R. (Robert Roger), Hurst, A.C. (Anna C.), Dean, J. (Joy), Schrier Vergano, S.A. (Samantha A.), Norman, J. (Jennifer), Mercimek-Andrews, S. (Saadet), Neira, J. (Juanita), Van Allen, M.I. (Margot I.), Longo, N. (Nicola), Sellars, E. (Elizabeth), Louie, R.J. (Raymond J.), Cathey, S.S. (Sara S.), Brokamp, E. (Elly), Héron, D. (Delphine), Snyder, M. (Molly), Vanderver, A. (Adeline), Simon, C. (Celeste), de la Cruz, X. (Xavier), Padilla, N. (Natália), Crump, J.G. (J Gage), Chung, W. (Wendy), Garcia, B. (Benjamin), Hakonarson, H. (Hakon), Bhoj, E.J. (Elizabeth J.), Bryant, L. (Laura), Li, D. (Dong), Cox, S.G. (Samuel G.), Marchione, D. (Dylan), Joiner, E.F. (Evan F.), Wilson, K. (Khadija), Janssen, K. (Kevin), Lee, P. (Pearl), March, K. (Keith), Nair, D. (Divya), Sherr, E. (Elliott), Fregeau, B. (Brieana), Wierenga, K.J. (Klaas J.), Wadley, A. (Alexandrea), Mancini, G.M.S. (Grazia), Powell-Hamilton, N. (Nina), Kamp, J.J.P. (Jacques) van de, Grebe, T. (Theresa), Dean, J. (John), Ross, A.J. (Alison), Crawford, H.P. (Heather P.), Powis, Z. (Zoe), Cho, M.T. (Megan T.), Willing, M.C. (Marcia C.), Manwaring, L. (Linda), Schot, R. (Rachel), Nava, C. (Caroline), Afenjar, A. (Alexandra), Lessel, D. (Davor), Wagner, M. (Matias), Klopstock, T. (Thomas), Winkelmann, B., Catarino, C.B. (Claudia B.), Retterer, K. (Kyle), Schuette, J.L. (Jane L.), Innis, J.W. (Jeffrey), Pizzino, A. (Amy), Lüttgen, S. (Sabine), Denecke, J. (Jonas), Strom, T.M. (Tim), Monaghan, K.G. (Kristin G.), Yuan, Z.-F. (Zuo-Fei), Dubbs, H. (Holly), Bend, R. (Renee), Lee, J.A. (Jennifer A.), Lyons, M.J. (Michael J.), Hoefele, J. (Julia), Günthner, R. (Roman), Reutter, H. (Heiko), Keren, B. (Boris), Radtke, K. (Kelly), Sherbini, O. (Omar), Mrokse, C. (Cameron), Helbig, K.L. (Katherine L.), Odent, S. (Sylvie), Cogne, B. (Benjamin), Mercier, S. (Sandra), Bezieau, S. (Stephane), Besnard, T. (Thomas), Kury, S. (Sebastien), Redon, R. (Richard), Reinson, K. (Karit), Wojcik, M.H. (Monica H.), Õunap, K. (Katrin), Ilves, P. (Pilvi), Innes, A.M. (A Micheil), Kernohan, K.D. (Kristin), Costain, G. (Gregory), Meyn, M.S. (M Stephen), Chitayat, D. (David), Zackai, E. (Elaine), Lehman, A. (Anna), Kitson, H. (Hilary), Martin, M.G. (Martin G.), Martinez-Agosto, J.A. (Julian A.), Nelson, S.F. (Stan F.), Palmer, C.G.S. (Christina G S), Papp, J.C. (Jeanette C.), Parker, N.H. (Neil H.), Sinsheimer, J.S. (Janet S.), Vilain, E. (Eric), Wan, J. (Jijun), Yoon, A.J. (Amanda J.), Zheng, A. (Allison), Brimble, E. (Elise), Ferrero, G.B. (Giovanni Battista), Radio, F.C. (Francesca Clementina), Carli, D. (Diana), Barresi, S. (Sabina), Brusco, A. (Alfredo), Tartaglia, M. (Marco), Thomas, J.M. (Jennifer Muncy), Umana, L. (Luis), Weiss, M.M. (Marjan M.), Gotway, G. (Garrett), Stuurman, K.E. (Kyra), Thompson, M.L. (Michelle L.), McWalter, K. (Kirsty), Stumpel, C.T.R.M. (Constance T R M), Stevens, S.J.C. (Servi J C), Stegmann, A.P.A. (Alexander P A), Tveten, K. (Kristian), Vøllo, A. (Arve), Prescott, T. (Trine), Fagerberg, C. (Christina), Laulund, L.W. (Lone Walentin), Larsen, M.J. (Martin J.), Byler, M. (Melissa), Lebel, R.R. (Robert Roger), Hurst, A.C. (Anna C.), Dean, J. (Joy), Schrier Vergano, S.A. (Samantha A.), Norman, J. (Jennifer), Mercimek-Andrews, S. (Saadet), Neira, J. (Juanita), Van Allen, M.I. (Margot I.), Longo, N. (Nicola), Sellars, E. (Elizabeth), Louie, R.J. (Raymond J.), Cathey, S.S. (Sara S.), Brokamp, E. (Elly), Héron, D. (Delphine), Snyder, M. (Molly), Vanderver, A. (Adeline), Simon, C. (Celeste), de la Cruz, X. (Xavier), Padilla, N. (Natália), Crump, J.G. (J Gage), Chung, W. (Wendy), Garcia, B. (Benjamin), Hakonarson, H. (Hakon), and Bhoj, E.J. (Elizabeth J.)
Abstract: Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.
Published: 2020
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6. International consensus recommendations on the diagnostic work-up for malformations of cortical development

Author: Oegema, R. (Renske), Barakat, T.S. (Tahsin Stefan), Wilke, M. (Martina), Stouffs, K. (Katrien), Amrom, D. (Dina), Aronica, E.M.A. (Eleonora), Bahi-Buisson, N. (Nadia), Conti, V. (Valerio), Fry, A.E. (Andrew E.), Geis, T. (Tobias), Andres, D.G. (David Gomez), Parrini, E. (Elena), Pogledic, I. (Ivana), Said, E. (Edith), Soler, D. (Doriette), Valor, L.M. (Luis M.), Zaki, M.S. (Maha), Mirzaa, G.M. (Ghayda), Dobyns, W.B. (William), Reiner, O. (Orly), Guerrini, R. (Renzo), Pilz, D.T. (Daniela), Hehr, U. (Ute), Leventer, R.J. (Richard), Jansen, A.C. (Anna C.), Mancini, G.M.S. (Grazia), Di Donato, N. (Nataliya), Oegema, R. (Renske), Barakat, T.S. (Tahsin Stefan), Wilke, M. (Martina), Stouffs, K. (Katrien), Amrom, D. (Dina), Aronica, E.M.A. (Eleonora), Bahi-Buisson, N. (Nadia), Conti, V. (Valerio), Fry, A.E. (Andrew E.), Geis, T. (Tobias), Andres, D.G. (David Gomez), Parrini, E. (Elena), Pogledic, I. (Ivana), Said, E. (Edith), Soler, D. (Doriette), Valor, L.M. (Luis M.), Zaki, M.S. (Maha), Mirzaa, G.M. (Ghayda), Dobyns, W.B. (William), Reiner, O. (Orly), Guerrini, R. (Renzo), Pilz, D.T. (Daniela), Hehr, U. (Ute), Leventer, R.J. (Richard), Jansen, A.C. (Anna C.), Mancini, G.M.S. (Grazia), and Di Donato, N. (Nataliya)
Abstract: Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management. In this article, the international MCD network Neuro-MIG provides consensus recommendations to aid both expert and non-expert clinicians in the diagnostic work-up of MCDs with the aim of improving patient management worldwide. We reviewed the literature on clinical presentation, aetiology and diagnostic approaches for the main MCD subtypes and collected data on current practices and recommendations from clinicians and diagnostic laboratories within Neuro-MIG. We reached consensus by 42 professionals from 20 countries, using expert discussions and a Delphi consensus process. We present a diagnostic workflow that can be applied to any individual with MCD and a comprehensive list of MCD-related genes with their associated phenotypes. The workflow is designed to maximize the diagnostic yield and increase the number of patients receiving personalized care and counselling on prognosis and recurrence risk.
Published: 2020
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7. Defining the phenotypical spectrum associated with variants in TUBB2A

Author: Brock, S. (Stefanie), Vanderhasselt, T. (Tim), Vermaning, S. (Sietske), Keymolen, K. (Kathelijn), Régal, L. (Luc), Romaniello, R. (Romina), Wieczorek, D. (Dagmar), Storm, T.M. (Tim Matthias), Schaeferhoff, K. (Karin), Hehr, U. (Ute), Kuechler, A. (Alma), Krägeloh-Mann, I. (Ingeborg), Haack, T.B. (Tobias B.), Kasteleijn, E. (Esmee), Schot, R. (Rachel), Mancini, G.M.S. (Grazia), Webster, R. (Richard), Mohammad, S. (Shekeeb), Leventer, R.J. (Richard), Mirzaa, G.M. (Ghayda), Dobyns, W.B. (William), Bahi-Buisson, N. (Nadia), Meuwissen, M.E.C. (Marije), Jansen, A.C. (Anna C.), Stouffs, K. (Katrien), Brock, S. (Stefanie), Vanderhasselt, T. (Tim), Vermaning, S. (Sietske), Keymolen, K. (Kathelijn), Régal, L. (Luc), Romaniello, R. (Romina), Wieczorek, D. (Dagmar), Storm, T.M. (Tim Matthias), Schaeferhoff, K. (Karin), Hehr, U. (Ute), Kuechler, A. (Alma), Krägeloh-Mann, I. (Ingeborg), Haack, T.B. (Tobias B.), Kasteleijn, E. (Esmee), Schot, R. (Rachel), Mancini, G.M.S. (Grazia), Webster, R. (Richard), Mohammad, S. (Shekeeb), Leventer, R.J. (Richard), Mirzaa, G.M. (Ghayda), Dobyns, W.B. (William), Bahi-Buisson, N. (Nadia), Meuwissen, M.E.C. (Marije), Jansen, A.C. (Anna C.), and Stouffs, K. (Katrien)
Abstract: BACKGROUND: Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis. METHODS: In order to further refine the phenotypical spectrum associated with TUBB2A, clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed. RESULTS: We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy. CONCLUSION: The imaging phenotype associated with pathogenic v
Published: 2020
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8. Human RAD50 deficiency: Confirmation of a distinctive phenotype

Author: Ragamin, A. (Aviël), Yigit, G. (Gökhan), Bousset, K. (Kristine), Beleggia, F. (Filippo), Verheijen, F.W. (Frans), Wit, M.C.Y. (Marie Claire) de, Strom, T.M. (Tim M.), Dörk, T. (Thilo), Wollnik, B. (Bernd), Mancini, G.M.S. (Grazia), Ragamin, A. (Aviël), Yigit, G. (Gökhan), Bousset, K. (Kristine), Beleggia, F. (Filippo), Verheijen, F.W. (Frans), Wit, M.C.Y. (Marie Claire) de, Strom, T.M. (Tim M.), Dörk, T. (Thilo), Wollnik, B. (Bernd), and Mancini, G.M.S. (Grazia)
Abstract: DNA double-strand breaks (DSBs) are highly toxic DNA lesions that can lead to chromosomal instability, loss of genes and cancer. The MRE11/RAD50/NBN (MRN) complex is keystone involved in signaling processes inducing the repair of DSB by, for example, in activating pathways leading to homologous recombination repair and nonhomologous end joining. Additionally, the MRN complex also plays an important role in the maintenance of telomeres and can act as a stabilizer at replication forks. Mutations in NBN and MRE11 are associated with Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT)-like disorder, respectively. So far, only one single patient with biallelic loss of function variants in RAD50 has been reported presenting with features classified as NBS-like disorder. Here, we report a long-term follow-up of an unrelated patient with facial dysmorphisms, microcephaly, skeletal features, and short stature who is homozygous for a novel variant in RAD50. We could show that this variant, c.2524G > A in exon 15 of the RAD50 gene, induces aberrant splicing of RAD50 mRNA mainly leading to premature protein truncation and thereby, most likely, to loss of RAD50 function. Using patient-derived primary fibroblasts, we could show abnormal radioresistant DNA synthesis confirming pathogenicity of the identified variant. Immunoblotting experiments showed strongly reduced protein levels of RAD50 in the pat
Published: 2020
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9. EML1-associated brain overgrowth syndrome with ribbon-like heterotopia

Author: Oegema, R. (Renske), McGillivray, G. (George), Leventer, R.J. (Richard), Le Moing, A.-G. (Anne-Gaëlle), Bahi-Buisson, N. (Nadia), Barnicoat, A. (Angela), Mandelstam, S. (Simone), Francis, D. (David), Francis, F. (Fiona), Mancini, G.M.S. (Grazia), Savelberg, S.M.C. (Sanne M.C.), Haaften, G. (Gijs) van, Mankad, K. (Kshitij), Leguin, M. (Maarten), Oegema, R. (Renske), McGillivray, G. (George), Leventer, R.J. (Richard), Le Moing, A.-G. (Anne-Gaëlle), Bahi-Buisson, N. (Nadia), Barnicoat, A. (Angela), Mandelstam, S. (Simone), Francis, D. (David), Francis, F. (Fiona), Mancini, G.M.S. (Grazia), Savelberg, S.M.C. (Sanne M.C.), Haaften, G. (Gijs) van, Mankad, K. (Kshitij), and Leguin, M. (Maarten)
Abstract: EML1 encodes the protein Echinoderm microtubule-associated protein-like 1 or EMAP-1 that binds to the microtubule complex. Mutations in this gene resulting in complex brain malformations have only recently been published with limited clinical descriptions. We provide further clinical and imaging details on three previously published families, and describe two novel unrelated individuals with a homozygous partial EML1 deletion and a homozygous missense variant c.760G>A, p.(Val254Met), respectively. From review of the clinical and imaging data of eight individuals from five families with biallelic EML1 variants, a very consistent imaging phenotype emerges. The clinical syndrome is characterized by mainly neurological features including severe developmental delay, drug-resistant seizures and visual impairment. On brain imaging there is megalencephaly with a characteristic ribbo
Published: 2019
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10. Subcortical heterotopic gray matter brain malformations: Classification study of 107 individuals

Author: Oegema, R. (Renske), Barkovich, J. (James), Mancini, G.M.S. (Grazia), Guerrini, R. (Renzo), Dobyns, W.B. (William), Oegema, R. (Renske), Barkovich, J. (James), Mancini, G.M.S. (Grazia), Guerrini, R. (Renzo), and Dobyns, W.B. (William)
Abstract: OBJECTIVE: To better evaluate the imaging spectrum of subcortical heterotopic gray matter brain malformations (subcortical heterotopia [SUBH]), we systematically reviewed neuroimaging and clinical data of 107 affected individuals. METHODS: SUBH is defined as heterotopic gray matter, located within the white matter between the cortex and lateral ventricles. Four large brain malformation databases were searched for individuals with these malformations; data on imaging, clinical outcomes, and results of molecular testing were systematically reviewed and integrated with all previously published subtypes to create a single classification system. RESULTS: Review of the databases revealed 107 patients with SUBH, the large majority scanned during childhood (84%), including more than half before 4 years (59%). Although most individuals had cognitive or motor disability, 19% had normal development. Epilepsy was documented in 69%. Additional brain malformations were common and included abnormalities of the corpus callosum (65/102 [64%]), and, often, brainstem or cerebellum (47/106 [44%]). Extent of the heterotopic gray matter brain malformations (unilateral or bilateral) did not influence the presence or age at onset of seizures. Although genetic testing was not systematically performed in this group, the sporadic occurrence and frequent asymmetry suggests either postzygotic mutations or prenatal disruptive events. Several rare, bilateral forms are caused by mutations in
Published: 2019
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11. Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission

Author: Guo, H. (Hui), Li, Y. (Ying), Shen, L. (Lu), Wang, T. (Tianyun), Jia, X. (Xiangbin), Liu, L. (Lijuan), Xu, T. (Tao), Ou, M. (Mengzhu), Hoekzema, K. (Kendra), Wu, H. (Huidan), Gillentine, M.A. (Madelyn A.), Liu, C. (Cenying), Ni, H. (Hailun), Peng, P. (Pengwei), Zhao, R. (Rongjuan), Zhang, Y. (Yu), Phornphutkul, C. (Chanika), Stegmann, A.P.A. (Alexander P.A.), Prada, C.E. (C.), Hopkin, R., Shieh, J.T. (Joseph T.), McWalter, K. (Kirsty), Monaghan, K.G. (Kristin G.), Hasselt, P.M. (Peter) van, van Gassen, K. (Koen), Bai, T. (Ting), Long, M. (Min), Han, L. (Lin), Quan, Y. (Yingting), Chen, M. (Meilin), Zhang, Y. (Yaowen), Li, K. (Kuokuo), Zhang, Q. (Qiumeng), Tan, J. (Jieqiong), Zhu, T. (Tengfei), Liu, Y. (Yaning), Pang, N. (Nan), Peng, J. (Jing), Scott, D.A., Lalani, S.R. (Seema R.), Azamian, M. (Mahshid), Mancini, G.M.S. (Grazia), Adams, D.J. (Darius J.), Kvarnung, M. (Malin), Lindstrand, A. (Anna), Nordgren, A. (Ann), Pevsner, J. (Jonathan), Osei-Owusu, I.A. (Ikeoluwa A.), Romano, C. (Corrado), Calabrese, G. (Giuseppe), Galesi, O. (O.), Gecz, J. (Jozef), Haan, E. (Eric), Ranells, J. (Judith), Racobaldo, M. (Melissa), Nordenskjöld, M., Madan-Khetarpal, S. (Suneeta), Sebastian, J. (Jessica), Ball, S. (Susie), Zou, X. (Xiaobing), Zhao, J. (Jingping), Hu, Z. (Zhengmao), Xia, F. (Fan), Liu, P. (Pengfei), Rosenfeld, J.A. (Jill), Vries, B. (Boukje) de, Bernier, R.A. (Raphael A.), Xu, Z.-Q.D. (Zhi-Qing David), Li, H. (Honghui), Xie, W. (Wei), Hufnagel, R.B. (Robert B.), Eichler, E.E. (Evan), Xia, K. (Kun), Guo, H. (Hui), Li, Y. (Ying), Shen, L. (Lu), Wang, T. (Tianyun), Jia, X. (Xiangbin), Liu, L. (Lijuan), Xu, T. (Tao), Ou, M. (Mengzhu), Hoekzema, K. (Kendra), Wu, H. (Huidan), Gillentine, M.A. (Madelyn A.), Liu, C. (Cenying), Ni, H. (Hailun), Peng, P. (Pengwei), Zhao, R. (Rongjuan), Zhang, Y. (Yu), Phornphutkul, C. (Chanika), Stegmann, A.P.A. (Alexander P.A.), Prada, C.E. (C.), Hopkin, R., Shieh, J.T. (Joseph T.), McWalter, K. (Kirsty), Monaghan, K.G. (Kristin G.), Hasselt, P.M. (Peter) van, van Gassen, K. (Koen), Bai, T. (Ting), Long, M. (Min), Han, L. (Lin), Quan, Y. (Yingting), Chen, M. (Meilin), Zhang, Y. (Yaowen), Li, K. (Kuokuo), Zhang, Q. (Qiumeng), Tan, J. (Jieqiong), Zhu, T. (Tengfei), Liu, Y. (Yaning), Pang, N. (Nan), Peng, J. (Jing), Scott, D.A., Lalani, S.R. (Seema R.), Azamian, M. (Mahshid), Mancini, G.M.S. (Grazia), Adams, D.J. (Darius J.), Kvarnung, M. (Malin), Lindstrand, A. (Anna), Nordgren, A. (Ann), Pevsner, J. (Jonathan), Osei-Owusu, I.A. (Ikeoluwa A.), Romano, C. (Corrado), Calabrese, G. (Giuseppe), Galesi, O. (O.), Gecz, J. (Jozef), Haan, E. (Eric), Ranells, J. (Judith), Racobaldo, M. (Melissa), Nordenskjöld, M., Madan-Khetarpal, S. (Suneeta), Sebastian, J. (Jessica), Ball, S. (Susie), Zou, X. (Xiaobing), Zhao, J. (Jingping), Hu, Z. (Zhengmao), Xia, F. (Fan), Liu, P. (Pengfei), Rosenfeld, J.A. (Jill), Vries, B. (Boukje) de, Bernier, R.A. (Raphael A.), Xu, Z.-Q.D. (Zhi-Qing David), Li, H. (Honghui), Xie, W. (Wei), Hufnagel, R.B. (Robert B.), Eichler, E.E. (Evan), and Xia, K. (Kun)
Abstract: RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely genedisrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITSCLIP revealed that Csde1binding targets are enriched in autismassociated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity–related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autismrelated syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.
Published: 2019
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12. Mutations in the Heterotopia Gene Eml1/EML1 Severely Disrupt the Formation of Primary Cilia

Author: Uzquiano, A. (Ana), Cifuentes-Diaz, C. (Carmen), Jabali, A. (A.), Romero, D.M. (Delfina M.), Houllier, A. (Anne), Dingli, F. (Florent), Maillard, C. (Camille), Boland, A. (Anne), Deleuze, J.-F. (Jean-François), Loew, D. (Damarys), Mancini, G.M.S. (Grazia), Bahi-Buisson, N. (Nadia), Ladewig, J. (J.), Francis, F. (Fiona), Uzquiano, A. (Ana), Cifuentes-Diaz, C. (Carmen), Jabali, A. (A.), Romero, D.M. (Delfina M.), Houllier, A. (Anne), Dingli, F. (Florent), Maillard, C. (Camille), Boland, A. (Anne), Deleuze, J.-F. (Jean-François), Loew, D. (Damarys), Mancini, G.M.S. (Grazia), Bahi-Buisson, N. (Nadia), Ladewig, J. (J.), and Francis, F. (Fiona)
Abstract: Apical radial glia (aRGs) are predominant progenitors during corticogenesis. Perturbing their function leads to cortical malformations, including subcortical heterotopia (SH), characterized by the presence of neurons below the cortex. EML1/Eml1 mutations lead to SH in patients, as well as to heterotopic cortex (HeCo) mutant mice. In HeCo mice, some aRGs are abnormally positioned away from the ventricular zone (VZ). Thus, unraveling EML1/Eml1 function will clarify mechanisms maintaining aRGs in the VZ. We pinpoint an unknown EML1/Eml1 function in primary cilium formation. In HeCo aRGs, cilia are shorter, less numerous, and often found aberrantly oriented within vesicles. Patient fibroblasts and human cortical progenitors show similar defects. EML1 interacts with RPGRIP1L, a ciliary protein, and RPGRIP1L mutations were revealed in a heterotopia patient. We also identify Golgi apparatus abnormalities in EML1/Eml1 mutant cells, potentially upstream of the cilia phenotype. We thus reveal primary cilia mechanisms impacting aRG dynamics in physiological and pathological conditions. Uzquiano et al. show that mutations in Eml1/EML1, found in mice and patients with subcortical heterotopia, impair primary cilia formation in apical progenitors. Perturbed anterograde trafficking from the Golgi apparatus seems likely to contribute to this ciliary phenotype. This work uncovers pathological mechanisms potentially triggering the formation of the heterotopia.
Published: 2019
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13. Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics

Author: Vandervore, L.V., Schot, R. (Rachel), Kasteleijn, E., Oegema, R., Stouffs, K., Gheldof, A, Grochowska, M.M. (Martyna), Sterre, M.L.T. (Marianne) van der, van Unen, L.M.A., Wilke, M. (Martina), Elfferich, P.C., Spek, P.J. (Peter) van der, Heijsman, D. (Daphne), Grandone, A., Demmers, J.A.A. (Jeroen), Dekkers, D.H. (Dick), Slotman, J.A., Kremers, G.J. (Gert-Jan), Schaaf, G.J., Masius, R.G., Essen, J.A. (Anthonie) van, Rump, P, Haeringen, A. (Arie) van, Peeters, E. (Ellen), Altunoglu, U. (Umut), Kalayci, T., Poot, R.A. (Raymond), Dobyns, W.B. (William), Bahi-Buisson, N. (Nadia), Verheijen, F.W. (Frans), Jansen, AC, Mancini, G.M.S. (Grazia), Vandervore, L.V., Schot, R. (Rachel), Kasteleijn, E., Oegema, R., Stouffs, K., Gheldof, A, Grochowska, M.M. (Martyna), Sterre, M.L.T. (Marianne) van der, van Unen, L.M.A., Wilke, M. (Martina), Elfferich, P.C., Spek, P.J. (Peter) van der, Heijsman, D. (Daphne), Grandone, A., Demmers, J.A.A. (Jeroen), Dekkers, D.H. (Dick), Slotman, J.A., Kremers, G.J. (Gert-Jan), Schaaf, G.J., Masius, R.G., Essen, J.A. (Anthonie) van, Rump, P, Haeringen, A. (Arie) van, Peeters, E. (Ellen), Altunoglu, U. (Umut), Kalayci, T., Poot, R.A. (Raymond), Dobyns, W.B. (William), Bahi-Buisson, N. (Nadia), Verheijen, F.W. (Frans), Jansen, AC, and Mancini, G.M.S. (Grazia)
Published: 2019
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14. Loss of USP18 in microglia induces white matter pathology

Author: Schwabenland, M. (Marius), Mossad, O. (Omar), Peres, A.G. (Adam G.), Kessler, F. (Franziska), Maron, F.J.M. (Feres Jose Mocayar), Harsan, L.-A. (Laura-Adela), Bienert, T. (Thomas), von Elverfeldt, D. (Dominik), Knobeloch, K.-P. (Klaus-Peter), Staszewski, O. (Ori), Heppner, F.L. (Frank ), Meuwissen, M.E.C. (Marije), Mancini, G.M.S. (Grazia), Prinz, M. (Marco), Blank, T. (Thomas), Schwabenland, M. (Marius), Mossad, O. (Omar), Peres, A.G. (Adam G.), Kessler, F. (Franziska), Maron, F.J.M. (Feres Jose Mocayar), Harsan, L.-A. (Laura-Adela), Bienert, T. (Thomas), von Elverfeldt, D. (Dominik), Knobeloch, K.-P. (Klaus-Peter), Staszewski, O. (Ori), Heppner, F.L. (Frank ), Meuwissen, M.E.C. (Marije), Mancini, G.M.S. (Grazia), Prinz, M. (Marco), and Blank, T. (Thomas)
Published: 2019
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15. The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

Author: van der Sluijs, E.P.J. (Eline (P.J.)), Jansen, S. (Sandra), Vergano, S.A. (Samantha A.), Adachi-Fukuda, M. (Miho), Alanay, Y. (Yasemin), AlKindy, A. (Adila), Baban, A. (Anwar), Bayat, A. (Allan), Beck-Wödl, S. (Stefanie), Berry, K. (Katherine), Bijlsma, E.K. (Emilia), Bok, L.A. (Levinus), Brouwer, A.F.J. (Alwin F. J.), Burgt, I. (Ineke) van der, Campeau, P.M. (Philippe M.), Canham, N. (Natalie), Chrzanowska, K.H. (Krystyna), Chu, Y.W.Y. (Yoyo W. Y.), Chung, B.H.Y. (Brain H. Y.), Dahan, K. (Karin), De Rademaeker, M. (Marjan), Destrée, A. (Anne), Dudding-Byth, T. (Tracy), Earl, R. (Rachel), Elcioglu, N.H. (Nursel), Elias, E.R. (Ellen R.), Fagerberg, C. (Christina), Gardham, A. (Alice), Gener, B. (Blanca), Gerkes, E.H. (Erica H), Grasshoff, U. (Ute), Haeringen, A. (Arie) van, Heitink, K.R. (Karin R.), Herkert, J.C. (Johanna), Hollander, N.S. (Nicolette) den, Horn, D. (Denise), Hunt, D. (David), Kant, S.G. (Sarina), Kato, M. (Mitsuhiro), Kayserili, H. (Hülya), Kersseboom, R. (Rogier), Kilic, E. (Esra), Krajewska-Walasek, M. (Malgorzata), Lammers, K. (Kylin), Laulund, L.W. (Lone W.), Lederer, D. (Damien), Lees, M.M. (Melissa), López-González, V. (V.), Maas, S.M. (Saskia), Mancini, G.M.S. (Grazia), Marcelis, C.L.M. (Carlo), Martinez, F. (Francisco), Maystadt, I. (Isabelle), McGuire, M. (Marianne), McKee, S., Mehta, S. (Sarju), Metcalfe, K. (Kay), Milunsky, J.M. (Jeff), Mizuno, S. (Seiji), Moeschler, J.B. (John B.), Netzer, C. (Christian), Ockeloen, C. (Charlotte), Oehl-Jaschkowitz, B. (Barbara), Okamoto, N. (Nobuhiko), Olminkhof, S.N.M. (Sharon N. M.), Orellana, C. (Carmen), Pasquier, L. (Laurent), Pottinger, C. (Caroline), Riehmer, V. (Vera), Robertson, S.P. (Stephen), Roifman, M. (Maian), Rooryck, C. (Caroline), Ropers, F.G. (Fabienne G.), Rosello, M. (Monica), Ruivenkamp, C.A. (Claudia), Sagiroglu, M.S. (Mahmut S.), Sallevelt, S.C.E.H. (Suzanne), Sanchis Calvo, A. (Amparo), Simsek-Kiper, P.O. (P.), Soares, G. (Gabriela), Solaeche, L. (Lucia), Mujgan Sonmez, F. (Fatma), Splitt, M. (M.), Steenbeek, D. (Duco), Stegmann, A.P.A. (Alexander P. A.), Stumpel, C. (Connie), Tanabe, S. (Saori), Uctepe, E. (Eyyup), Utine, G.E. (G. Eda), Veenstra-Knol, H.E. (Hermine), Venkateswaran, S. (Sunita), Vilain, C. (Catheline), Vincent-Delorme, C. (Catherine), Vulto-van Silfhout, A.T. (Anneke), Wheeler, P. (Patricia), Wilson, G.N. (Golder N.), Wilson, L.C. (Louise), Wollnik, B. (Bernd), Kosho, T. (Tomoki), Wieczorek, D. (Dagmar), Eichler, E.E. (Evan), Pfundt, R. (Rolph), Vries, B. (Boukje) de, Clayton-Smith, J., Santen, G.W.E. (Gijs), van der Sluijs, E.P.J. (Eline (P.J.)), Jansen, S. (Sandra), Vergano, S.A. (Samantha A.), Adachi-Fukuda, M. (Miho), Alanay, Y. (Yasemin), AlKindy, A. (Adila), Baban, A. (Anwar), Bayat, A. (Allan), Beck-Wödl, S. (Stefanie), Berry, K. (Katherine), Bijlsma, E.K. (Emilia), Bok, L.A. (Levinus), Brouwer, A.F.J. (Alwin F. J.), Burgt, I. (Ineke) van der, Campeau, P.M. (Philippe M.), Canham, N. (Natalie), Chrzanowska, K.H. (Krystyna), Chu, Y.W.Y. (Yoyo W. Y.), Chung, B.H.Y. (Brain H. Y.), Dahan, K. (Karin), De Rademaeker, M. (Marjan), Destrée, A. (Anne), Dudding-Byth, T. (Tracy), Earl, R. (Rachel), Elcioglu, N.H. (Nursel), Elias, E.R. (Ellen R.), Fagerberg, C. (Christina), Gardham, A. (Alice), Gener, B. (Blanca), Gerkes, E.H. (Erica H), Grasshoff, U. (Ute), Haeringen, A. (Arie) van, Heitink, K.R. (Karin R.), Herkert, J.C. (Johanna), Hollander, N.S. (Nicolette) den, Horn, D. (Denise), Hunt, D. (David), Kant, S.G. (Sarina), Kato, M. (Mitsuhiro), Kayserili, H. (Hülya), Kersseboom, R. (Rogier), Kilic, E. (Esra), Krajewska-Walasek, M. (Malgorzata), Lammers, K. (Kylin), Laulund, L.W. (Lone W.), Lederer, D. (Damien), Lees, M.M. (Melissa), López-González, V. (V.), Maas, S.M. (Saskia), Mancini, G.M.S. (Grazia), Marcelis, C.L.M. (Carlo), Martinez, F. (Francisco), Maystadt, I. (Isabelle), McGuire, M. (Marianne), McKee, S., Mehta, S. (Sarju), Metcalfe, K. (Kay), Milunsky, J.M. (Jeff), Mizuno, S. (Seiji), Moeschler, J.B. (John B.), Netzer, C. (Christian), Ockeloen, C. (Charlotte), Oehl-Jaschkowitz, B. (Barbara), Okamoto, N. (Nobuhiko), Olminkhof, S.N.M. (Sharon N. M.), Orellana, C. (Carmen), Pasquier, L. (Laurent), Pottinger, C. (Caroline), Riehmer, V. (Vera), Robertson, S.P. (Stephen), Roifman, M. (Maian), Rooryck, C. (Caroline), Ropers, F.G. (Fabienne G.), Rosello, M. (Monica), Ruivenkamp, C.A. (Claudia), Sagiroglu, M.S. (Mahmut S.), Sallevelt, S.C.E.H. (Suzanne), Sanchis Calvo, A. (Amparo), Simsek-Kiper, P.O. (P.), Soares, G. (Gabriela), Solaeche, L. (Lucia), Mujgan Sonmez, F. (Fatma), Splitt, M. (M.), Steenbeek, D. (Duco), Stegmann, A.P.A. (Alexander P. A.), Stumpel, C. (Connie), Tanabe, S. (Saori), Uctepe, E. (Eyyup), Utine, G.E. (G. Eda), Veenstra-Knol, H.E. (Hermine), Venkateswaran, S. (Sunita), Vilain, C. (Catheline), Vincent-Delorme, C. (Catherine), Vulto-van Silfhout, A.T. (Anneke), Wheeler, P. (Patricia), Wilson, G.N. (Golder N.), Wilson, L.C. (Louise), Wollnik, B. (Bernd), Kosho, T. (Tomoki), Wieczorek, D. (Dagmar), Eichler, E.E. (Evan), Pfundt, R. (Rolph), Vries, B. (Boukje) de, Clayton-Smith, J., and Santen, G.W.E. (Gijs)
Abstract: Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin–Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive web-based survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.
Published: 2018
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16. SYT1-associated neurodevelopmental disorder: a case series

Author: Baker, K. (Kate), Gordon, S.L. (Sarah L.), Melland, H. (Holly), Bumbak, F. (Fabian), Scott, D.J. (Daniel J.), Jiang, T.J. (Tess J.), Owen, D. (David), Turner, B.J. (Bradley J.), Boyd, S.G. (Stewart G.), Rossi, M. (Mari), Al-Raqad, M. (Mohammed), Elpeleg, O. (Orly), Peck, D. (Dawn), Mancini, G.M.S. (Grazia), Wilke, M. (Martina), Zollino, M., Marangi, G. (Giuseppe), Weigand, H. (Heike), Borggraefe, I. (Ingo), Haack, T. (Tobias), Stark, Z. (Zornitza), Sadedin, S. (Simon), Tan, T.Y. (Tiong Yang), Jiang, Y. (Yunyun), Gibbs, R.A. (Richard A.), Ellingwood, S. (Sara), Amaral, M. (Michelle), Kelley, W. (Whitley), Kurian, M.A. (Manju A.), Cousin, M.A. (Michael A.), Raymond, F.L. (F. Lucy), Baker, K. (Kate), Gordon, S.L. (Sarah L.), Melland, H. (Holly), Bumbak, F. (Fabian), Scott, D.J. (Daniel J.), Jiang, T.J. (Tess J.), Owen, D. (David), Turner, B.J. (Bradley J.), Boyd, S.G. (Stewart G.), Rossi, M. (Mari), Al-Raqad, M. (Mohammed), Elpeleg, O. (Orly), Peck, D. (Dawn), Mancini, G.M.S. (Grazia), Wilke, M. (Martina), Zollino, M., Marangi, G. (Giuseppe), Weigand, H. (Heike), Borggraefe, I. (Ingo), Haack, T. (Tobias), Stark, Z. (Zornitza), Sadedin, S. (Simon), Tan, T.Y. (Tiong Yang), Jiang, Y. (Yunyun), Gibbs, R.A. (Richard A.), Ellingwood, S. (Sara), Amaral, M. (Michelle), Kelley, W. (Whitley), Kurian, M.A. (Manju A.), Cousin, M.A. (Michael A.), and Raymond, F.L. (F. Lucy)
Abstract: Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics include sleep disturbance and episodic agitation. Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features. Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations. The functional impact of these five de novo SYT1 mutations has been assessed by expressing rat SYT1 protein containing the equivalent human varian
Published: 2018
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17. Toward clinical and molecular understanding of pathogenic variants in the ZBTB18 gene

Author: van der Schoot, V. (Vyne), Munnik, S.A. (Sonja) de, Venselaar, H. (Hanka), Elting, M. (Mariet), Mancini, G.M.S. (Grazia), Ravenswaaij-Arts, C.M.A. (Conny M. A.), Anderlid, B.-M.M. (Britt-Marie M.), Brunner, H.G., Stevens, S.J.C. (Servi J. C.), van der Schoot, V. (Vyne), Munnik, S.A. (Sonja) de, Venselaar, H. (Hanka), Elting, M. (Mariet), Mancini, G.M.S. (Grazia), Ravenswaaij-Arts, C.M.A. (Conny M. A.), Anderlid, B.-M.M. (Britt-Marie M.), Brunner, H.G., and Stevens, S.J.C. (Servi J. C.)
Abstract: Background: Patients with pathogenic variants in ZBTB18 present with Intellectual Disability (ID) with frequent co-occurrence of corpus callosum (CC) anomalies, hypotonia, microcephaly, growth problems and variable facial dysmorphologies. These features illustrate a key role for ZBTB18 in brain development. Methods: Patients with a pathogenic variant in ZBTB18 were detected by diagnostic whole exome sequencing (WES) performed in our center. We reviewed the literature and used GeneMatcher to include other cases. YASARA and WHAT IF were used to provide insight into the structural effect of missense variants located in the C2H2 zinc finger domains of the ZBTB18 protein. Results: We give a complete overview of pathogenic variants in ZBTB18 detected to date, showing inconsistent presence of clinical features, including CC anomalies. We present four new cases with a de novo pathogenic variant in the ZBTB18 gene, including the fourth case in which a de novo p.Arg464His variant was found. Conclusion: Homology modeling of protein structure points to a variable degree of impaired DNA binding caused by missense variants in these domains probably leading to Loss of Function (LoF). Putative partial LoF may present with a less distinctive phenotype than complete LoF, as seen in truncating variants, which presents with an extensive variability in the phenotypic spectrum. Our data do not support a clear genotype to phenotype correlation.
Published: 2018
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18. Mixoploidy combined with aneuploidy in a 13 year-old patient with severe multiple congenital abnormalities and intellectual disability

Author: Zutven, L.J.C.M. (Laura) van, Mancini, G.M.S. (Grazia M. S.), Bindels-de Heus, G.C.B. (Karen), van den Akker, E.L.T. (Erica L. T.), Hulsman, L.O.M. (Lorette), Smit, M. (Marjan), Beverloo, H.B. (Berna), Zutven, L.J.C.M. (Laura) van, Mancini, G.M.S. (Grazia M. S.), Bindels-de Heus, G.C.B. (Karen), van den Akker, E.L.T. (Erica L. T.), Hulsman, L.O.M. (Lorette), Smit, M. (Marjan), and Beverloo, H.B. (Berna)
Published: 2018
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19. Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis

Author: Mattioli, F. (Francesca), Schaefer, E. (Elise), Magee, A. (Alex), Mark, P. (Paul), Mancini, G.M.S. (Grazia), Dieterich, K. (Klaus), Von Allmen, G. (Gretchen), Alders, M. (Marielle), Coutton, C. (Charles), Slegtenhorst, M.A. (Marjon) van, Vieville, G. (Gaëlle), Engelen, M. (Mark), Cobben, J.M. (Jan Maarten), Juusola, J. (Jane), Pujol, A. (Aurora), Mandel, J.-L. (Jean-Louis), Piton, A. (Amélie), Mattioli, F. (Francesca), Schaefer, E. (Elise), Magee, A. (Alex), Mark, P. (Paul), Mancini, G.M.S. (Grazia), Dieterich, K. (Klaus), Von Allmen, G. (Gretchen), Alders, M. (Marielle), Coutton, C. (Charles), Slegtenhorst, M.A. (Marjon) van, Vieville, G. (Gaëlle), Engelen, M. (Mark), Cobben, J.M. (Jan Maarten), Juusola, J. (Jane), Pujol, A. (Aurora), Mandel, J.-L. (Jean-Louis), and Piton, A. (Amélie)
Abstract: Intellectual disability (ID) is a common neurodevelopmental disorder exhibiting extreme genetic heterogeneity, and more than 500 genes have been implicated in Mendelian forms of ID. We performed exome sequencing in a large family affected by an autosomal-dominant form of mild syndromic ID with ptosis, growth retardation, and hypotonia, and we identified an inherited 2 bp deletion causing a frameshift in BRPF1 (c.1052_1053del) in five affected family members. BRPF1 encodes a protein modifier of two histone acetyltransferases associated with ID: KAT6A (also known as MOZ or MYST3) and KAT6B (MORF or MYST4). The mRNA transcript was not significantly reduced in affected fibroblasts and most likely produces a truncated protein (p.Val351Glyfs*8). The protein variant shows an aberrant cellular location, loss of certain protein interactions, and decreased histone H3K23 acetylation. We identified BRPF1 deletions or point mutations in six additional individuals with a similar phenotype. Deletions of the 3p25 region, containing BRPF1 and SETD5, cause a defined ID syndrome where most of the clinical features are attributed to SETD5 deficiency. We compared the clinical symptoms of individuals carrying mutations or small deletions of BRPF1 alone or SETD5 alone with those of individuals with deletions encompassing both BRPF1 and SETD5. We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency.
Published: 2017
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20. RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes

Author: Reijnders, M.R.F. (Margot R.F.), Ansor, N.M. (Nurhuda M.), Kousi, M. (Maria), Yue, W.W. (Wyatt W.), Tan, P.L. (Perciliz L.), Clarkson, K. (Katie), Clayton-Smith, J., Corning, K. (Ken), Jones, J.R. (Julie R.), Lam, W.W.K. (Wayne W.K.), Mancini, G.M.S. (Grazia), Marcelis, C.L.M. (Carlo), Mohammed, S. (Shabaz), Pfundt, R. (Rolph), Roifman, M. (Maian), Cohn, R.D., Chitayat, D. (David), Millard, T.H. (Tom H.), Katsanis, N. (Nicholas), Brunner, H.G., Banka, S. (Siddharth), Reijnders, M.R.F. (Margot R.F.), Ansor, N.M. (Nurhuda M.), Kousi, M. (Maria), Yue, W.W. (Wyatt W.), Tan, P.L. (Perciliz L.), Clarkson, K. (Katie), Clayton-Smith, J., Corning, K. (Ken), Jones, J.R. (Julie R.), Lam, W.W.K. (Wayne W.K.), Mancini, G.M.S. (Grazia), Marcelis, C.L.M. (Carlo), Mohammed, S. (Shabaz), Pfundt, R. (Rolph), Roifman, M. (Maian), Cohn, R.D., Chitayat, D. (David), Millard, T.H. (Tom H.), Katsanis, N. (Nicholas), Brunner, H.G., and Banka, S. (Siddharth)
Abstract: RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between −2.5 to −5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of ∼10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.
Published: 2017
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21. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders

Author: Wolff, M. (Markus), Johannesen, K.M. (Katrine M.), Hedrich, U.B.S. (Ulrike B. S.), Masnada, S. (Silvia), Rubboli, G. (Guido), Gardella, E. (Elena), Lesca, G. (Gaetan), Ville, D. (Dorothée), Milh, M. (Mathieu), Villard, L. (Laurent), Afenjar, A. (Alexandra), Chantot-Bastaraud, S. (Sandra), Mignot, A., Lardennois, C. (Caroline), Nava, C. (Caroline), Schwarz, N. (Niklas), Gérard, M. (Marion), Perrin, L. (Laurence), Doummar, D. (Diane), Auvin, S. (Stéphane), Miranda, M.J. (Maria J.), Hempel, M. (Maja), Brilstra, E. (Eva), Knoers, N.V.A.M. (Nine), Verbeek, N.E. (Nienke), Kempen, M.J.A. (M. J A) van, Braun, K.P. (Kees P.), Mancini, G.M.S. (Grazia), Biskup, S. (Saskia), Hörtnagel, K. (Konstanze), Döcker, M. (Miriam), Bast, T. (Thomas), Loddenkemper, T. (Tobias), Wong-Kisiel, L. (Lily), Baumeister, F.M. (Friedrich M.), Fazeli, W. (Walid), Striano, P. (Pasquale), Dilena, R. (Robertino), Fontana, E. (Elena), Zara, F. (Federico), Kurlemann, G. (Gerhard), Klepper, J. (Joerg), Thoene, J.G. (Jess G.), Arndt, D.H. (Daniel H.), Deconinck, N. (Nicolas), Schmitt-Mechelke, T. (Thomas), Maier, O. (Oliver), Muhle, H. (Hiltrud), Wical, B. (Beverly), Finetti, C. (Claudio), Brückner, R. (Reinhard), Pietz, J. (Joachim), Golla, G. (Günther), Jillella, D. (Dinesh), Linnet, K.M. (Karen M.), Charles, P. (Perrine), Moog, U. (Ute), Õiglane-Shlik, E. (Eve), Mantovani, J.F. (John F.), Park, K. (Kristen), Deprez, M. (Marie), Lederer, D. (Damien), Mary, S. (Sandrine), Scalais, E. (Emmanuel), Selim, L. (Laila), Coster, R.N.A. (R. N A) van, Lagae, L. (Lieven), Nikanorova, M. (Marina), Hjalgrim, H. (Helle), Korenke, G.C. (Christoph), Trivisano, M. (Marina), Specchio, N. (Nicola), Ceulemans, B. (Berten), Dorn, T. (Thomas), Helbig, K.L. (Katherine L.), Hardies, K. (K.), Stamberger, H. (Hannah), Jonghe, P. (P.) de, Weckhuysen, S. (Sarah), Lemke, J.R. (Johannes R.), Krägeloh-Mann, I. (Ingeborg), Helbig, I. (Ingo), Kluger, G. (Gerhard), Lerche, H. (Holger), Møller, R.S. (Rikke), Wolff, M. (Markus), Johannesen, K.M. (Katrine M.), Hedrich, U.B.S. (Ulrike B. S.), Masnada, S. (Silvia), Rubboli, G. (Guido), Gardella, E. (Elena), Lesca, G. (Gaetan), Ville, D. (Dorothée), Milh, M. (Mathieu), Villard, L. (Laurent), Afenjar, A. (Alexandra), Chantot-Bastaraud, S. (Sandra), Mignot, A., Lardennois, C. (Caroline), Nava, C. (Caroline), Schwarz, N. (Niklas), Gérard, M. (Marion), Perrin, L. (Laurence), Doummar, D. (Diane), Auvin, S. (Stéphane), Miranda, M.J. (Maria J.), Hempel, M. (Maja), Brilstra, E. (Eva), Knoers, N.V.A.M. (Nine), Verbeek, N.E. (Nienke), Kempen, M.J.A. (M. J A) van, Braun, K.P. (Kees P.), Mancini, G.M.S. (Grazia), Biskup, S. (Saskia), Hörtnagel, K. (Konstanze), Döcker, M. (Miriam), Bast, T. (Thomas), Loddenkemper, T. (Tobias), Wong-Kisiel, L. (Lily), Baumeister, F.M. (Friedrich M.), Fazeli, W. (Walid), Striano, P. (Pasquale), Dilena, R. (Robertino), Fontana, E. (Elena), Zara, F. (Federico), Kurlemann, G. (Gerhard), Klepper, J. (Joerg), Thoene, J.G. (Jess G.), Arndt, D.H. (Daniel H.), Deconinck, N. (Nicolas), Schmitt-Mechelke, T. (Thomas), Maier, O. (Oliver), Muhle, H. (Hiltrud), Wical, B. (Beverly), Finetti, C. (Claudio), Brückner, R. (Reinhard), Pietz, J. (Joachim), Golla, G. (Günther), Jillella, D. (Dinesh), Linnet, K.M. (Karen M.), Charles, P. (Perrine), Moog, U. (Ute), Õiglane-Shlik, E. (Eve), Mantovani, J.F. (John F.), Park, K. (Kristen), Deprez, M. (Marie), Lederer, D. (Damien), Mary, S. (Sandrine), Scalais, E. (Emmanuel), Selim, L. (Laila), Coster, R.N.A. (R. N A) van, Lagae, L. (Lieven), Nikanorova, M. (Marina), Hjalgrim, H. (Helle), Korenke, G.C. (Christoph), Trivisano, M. (Marina), Specchio, N. (Nicola), Ceulemans, B. (Berten), Dorn, T. (Thomas), Helbig, K.L. (Katherine L.), Hardies, K. (K.), Stamberger, H. (Hannah), Jonghe, P. (P.) de, Weckhuysen, S. (Sarah), Lemke, J.R. (Johannes R.), Krägeloh-Mann, I. (Ingeborg), Helbig, I. (Ingo), Kluger, G. (Gerhard), Lerche, H. (Holger), and Møller, R.S. (Rikke)
Abstract: Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatme
Published: 2017
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22. Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

Author: Lehman, S. (Sanaz), Thouta, S. (Samrat), Mancini, G.M.S. (Grazia), Naidu, S. (Sakkubai), Slegtenhorst, M.A. (Marjon) van, McWalter, K. (Kirsty), Person, R. (Rick), Mwenifumbo, J. (Jill), Salvarinova, R. (Ramona), Guella, I. (Ilaria), McKenzie, M.B. (Marna B.), Datta, A. (Anita), Connolly, M.B. (Mary B.), Kalkhoran, S.M. (Somayeh Mojard), Poburko, D. (Damon), Friedman, J.M. (Jan M.), Farrer, M.J. (Matthew), Demos, M. (Michelle), Desai, S. (Sonal), Claydon, T. (Thomas), Lehman, S. (Sanaz), Thouta, S. (Samrat), Mancini, G.M.S. (Grazia), Naidu, S. (Sakkubai), Slegtenhorst, M.A. (Marjon) van, McWalter, K. (Kirsty), Person, R. (Rick), Mwenifumbo, J. (Jill), Salvarinova, R. (Ramona), Guella, I. (Ilaria), McKenzie, M.B. (Marna B.), Datta, A. (Anita), Connolly, M.B. (Mary B.), Kalkhoran, S.M. (Somayeh Mojard), Poburko, D. (Damon), Friedman, J.M. (Jan M.), Farrer, M.J. (Matthew), Demos, M. (Michelle), Desai, S. (Sonal), and Claydon, T. (Thomas)
Abstract: KCNQ5 is a highly conserved gene encoding an important channel for neuronal function; it is widely expressed in the brain and generates M-type current. Exome sequencing identified de novo heterozygous missense mutations in four probands with intellectual disability, abnormal neurological findings, and treatment-resistant epilepsy (in two of four). Comprehensive analysis of this potassium channel for the four variants expressed in frog oocytes revealed shifts in the voltage dependence of activation, including altered activation and deactivation kinetics. Specifically, both loss-of-function and gain-of-function KCNQ5 mutations, associated with increased excitability and decreased repolarization reserve, lead to pathophysiology.
Published: 2017
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23. Progressive leukoencephalopathy impairs neurobehavioral development in sialin-deficient mice

Author: Stroobants, S. (Stijn), Van Acker, N.G.G. (Nathalie G.G.), Verheijen, F.W. (Frans), Goris, I. (Ilse), Daneels, R.F., Schot, R. (Rachel), Verbeek, E. (Elly), Knaapen, M.W. (Michiel), Bondt, A. (An) de, Göhlmann, H.W.H. (Hinrich W. H.), Crauwels, M.L.A. (Marion L.A.), Mancini, G.M.S. (Grazia), Andries, L.J. (Luc J.), Moechars, D. (Dieder), D'Hooge, R. (Rudi), Stroobants, S. (Stijn), Van Acker, N.G.G. (Nathalie G.G.), Verheijen, F.W. (Frans), Goris, I. (Ilse), Daneels, R.F., Schot, R. (Rachel), Verbeek, E. (Elly), Knaapen, M.W. (Michiel), Bondt, A. (An) de, Göhlmann, H.W.H. (Hinrich W. H.), Crauwels, M.L.A. (Marion L.A.), Mancini, G.M.S. (Grazia), Andries, L.J. (Luc J.), Moechars, D. (Dieder), and D'Hooge, R. (Rudi)
Abstract: Slc17a5−/− mice represent an animal model for the infantile form of sialic acid storage disease (SASD). We analyzed genetic and histological time-course expression of myelin and oligodendrocyte (OL) lineage markers in different parts of the CNS, and related this to postnatal neurobehavioral development in these mice. Sialin-deficient mice display a distinct spatiotemporal pattern of sialic acid storage, CNS hypomyelination and leukoencephalopathy. Whereas few genes are differentially expressed in the perinatal stage (p0), microarray analysis revealed increased differential gene expression in later postnatal stages (p10–p18). This included progressive upregulation of neuroinflammatory genes, as well as continuous down-regulation of genes that encode myelin constituents and typical OL lineage markers. Age-related histopathological analysis indicates that initial myelination occurs normally in hindbrain regions, but progression to more frontal areas is affected in Slc17a5−/− mice. This course of progressive leukoencephalopathy and CNS hypomyelination delays neurobehavioral development in sialin-deficient mice. Slc17a5−/− mice successfully achieve early neurobehavioral milestones, but exhibit progressive delay of later-stage sensory and motor milestones. The present findings may contribute to further understanding of the processes of CNS myelination as well as help to develop therapeutic strategies for SASD and other myelination disorders.
Published: 2017
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24. Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

Author: De Mori, R. (Roberta), Romani, M. (Marta), D'Arrigo, S. (Stefano), Zaki, M.S. (Maha), Lorefice, E. (Elisa), Tardivo, S. (Silvia), Biagini, T. (Tommaso), Stanley, V. (Valentina), Musaev, D. (Damir), Fluss, J. (Joel), Micalizzi, A. (Alessia), Nuovo, S. (Sara), Illi, B. (Barbara), Chiapparini, L. (Luisa), Di Marcotullio, L. (Lucia), Issa, M.Y. (Mahmoud Y.), Anello, D. (Danila), Casella, A. (Antonella), Ginevrino, M. (Monia), Leggins, A.S. (Autumn Sa'na), Roosing, S. (Susanne), Alfonsi, R. (Romina), Rosati, J. (Jessica), Schot, R. (Rachel), Mancini, G.M.S. (Grazia), Bertini, E. (Enrico), Dobyns, W.B. (William), Mazza, T. (Tommaso), Gleeson, J.G. (Joseph G.), Valente, J. (José), De Mori, R. (Roberta), Romani, M. (Marta), D'Arrigo, S. (Stefano), Zaki, M.S. (Maha), Lorefice, E. (Elisa), Tardivo, S. (Silvia), Biagini, T. (Tommaso), Stanley, V. (Valentina), Musaev, D. (Damir), Fluss, J. (Joel), Micalizzi, A. (Alessia), Nuovo, S. (Sara), Illi, B. (Barbara), Chiapparini, L. (Luisa), Di Marcotullio, L. (Lucia), Issa, M.Y. (Mahmoud Y.), Anello, D. (Danila), Casella, A. (Antonella), Ginevrino, M. (Monia), Leggins, A.S. (Autumn Sa'na), Roosing, S. (Susanne), Alfonsi, R. (Romina), Rosati, J. (Jessica), Schot, R. (Rachel), Mancini, G.M.S. (Grazia), Bertini, E. (Enrico), Dobyns, W.B. (William), Mazza, T. (Tommaso), Gleeson, J.G. (Joseph G.), and Valente, J. (José)
Abstract: The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Indeed, Sufu knock-out is lethal in mice, and recessive pathogenic variants of this gene have never been reported in humans. Through whole-exome sequencing in subjects with Joubert syndrome, we identified four children from two unrelated families carrying homozygous missense variants in SUFU. The children presented congenital ataxia and cerebellar vermis hypoplasia with elongated superior cerebellar peduncles (mild "molar tooth sign"), typical cranio-facial dysmorphisms (hypertelorism, depressed nasal bridge, frontal bossing), and postaxial polydactyly. Two siblings also showed polymicrogyria. Molecular dynamics simulation predicted random movements of the mutated residues, with loss of the native enveloping movement of the binding site around its ligand GLI3. Functional studies on cellular models and fibroblasts showed that both variants significantly reduced SUFU stability and its capacity to bind GLI3 and promote its cleavage into the repressor form GLI3R. In turn, this impaired SUFU-mediated repression of the SHH pathway, as shown by altered expression levels of several target genes. We demonstrate that germline hypomorphic variants of SUFU cause deregulation of SHH signaling, resulting in recessive developmental defects of the CNS and limbs which share features with both SHH-related disorders and ciliopathies.
Published: 2017
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25. XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia

Author: Hoch, N.C. (Nicolas C.), Hanzlikova, H. (Hana), Rulten, S.L. (Stuart L.), Tétreault, M. (Martine), Komulainen, E. (Emilia), Ju, L. (Limei), Hornyak, P. (Peter), Zeng, Z. (Zhihong), Gittens, W. (William), Rey, S.A. (Stephanie A.), Staras, K. (Kevin), Mancini, G.M.S. (Grazia), McKinnon, P.J. (Peter J.), Wang, Z.-Q. (Zhao-Qi), Wagner, J.D. (Justin D.), Yoon, G. (Grace), Caldecott, K.W. (Keith W.), Hoch, N.C. (Nicolas C.), Hanzlikova, H. (Hana), Rulten, S.L. (Stuart L.), Tétreault, M. (Martine), Komulainen, E. (Emilia), Ju, L. (Limei), Hornyak, P. (Peter), Zeng, Z. (Zhihong), Gittens, W. (William), Rey, S.A. (Stephanie A.), Staras, K. (Kevin), Mancini, G.M.S. (Grazia), McKinnon, P.J. (Peter J.), Wang, Z.-Q. (Zhao-Qi), Wagner, J.D. (Justin D.), Yoon, G. (Grace), and Caldecott, K.W. (Keith W.)
Abstract: XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations
Published: 2017
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26. Human mutations in integrator complex subunits link transcriptome integrity to brain development

Author: Oegema, R. (Renske), Baillat, D. (David), Schot, R. (Rachel), Unen, L. (Leontine) van, Brooks, A.S. (Alice), Kia, S.K., Hoogeboom, A.J.M. (Jeannette), Xia, Z. (Zheng), Li, W. (Wei), Cesaroni, M. (Matteo), Leguin, M. (Maarten), Slegtenhorst, M.A. (Marjon) van, Dobyns, W.B. (William), Coo, I.F.M. (René) de, Verheijen, F.W. (Frans), Kremer, A.E. (Andreas), Spek, P.J. (Peter) van der, Heijsman, D. (Daphne), Wagner, E.J. (Eric J.), Fornerod, M.W.J. (Maarten), Mancini, G.M.S. (Grazia), Oegema, R. (Renske), Baillat, D. (David), Schot, R. (Rachel), Unen, L. (Leontine) van, Brooks, A.S. (Alice), Kia, S.K., Hoogeboom, A.J.M. (Jeannette), Xia, Z. (Zheng), Li, W. (Wei), Cesaroni, M. (Matteo), Leguin, M. (Maarten), Slegtenhorst, M.A. (Marjon) van, Dobyns, W.B. (William), Coo, I.F.M. (René) de, Verheijen, F.W. (Frans), Kremer, A.E. (Andreas), Spek, P.J. (Peter) van der, Heijsman, D. (Daphne), Wagner, E.J. (Eric J.), Fornerod, M.W.J. (Maarten), and Mancini, G.M.S. (Grazia)
Abstract: Integrator is an RNA polymerase II (RNAPII)-associated complex that was recently identified to have a broad role in both RNA processing and transcription regulation. Importantly, its role in human development and disease is so far largely unexplored. Here, we provide evidence that biallelic Integrator Complex Subunit 1 (INTS1) and Subunit 8 (INTS8) gene mutations are associated with rare recessive human neurodevelopmental syndromes. Three unrelated individuals of Dutch ancestry showed the same homozygous truncating INTS1 mutation. Three siblings harboured compound heterozygous INTS8 mutations. Shared features by these six individuals are severe neurodevelopmental delay and a distinctive appearance. The INTS8 family in addition presented with neuronal migration defects (periventricular nodular heterotopia). We show that the first INTS8 mutation, a nine base-pair deletion, leads to a protein that disrupts INT complex stability, while the second missense mutation introduces an alternative splice site leading to an unstable messenger. Cells from patients with INTS8 mutations show increased levels of unprocessed UsnRNA, compatible with the INT function in the 3’-end maturation of UsnRNA, and display significant disruptions in gene expression and RNA processing. Finally, the introduction of the INTS8 deletion mutation in P19 cells using genome editing alters gene expression throughout the course of retinoic acid-induced neural differentiation. Altogether, our results confirm the essential role of Integrator to transcriptome integrity and point to the requirement of the Integrator complex in human brain development.
Published: 2017
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27. Altered synaptobrevin-II trafficking in neurons expressing a synaptophysin mutation associated with a severe neurodevelopmental disorder

Author: Harper, C.B. (Callista B.), Mancini, G.M.S. (Grazia), Slegtenhorst, M.A. (Marjon) van, Cousin, M.A. (Michael A.), Harper, C.B. (Callista B.), Mancini, G.M.S. (Grazia), Slegtenhorst, M.A. (Marjon) van, and Cousin, M.A. (Michael A.)
Abstract: Following exocytosis, synaptic vesicles (SVs) have to be reformed with the correct complement of proteins in the correct stoichiometry to ensure continued neurotransmission. Synaptophysin is a highly abundant, integral SV protein necessary for the efficient retrieval of the SV SNARE protein, synaptobrevin II (sybII). However the molecular mechanism underpinning synaptophysin-dependent sybII retrieval is still unclear. We recently identified a male patient with severe intellectual disability, hypotonia, epilepsy and callosal agenesis who has a point mutation in the juxtamembrane region of the fourth transmembrane domain of synaptophysin (T198I). This mutation had no effect on the activity-dependent retrieval of synaptophysin that was tagged with the genetically-encoded pH-sensitive reporter (pHluorin) in synaptophysin knockout hippocampal cultures. This suggested the mutant has no global effect on SV endocytosis, which was confirmed when retrieval of a different SV cargo (the glutamate transporter vGLUT1) was examined. However neurons expressing this T198I mutant did display impaired activity-dependent sybII retrieval, similar to that observed in synaptophysin knockout neurons. Interestingly this impairment did not result in an increased stranding of sybII at the plasma membrane. Screening of known human synaptophysin mutations revealed a similar presynaptic phenotype between T198I and a mutation found in X-linked intellectual disability. Thus this novel human synaptophysin mutation has re
Published: 2017
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28. Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability

Author: Reijnders, M.R.F. (Margot R.F.), Kousi, M. (M.), Woerden, G.M. (Geeske) van, Klein, M. (Marieke), Bralten, L.B.C. (Linda), Mancini, G.M.S. (Grazia), Essen, T. (Ton) van, Proietti-Onori, M. (Martina), Smeets, E.E.J. (Eric E.J.), Van Gastel, M. (M.), Stegmann, A.P.A. (A. P.A.), Stevens, S.J.C. (S. J.C.), Lelieveld, S.H. (S. H.), Gilissen, C. (Christian), Pfundt, R. (Rolph), Tan, P.L. (P. L.), Kleefstra, T. (Tjitske), Franke, B. (Barbara), Elgersma, Y. (Ype), Katsanis, N. (Nicholas), Brunner, H.G., Reijnders, M.R.F. (Margot R.F.), Kousi, M. (M.), Woerden, G.M. (Geeske) van, Klein, M. (Marieke), Bralten, L.B.C. (Linda), Mancini, G.M.S. (Grazia), Essen, T. (Ton) van, Proietti-Onori, M. (Martina), Smeets, E.E.J. (Eric E.J.), Van Gastel, M. (M.), Stegmann, A.P.A. (A. P.A.), Stevens, S.J.C. (S. J.C.), Lelieveld, S.H. (S. H.), Gilissen, C. (Christian), Pfundt, R. (Rolph), Tan, P.L. (P. L.), Kleefstra, T. (Tjitske), Franke, B. (Barbara), Elgersma, Y. (Ype), Katsanis, N. (Nicholas), and Brunner, H.G.
Abstract: De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.
Published: 2017
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29. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

Author: Kim, J.-H. (Jung-Hyun), Shinde, D.N. (Deepali N.), Reijnders, M.R.F. (Margot R.F.), Hauser, N.S. (Natalie S.), Belmonte, R.L. (Rebecca L.), Wilson, G.R. (Gregory R.), Bosch, D.G.M. (Daniëlle G.M.), Bubulya, P.A. (Paula A.), Shashi, V. (Vandana), Petrovski, S. (Slavé), Stone, J.K. (Joshua K.), Park, E.Y. (Eun Young), Veltman, J.A. (Joris), Sinnema, M. (Margje), Stumpel, C. (Connie), Draaisma, J. (Jos), Nicolai, J. (Joost), Yntema, H.G., Lindstrom, K. (Kristin), Vries, B. (Boukje) de, Jewett, T. (Tamison), Santoro, S.L. (Stephanie L.), Vogt, J. (Julie), Bachman, K.K. (Kristine K.), Seeley, A.H. (Andrea ), Krokosky, A. (Alyson), Turner, C. (Clesson), Rohena, L. (Luis), Hempel, M. (Maja), Kortüm, F. (Fanny), Lessel, D. (Davor), Neu, A. (Axel), Strom, T.M. (Tim), Wieczorek, D. (Dagmar), Bramswig, N. (Nuria), Laccone, F.A. (Franco A.), Behunova, J. (Jana), Rehder, H. (Helga), Gordon, C.T. (Christopher T.), Rio, M. (Marlène), Romana, S. (Serge), Tang, S. (Sha), El-Khechen, D. (Dima), Cho, M.T. (Megan T.), McWalter, K. (Kirsty), Douglas, G. (Ganka), Baskin, B. (Berivan), Begtrup, A. (Amber), Funari, T. (Tara), Schoch, K. (Kelly), Stegmann, A.P.A. (Alexander P.A.), Stevens, S.J., Zhang, D.-E. (Dong-Er), Traver, D. (David), Yao, X. (Xu), MacArthur, D.G. (Daniel G.), Brunner, H.G., Mancini, G.M.S. (Grazia), Myers, R.H. (Richard), Owen, L.B. (Laurie B.), Lim, S.-T. (Ssang-Taek), Stachura, D.L. (David L.), Vissers, L.E.L.M., Ahn, E.-Y.E. (Eun-Young Erin), Kim, J.-H. (Jung-Hyun), Shinde, D.N. (Deepali N.), Reijnders, M.R.F. (Margot R.F.), Hauser, N.S. (Natalie S.), Belmonte, R.L. (Rebecca L.), Wilson, G.R. (Gregory R.), Bosch, D.G.M. (Daniëlle G.M.), Bubulya, P.A. (Paula A.), Shashi, V. (Vandana), Petrovski, S. (Slavé), Stone, J.K. (Joshua K.), Park, E.Y. (Eun Young), Veltman, J.A. (Joris), Sinnema, M. (Margje), Stumpel, C. (Connie), Draaisma, J. (Jos), Nicolai, J. (Joost), Yntema, H.G., Lindstrom, K. (Kristin), Vries, B. (Boukje) de, Jewett, T. (Tamison), Santoro, S.L. (Stephanie L.), Vogt, J. (Julie), Bachman, K.K. (Kristine K.), Seeley, A.H. (Andrea ), Krokosky, A. (Alyson), Turner, C. (Clesson), Rohena, L. (Luis), Hempel, M. (Maja), Kortüm, F. (Fanny), Lessel, D. (Davor), Neu, A. (Axel), Strom, T.M. (Tim), Wieczorek, D. (Dagmar), Bramswig, N. (Nuria), Laccone, F.A. (Franco A.), Behunova, J. (Jana), Rehder, H. (Helga), Gordon, C.T. (Christopher T.), Rio, M. (Marlène), Romana, S. (Serge), Tang, S. (Sha), El-Khechen, D. (Dima), Cho, M.T. (Megan T.), McWalter, K. (Kirsty), Douglas, G. (Ganka), Baskin, B. (Berivan), Begtrup, A. (Amber), Funari, T. (Tara), Schoch, K. (Kelly), Stegmann, A.P.A. (Alexander P.A.), Stevens, S.J., Zhang, D.-E. (Dong-Er), Traver, D. (David), Yao, X. (Xu), MacArthur, D.G. (Daniel G.), Brunner, H.G., Mancini, G.M.S. (Grazia), Myers, R.H. (Richard), Owen, L.B. (Laurie B.), Lim, S.-T. (Ssang-Taek), Stachura, D.L. (David L.), Vissers, L.E.L.M., and Ahn, E.-Y.E. (Eun-Young Erin)
Abstract: The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses c
Published: 2016
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30. Expanding the Phenotype Associated with NAA10-Related N-Terminal Acetylation Deficiency

Author: Saunier, C. (Chloé), Støve, S.I. (Svein Isungset), Popp, B. (Bernt), Gérard, B. (Bénédicte), Blenski, M. (Marina), Ahmew, N. (Nicholas), de Bie, C. (Charlotte), Goldenberg, P. (Paula), Isidor, B. (Bertrand), Keren, B. (Boris), Leheup, B. (Bruno), Lampert, L. (Laetitia), Mignot, A., Tezcan, K. (Kamer), Mancini, G.M.S. (Grazia), Nava, C. (Caroline), Wasserstein, M. (Melissa), Bruel, A.-L. (Ange-Line), Thevenon, J. (Julien), Masurel, A. (Alice), Duffourd, Y. (Yannis), Kuentz, P. (Paul), Huet, F. (Frédéric), Riviere, J.-B., Slegtenhorst, M.A. (Marjon) van, Faivre, L. (Laurence), Piton, A. (Amélie), Reis, A. (André), Arnesen, T. (Thomas), Thauvin-Robinet, C. (Christel), Zweier, C. (Christiane), Saunier, C. (Chloé), Støve, S.I. (Svein Isungset), Popp, B. (Bernt), Gérard, B. (Bénédicte), Blenski, M. (Marina), Ahmew, N. (Nicholas), de Bie, C. (Charlotte), Goldenberg, P. (Paula), Isidor, B. (Bertrand), Keren, B. (Boris), Leheup, B. (Bruno), Lampert, L. (Laetitia), Mignot, A., Tezcan, K. (Kamer), Mancini, G.M.S. (Grazia), Nava, C. (Caroline), Wasserstein, M. (Melissa), Bruel, A.-L. (Ange-Line), Thevenon, J. (Julien), Masurel, A. (Alice), Duffourd, Y. (Yannis), Kuentz, P. (Paul), Huet, F. (Frédéric), Riviere, J.-B., Slegtenhorst, M.A. (Marjon) van, Faivre, L. (Laurence), Piton, A. (Amélie), Reis, A. (André), Arnesen, T. (Thomas), Thauvin-Robinet, C. (Christel), and Zweier, C. (Christiane)
Abstract: N-terminal acetylation is a common protein modification in eukaryotes associated with numerous cellular processes. Inherited mutations in NAA10, encoding the catalytic subunit of the major N-terminal acetylation complex NatA have been associated with diverse, syndromic X-linked recessive disorders, whereas de novo missense mutations have been reported in one male and one female individual with severe intellectual disability but otherwise unspecific phenotypes. Thus, the full genetic and clinical spectrum of NAA10 deficiency is yet to be delineated. We identified three different novel and one known missense mutation in NAA10, de novo in 11 females, and due to maternal germ line mosaicism in another girl and her more severely affected and deceased brother. In vitro enzymatic assays for the novel, recurrent mutations p.(Arg83Cys) and p.(Phe128Leu) revealed reduced catalytic activity. X-inactivation was random in five females. The core phenotype of X-linked NAA10-related N-terminal-acetyltransferase deficiency in both males and females includes developmental delay, severe intellectual disability, postnatal growth failure with severe microcephaly, and skeletal or cardiac anomalies. Genotype-phenotype correlations within and between both genders are complex and may include various factors such as location and nature of mutations, enzymatic stability and activity, and X-inactivation in females.
Published: 2016
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31. Expanding the Phenotype Associated with NAA10-Related N-Terminal Acetylation Deficiency

Author: Saunier, C. (Chloé), Støve, S.I. (Svein Isungset), Popp, B. (Bernt), Gérard, B. (Bénédicte), Blenski, M. (Marina), Ahmew, N. (Nicholas), de Bie, C. (Charlotte), Goldenberg, P. (Paula), Isidor, B. (Bertrand), Keren, B. (Boris), Leheup, B. (Bruno), Lampert, L. (Laetitia), Mignot, A., Tezcan, K. (Kamer), Mancini, G.M.S. (Grazia), Nava, C. (Caroline), Wasserstein, M. (Melissa), Bruel, A.-L. (Ange-Line), Thevenon, J. (Julien), Masurel, A. (Alice), Duffourd, Y. (Yannis), Kuentz, P. (Paul), Huet, F. (Frédéric), Riviere, J.-B., Slegtenhorst, M.A. (Marjon) van, Faivre, L. (Laurence), Piton, A. (Amélie), Reis, A. (André), Arnesen, T. (Thomas), Thauvin-Robinet, C. (Christel), Zweier, C. (Christiane), Saunier, C. (Chloé), Støve, S.I. (Svein Isungset), Popp, B. (Bernt), Gérard, B. (Bénédicte), Blenski, M. (Marina), Ahmew, N. (Nicholas), de Bie, C. (Charlotte), Goldenberg, P. (Paula), Isidor, B. (Bertrand), Keren, B. (Boris), Leheup, B. (Bruno), Lampert, L. (Laetitia), Mignot, A., Tezcan, K. (Kamer), Mancini, G.M.S. (Grazia), Nava, C. (Caroline), Wasserstein, M. (Melissa), Bruel, A.-L. (Ange-Line), Thevenon, J. (Julien), Masurel, A. (Alice), Duffourd, Y. (Yannis), Kuentz, P. (Paul), Huet, F. (Frédéric), Riviere, J.-B., Slegtenhorst, M.A. (Marjon) van, Faivre, L. (Laurence), Piton, A. (Amélie), Reis, A. (André), Arnesen, T. (Thomas), Thauvin-Robinet, C. (Christel), and Zweier, C. (Christiane)
Published: 2016
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32. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TOR CH syndrome

Author: Meuwissen, M.E.C. (Marije), Schot, R. (Rachel), Buta, S. (Sofija), Oudesluijs, G.G. (Grétel), Tinschert, S. (Sigrid), Speer, S.D. (Scott D.), Li, Z. (Zhi), Unen, L. (Leontine) van, Heijsman, D. (Daphne), Goldmann, T. (Tobias), Leguin, M. (Maarten), Kros, J.M. (Johan), Stam, W. (Wendy), Hermann, M. (Mark), Willemsen, R. (Rob), Brouwer, R.W.W. (Rutger), IJcken, W.F.J. (Wilfred) van, Martin-Fernandez, M. (Marta), Coo, I.F.M. (René) de, Dudink, J. (Jeroen), Vries, F.A.T. (Femke) de, Avella, A.B. (Aida Bertoli), Prinz, M. (Marco), Crow, Y.J. (Yanick J.), Verheijen, F.W. (Frans), Pellegrini, S. (Sandra), Bogunovic, D. (Dusan), Mancini, G.M.S. (Grazia), Meuwissen, M.E.C. (Marije), Schot, R. (Rachel), Buta, S. (Sofija), Oudesluijs, G.G. (Grétel), Tinschert, S. (Sigrid), Speer, S.D. (Scott D.), Li, Z. (Zhi), Unen, L. (Leontine) van, Heijsman, D. (Daphne), Goldmann, T. (Tobias), Leguin, M. (Maarten), Kros, J.M. (Johan), Stam, W. (Wendy), Hermann, M. (Mark), Willemsen, R. (Rob), Brouwer, R.W.W. (Rutger), IJcken, W.F.J. (Wilfred) van, Martin-Fernandez, M. (Marta), Coo, I.F.M. (René) de, Dudink, J. (Jeroen), Vries, F.A.T. (Femke) de, Avella, A.B. (Aida Bertoli), Prinz, M. (Marco), Crow, Y.J. (Yanick J.), Verheijen, F.W. (Frans), Pellegrini, S. (Sandra), Bogunovic, D. (Dusan), and Mancini, G.M.S. (Grazia)
Abstract: Pseudo-TOR CH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, by systemic features at birth resembling the sequelae of congenital infection but in the absence of an infectious agent. Genetic defects resulting in activation of type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutières syndrome, which is a cause of PTS. Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. In this study, we identified loss-of-function recessive mutations of USP18 in five PTS patients from two unrelated families. Ex vivo brain autopsy material demonstrated innate immune inflammation with calcification and polymicrogyria. In vitro, patient fibroblasts displayed severely enhanced IFN-induced inflammation, which was completely rescued by lentiviral transduction of USP18. These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies. Moreover, USP18 deficiency represents the first genetic disorder of PTS caused by dysregulation of the response to type I IFNs. Therapeutically, this places USP18 as a promising target not only for genetic but also acquired IFN-mediated CNS disorders.
Published: 2016
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33. De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

Author: Reijnders, M.R.F. (Margot R.F.), Zachariadis, V. (Vasilios), Latour, B. (Brooke), Jolly, L. (Lachlan), Mancini, G.M.S. (Grazia), Pfundt, R. (Rolph), Wu, K.M. (Ka Man), Ravenswaaij-Arts, C.M.A. (Conny) van, Veenstra-Knol, H.E. (Hermine), Anderlid, B.-M.M. (Britt-Marie M.), Wood, S.A. (Stephen A.), Cheung, S.W. (Sau Wai), Barnicoat, A. (Angela), Probst, F. (Frank), Magoulas, P. (Pilar), Brooks, A.S. (Alice), Malmgren, H. (Helena), Harila-Saari, A. (Arja), Marcelis, C.M. (Carlo M.), Vreeburg, J.T.M. (Jan), Hobson, E. (Emma), Sutton, V.R. (V. Reid), Stark, Z. (Zornitza), Vogt, J. (Julie), Cooper, N. (Nicola), Lim, J.Y. (Jiin Ying), Price, S. (Susan), Lai, A.H.M. (Angeline Hwei Meeng), Domingo, D. (Deepti), Reversade, B. (Bruno), Gecz, J. (Jozef), Gilissen, C. (Christian), Brunner, H.G. (Han G.), Kini, U. (Usha), Roepman, R. (Ronald), Nordgren, A. (Ann), Kleefstra, T. (Tjitske), Reijnders, M.R.F. (Margot R.F.), Zachariadis, V. (Vasilios), Latour, B. (Brooke), Jolly, L. (Lachlan), Mancini, G.M.S. (Grazia), Pfundt, R. (Rolph), Wu, K.M. (Ka Man), Ravenswaaij-Arts, C.M.A. (Conny) van, Veenstra-Knol, H.E. (Hermine), Anderlid, B.-M.M. (Britt-Marie M.), Wood, S.A. (Stephen A.), Cheung, S.W. (Sau Wai), Barnicoat, A. (Angela), Probst, F. (Frank), Magoulas, P. (Pilar), Brooks, A.S. (Alice), Malmgren, H. (Helena), Harila-Saari, A. (Arja), Marcelis, C.M. (Carlo M.), Vreeburg, J.T.M. (Jan), Hobson, E. (Emma), Sutton, V.R. (V. Reid), Stark, Z. (Zornitza), Vogt, J. (Julie), Cooper, N. (Nicola), Lim, J.Y. (Jiin Ying), Price, S. (Susan), Lai, A.H.M. (Angeline Hwei Meeng), Domingo, D. (Deepti), Reversade, B. (Bruno), Gecz, J. (Jozef), Gilissen, C. (Christian), Brunner, H.G. (Han G.), Kini, U. (Usha), Roepman, R. (Ronald), Nordgren, A. (Ann), and Kleefstra, T. (Tjitske)
Abstract: Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected
Published: 2016
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34. USP18 lack in microglia causes destructive interferonopathy of the mouse brain

Author: Goldmann, T. (Tobias), Zeller, N. (Nicolas), Raasch, J. (Jenni), Kierdorf, K. (Katrin), Frenzel, K. (Kathrin), Ketscher, L. (Lars), Basters, A. (Anja), Staszewski, O. (Ori), Brendecke, S.M. (Stefanie M.), Spiess, A. (Alena), Tay, T.L. (Tuan Leng), Kreutz, C. (Clemens), Timmer, J. (Jens), Mancini, G.M.S. (Grazia), Blank, T. (Thomas), Fritz, G. (Günter), Biber, K.P.H. (Knut), Lang, R. (Roland), Malo, D. (Danielle), Merkler, D. (Doron), Heikenwälder, M. (Mathias), Knobeloch, K.-P. (Klaus-Peter), Prinz, M. (Marco), Goldmann, T. (Tobias), Zeller, N. (Nicolas), Raasch, J. (Jenni), Kierdorf, K. (Katrin), Frenzel, K. (Kathrin), Ketscher, L. (Lars), Basters, A. (Anja), Staszewski, O. (Ori), Brendecke, S.M. (Stefanie M.), Spiess, A. (Alena), Tay, T.L. (Tuan Leng), Kreutz, C. (Clemens), Timmer, J. (Jens), Mancini, G.M.S. (Grazia), Blank, T. (Thomas), Fritz, G. (Günter), Biber, K.P.H. (Knut), Lang, R. (Roland), Malo, D. (Danielle), Merkler, D. (Doron), Heikenwälder, M. (Mathias), Knobeloch, K.-P. (Klaus-Peter), and Prinz, M. (Marco)
Abstract: Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis. Microglia dysr
Published: 2015
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35. WDR73 Mutations Cause Infantile Neurodegeneration and Variable Glomerular Kidney Disease

Author: Vodopiutz, J. (Julia), Seidl, R. (Rainer), Prayer, D. (Daniela), Khan, M.I. (M. Imran), Mayr, J.A. (Johannes A.), Streubel, B. (Berthold), Steiß, J.-O. (Jens-Oliver), Hahn, A. (Andreas), Csaicsich, D. (Dagmar), Castro, C. (Christel), Assoum, M. (Mirna), Müller, T. (Thomas), Wieczorek, D. (Dagmar), Mancini, G.M.S. (Grazia), Sadowski, C.E. (Carolin E.), Lévy, N. (Nicolas), Megarbane, A. (Andre), Godbole, K. (Koumudi), Schanze, D. (Denny), Hildebrandt, F. (Friedhelm), Delague, V. (Valérie), Janecke, A.R. (Andreas), Zenker, M. (Martin), Vodopiutz, J. (Julia), Seidl, R. (Rainer), Prayer, D. (Daniela), Khan, M.I. (M. Imran), Mayr, J.A. (Johannes A.), Streubel, B. (Berthold), Steiß, J.-O. (Jens-Oliver), Hahn, A. (Andreas), Csaicsich, D. (Dagmar), Castro, C. (Christel), Assoum, M. (Mirna), Müller, T. (Thomas), Wieczorek, D. (Dagmar), Mancini, G.M.S. (Grazia), Sadowski, C.E. (Carolin E.), Lévy, N. (Nicolas), Megarbane, A. (Andre), Godbole, K. (Koumudi), Schanze, D. (Denny), Hildebrandt, F. (Friedhelm), Delague, V. (Valérie), Janecke, A.R. (Andreas), and Zenker, M. (Martin)
Abstract: Infantile-onset cerebellar atrophy (CA) is a clinically and genetically heterogeneous trait. Galloway-Mowat syndrome (GMS) is a rare autosomal recessive disease, characterized by microcephaly with brain anomalies including CA in some cases, intellectual disability, and early-infantile-onset nephrotic syndrome. Very recently, WDR73 deficiency was identified as the cause of GMS in five individuals. To evaluate the role of WDR73 mutations as a cause of GMS and other forms of syndromic CA, we performed Sanger or exome sequencing in 51 unrelated patients with CA and variable brain anomalies and in 40 unrelated patients with a diagnosis of GMS. We identified 10 patients from three CA and from two GMS families with WDR73 mutations including the original family described with CA, mental retardation, optic atrophy, and skin abnormalities (CAMOS). There were five novel mutations, of which two were truncating and three were missense mutations affecting highly conserved residues. Individuals carrying homozygous WDR73 mutations mainly presented with a pattern of neurological and neuroimaging findings as well as intellectual disability, while kidney involvement was variable. We document postnatal onset of CA, a retinopathy, basal ganglia degeneration, and short stature as novel features of WDR73-related disease, and define WDR73-related disease as a new entity of infantile neurodegeneration.
Published: 2015
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36. Phenotype and genotype in 101 males with x-linked creatine transporter deficiency

Author: van de Kamp, J.M. (Jiddeke M.), Betsalel, O.T. (Ofir), Mercimek-Mahmutoglu, S. (Saadet), Abulhoul, L. (L.), Grünewald, S. (Sonja), Anselm, I. (I.), Azzouz, H. (H.), Bratkovic, D. (D.), Brouwer, A.P.M. (Arjan) de, Hamel, B.C. (Ben), Kleefstra, T. (Tjitske), Yntema, H.G., Campistol, J.M., Vilaseca, M.A. (M.), Cheillan, D. (David), D'Hooghe, M. (M.), Diogo, L. (Luisa), Garcia, P. (Paula), Valongo, C. (C.), Fonseca, M. (M.), Frints, S.G.M. (Suzanna), Wilcken, B. (Bridget), Haar, S. (Sigrun) von der, Meijers-Heijboer, E.J. (Hanne), Hofstede, F.C. (Floris), Johnson, D. (David), Kant, S.G. (Sarina), Lion-Francois, L. (Laurence), Pitelet, G. (G.), Longo, N. (N.), Maat-Kievit, A.A. (Anneke), Monteiro, J.P. (J.), Munnich, A. (Arnold), Muntau, A.C. (A.), Nassogne, M.C. (M.), Osaka, H. (H.), Õunap, K. (Katrin), Pinard, J.M. (J.), Quijano-Roy, S. (S.), Poggenburg, I. (I.), Poplawski, N. (Nicola), Abdul-Rahman, O.A. (Omar), Ribes, A. (A.), Arias Pérez, J.I. (José Ignacio), Yaplito-Lee, J. (J.), Schulze, A. (A.), Schwartz, C.E., Schwenger, S. (S.), Soares, G. (G.), Sznajer, Y. (Yves), Valayannopoulos, V. (Vassili), Esch, H. (Hilde) van, Waltz, S. (S.), Wamelink, M.M.C. (Mirjam), Pouwels, P.J.W. (Petra), Errami, A. (Abdellatif), Knaap, M.S. (Marjo) van der, Jakobs, C. (Cornelis), Mancini, G.M.S. (Grazia), Salomons, G.S. (Gajja), van de Kamp, J.M. (Jiddeke M.), Betsalel, O.T. (Ofir), Mercimek-Mahmutoglu, S. (Saadet), Abulhoul, L. (L.), Grünewald, S. (Sonja), Anselm, I. (I.), Azzouz, H. (H.), Bratkovic, D. (D.), Brouwer, A.P.M. (Arjan) de, Hamel, B.C. (Ben), Kleefstra, T. (Tjitske), Yntema, H.G., Campistol, J.M., Vilaseca, M.A. (M.), Cheillan, D. (David), D'Hooghe, M. (M.), Diogo, L. (Luisa), Garcia, P. (Paula), Valongo, C. (C.), Fonseca, M. (M.), Frints, S.G.M. (Suzanna), Wilcken, B. (Bridget), Haar, S. (Sigrun) von der, Meijers-Heijboer, E.J. (Hanne), Hofstede, F.C. (Floris), Johnson, D. (David), Kant, S.G. (Sarina), Lion-Francois, L. (Laurence), Pitelet, G. (G.), Longo, N. (N.), Maat-Kievit, A.A. (Anneke), Monteiro, J.P. (J.), Munnich, A. (Arnold), Muntau, A.C. (A.), Nassogne, M.C. (M.), Osaka, H. (H.), Õunap, K. (Katrin), Pinard, J.M. (J.), Quijano-Roy, S. (S.), Poggenburg, I. (I.), Poplawski, N. (Nicola), Abdul-Rahman, O.A. (Omar), Ribes, A. (A.), Arias Pérez, J.I. (José Ignacio), Yaplito-Lee, J. (J.), Schulze, A. (A.), Schwartz, C.E., Schwenger, S. (S.), Soares, G. (G.), Sznajer, Y. (Yves), Valayannopoulos, V. (Vassili), Esch, H. (Hilde) van, Waltz, S. (S.), Wamelink, M.M.C. (Mirjam), Pouwels, P.J.W. (Petra), Errami, A. (Abdellatif), Knaap, M.S. (Marjo) van der, Jakobs, C. (Cornelis), Mancini, G.M.S. (Grazia), and Salomons, G.S. (Gajja)
Abstract: Background: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype-genotype correlation has been lacking. Methods: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). Results and conclusions: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 30 end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.
Published: 2013
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37. COL4A2 mutation associated with familial porencephaly and small-vessel disease

Author: Verbeek, E. (Elly), Meuwissen, M.E.C. (Marije), Verheijen, F.W. (Frans), Govaert, P. (Paul), Licht, D.J. (Daniel), Kuo, D.S. (Debbie), Poulton, C.J. (Cathryn), Schot, R. (Rachel), Lequin, M.H. (Maarten), Dudink, J. (Jeroen), Halley, D.J.J. (Dicky), Coo, I.F.M. (René) de, Hollander, J.C. (Jan) den, Oegema, R. (Renske), Gould, D.B. (Douglas ), Mancini, G.M.S. (Grazia), Verbeek, E. (Elly), Meuwissen, M.E.C. (Marije), Verheijen, F.W. (Frans), Govaert, P. (Paul), Licht, D.J. (Daniel), Kuo, D.S. (Debbie), Poulton, C.J. (Cathryn), Schot, R. (Rachel), Lequin, M.H. (Maarten), Dudink, J. (Jeroen), Halley, D.J.J. (Dicky), Coo, I.F.M. (René) de, Hollander, J.C. (Jan) den, Oegema, R. (Renske), Gould, D.B. (Douglas ), and Mancini, G.M.S. (Grazia)
Abstract: Familial porencephaly, leukoencephalopathy and small-vessel disease belong to the spectrum of disorders ascribed to dominant mutations in the gene encoding for type IV collagen alpha-1 (COL4A1). Mice harbouring mutations in either Col4a1 or Col4a2 suffer from porencephaly, hydrocephalus, cerebral and ocular bleeding and developmental defects. We observed porencephaly and white matter lesions in members from two families that lack COL4A1 mutations. We hypothesized that COL4A2 mutations confer genetic predisposition to porencephaly, therefore we sequenced COL4A2 in the family members and characterized clinical, neuroradiological and biochemical phenotypes. Genomic sequencing of COL4A2 identified the heterozygous missense G1389R in exon 44 in one family and the c.3206delC change in exon 34 leading to frame shift and premature stop, in the second family. Fragmentation and duplication of epidermal basement membranes were observed by electron microscopy in a c.3206delC patient skin biopsy, consistent with abnormal collagen IV n
Published: 2012
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38. RTTN mutations link primary cilia function to organization of the human cerebral cortex

Author: Kia, S.K., Verbeek, E. (Elly), Engelen, M.P. (Erik), Schot, R. (Rachel), Poot, R.A. (Raymond), Coo, I.F.M. (René) de, Leguin, M. (Maarten), Poulton, C.J. (Cathryn), Pourfarzad, F. (Farzin), Grosveld, F.G. (Frank), Brehm, A. (António), Wit, M.C.Y. (Marie Claire) de, Oegema, R. (Renske), Dobyns, W.B. (William), Verheijen, F.W. (Frans), Mancini, G.M.S. (Grazia), Kia, S.K., Verbeek, E. (Elly), Engelen, M.P. (Erik), Schot, R. (Rachel), Poot, R.A. (Raymond), Coo, I.F.M. (René) de, Leguin, M. (Maarten), Poulton, C.J. (Cathryn), Pourfarzad, F. (Farzin), Grosveld, F.G. (Frank), Brehm, A. (António), Wit, M.C.Y. (Marie Claire) de, Oegema, R. (Renske), Dobyns, W.B. (William), Verheijen, F.W. (Frans), and Mancini, G.M.S. (Grazia)
Abstract: Polymicrogyria is a malformation of the developing cerebral cortex caused by abnormal organization and characterized by many small gyri and fusion of the outer molecular layer. We have identified autosomal-recessive mutations in RTTN, encoding Rotatin, in individuals with bilateral diffuse polymicrogyria from two separate families. Rotatin determines early embryonic axial rotation, as well as anteroposterior and dorsoventral patterning in the mouse. Human Rotatin has recently been identified as a centrosome-associated protein. The Drosophila melanogaster homolog of Rotatin, Ana3, is needed for structural integrity of centrioles and basal bodies and maintenance of sensory neurons. We show that Rotatin colocalizes with the basal bodies at the primary cilium. Cultured fibroblasts from affected individuals have structural abnormalities of the cilia and exhibit downregulation of BMP4, WNT5A, and WNT2B, which are key regulators of cortical patterning and are expressed at the cortical hem, the cortex-organizing center that gives rise to Cajal-Retzius (CR) neurons. Interestingly, we have shown that in mouse embryos, Rotatin colocalizes with CR neurons at the subpial marginal zone. Knockdown experiments in human fibroblasts and neural stem cells confirm a role for RTTN in cilia structure and function. RTTN mutations therefore link aberrant ciliary function to abnormal development and organization of the cortex in human individuals.
Published: 2012
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39. Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect

Author: van de Kamp, J.M. (Jiddeke M.), Pouwels, P.J.W. (Petra J.W.), Aarsen, F.K. (Femke), ten Hoopen, L.W. (Leontine W.), Knol, D.L. (Dirk L.), Klerk, J.B.C. (Johannes) de, Coo, I.F.M. (René) de, Huijmans, J.G.M. (Jan), Jakobs, C. (Cornelis), Knaap, M.S. (Marjo) van der, Salomons, G.S. (Gajja S.), Mancini, G.M.S. (Grazia), van de Kamp, J.M. (Jiddeke M.), Pouwels, P.J.W. (Petra J.W.), Aarsen, F.K. (Femke), ten Hoopen, L.W. (Leontine W.), Knol, D.L. (Dirk L.), Klerk, J.B.C. (Johannes) de, Coo, I.F.M. (René) de, Huijmans, J.G.M. (Jan), Jakobs, C. (Cornelis), Knaap, M.S. (Marjo) van der, Salomons, G.S. (Gajja S.), and Mancini, G.M.S. (Grazia)
Abstract: The creatine transporter (CRTR) defect is a recently discovered cause of X-linked intellectual disability for which treatment options have been explored. Creatine monotherapy has not proved effective, and the effect of treatment with L-arginine is still controversial. Nine boys between 8 months and 10 years old with molecularly confirmed CRTR defect were followed with repeated1H-MRS and neuropsychological assessments during 4-6 years of combination treatment with creatine monohydrate, L-arginine, and glycine. Treatment did not lead to a significant increase in cerebral creatine content as observed with H1-MRS. After an initial improvement in locomotor and personal-social IQ subscales, no lasting clinical improvement was recorded. Additionally, we noticed an age-related decline in IQ subscales in boys affected with the CRTR defect.
Published: 2012
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40. Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors

Author: Poulton, C.J. (Cathryn), Schot, R. (Rachel), Kia, S.K., Jones, M. (Marta), Verheijen, F.W. (Frans), Venselaar, H. (Hanka), Wit, M.C.Y. (Marie Claire) de, Graaff, E. (Esther) de, Bertoli Avella, A.M. (Aida), Mancini, G.M.S. (Grazia), Poulton, C.J. (Cathryn), Schot, R. (Rachel), Kia, S.K., Jones, M. (Marta), Verheijen, F.W. (Frans), Venselaar, H. (Hanka), Wit, M.C.Y. (Marie Claire) de, Graaff, E. (Esther) de, Bertoli Avella, A.M. (Aida), and Mancini, G.M.S. (Grazia)
Abstract: We describe a syndrome of primary microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes in two unrelated consanguineous families with at least three affected children. Linkage analysis revealed a region on chromosome 18 with a significant LOD score of 4.3. In this area, two homozygous nonconserved missense mutations in immediate early response 3 interacting protein 1 (IER3IP1) were found in patients from both families. IER3IP1 is highly expressed in the fetal brain cortex and fetal pancreas and is thought to be involved in endoplasmic reticulum stress response. We reported one of these families previously in a paper on Wolcott-Rallison syndrome (WRS). WRS is
Published: 2011
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41. Combined cardiological and neurological abnormalities due to filamin A gene mutation

Author: Wit, M.C.Y. (Marie Claire) de, Coo, I.F.M. (René) de, Lequin, M.H. (Maarten), Halley, D.J.J. (Dicky), Roos-Hesselink, J.W. (Jolien), Mancini, G.M.S. (Grazia), Wit, M.C.Y. (Marie Claire) de, Coo, I.F.M. (René) de, Lequin, M.H. (Maarten), Halley, D.J.J. (Dicky), Roos-Hesselink, J.W. (Jolien), and Mancini, G.M.S. (Grazia)
Abstract: Background: Cardiac defects can be the presenting symptom in patients with mutations in the X-linked gene FLNA. Dysfunction of this gene is associated with cardiac abnormalities, especially in the left ventricular outflow tract, but can also cause a congenital malformation of the cerebral cortex. We noticed that some patients diagnosed at the neurogenetics clinic had first presented to a cardiologist, suggesting that earlier recognition may be possible if the diagnosis is suspected. Methods and results: From the Erasmus MC cerebral malformations database 24 patients were identified with cerebral bilateral periventricular nodular heterotopia (PNH) without other cerebral cortical malformations. In six of these patients, a pathogenic mutation in FLNA was present. In five a cardiac defect was also found in the outflow tract. Four had presented to a cardiologist before the cerebral abnormalities were diagnosed. Conclusions: The cardiological phenotype typically consists of aortic or mitral regurgitation, coarctation of the aorta or other left-sided cardiac malformations. Most patients in this category will not have a FLNA mutation, but the presence of neurological complaints, hyperlaxity of the skin or joints and/or a family history with similar cardiac or neurological problems in a possibly X-linked pattern may alert the clinician to the possibility of a FLNA mutation.
Published: 2011
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42. Unbalanced der(5)t(5;20) translocation associated with megalencephaly, perisylvian polymicrogyria, polydactyly and hydrocephalus

Author: Verkerk, A.J.H.M. (Annemieke), Schot, R. (Rachel), Waterschoot, L. (Laura) van, Douben, H. (Hannie), Poddighe, P. (Pino), Leguin, M. (Maarten), Vries, L.S. (Linda) de, Terhal, P. (Paulien), Hahnemann, J.M.D. (Johanne), Coo, I.F.M. (René) de, Wit, M.C.Y. (Marie Claire) de, Wafelman, L.S. (Leontien), Garavelli, L. (Livia), Dobyns, W.B. (William), Spek, P.J. (Peter) van der, Klein, J.E.M.M. (Annelies) de, Mancini, G.M.S. (Grazia), Verkerk, A.J.H.M. (Annemieke), Schot, R. (Rachel), Waterschoot, L. (Laura) van, Douben, H. (Hannie), Poddighe, P. (Pino), Leguin, M. (Maarten), Vries, L.S. (Linda) de, Terhal, P. (Paulien), Hahnemann, J.M.D. (Johanne), Coo, I.F.M. (René) de, Wit, M.C.Y. (Marie Claire) de, Wafelman, L.S. (Leontien), Garavelli, L. (Livia), Dobyns, W.B. (William), Spek, P.J. (Peter) van der, Klein, J.E.M.M. (Annelies) de, and Mancini, G.M.S. (Grazia)
Abstract: The combination of megalencephaly, perisylvian polymicrogyria, polydactyly and hydrocephalus (MPPH) is a rare syndrome of unknown cause. We observed two first cousins affected by an MPPH-like phenotype with a submicroscopic chromosome 5q35 deletion as a result of an unbalanced der(5)t(5;20)(q35.2;q13.3) translocation, including the NSD1 Sotos syndrome locus. We describe the phenotype and the deletion breakpoints of the two MPPH-li
Published: 2010
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43. Unbalanced der(5)t(5;20) translocation associated with megalencephaly, perisylvian polymicrogyria, polydactyly and hydrocephalus

Author: Verkerk, A.J.H.M. (Annemieke), Schot, R. (Rachel), Waterschoot, L. (Laura) van, Douben, H. (Hannie), Poddighe, P. (Pino), Leguin, M. (Maarten), Vries, L.S. (Linda) de, Terhal, P. (Paulien), Hahnemann, J.M.D. (Johanne), Coo, I.F.M. (René) de, Wit, M.C.Y. (Marie Claire) de, Wafelman, L.S. (Leontien), Garavelli, L. (Livia), Dobyns, W.B. (William), Spek, P.J. (Peter) van der, Klein, J.E.M.M. (Annelies) de, Mancini, G.M.S. (Grazia), Verkerk, A.J.H.M. (Annemieke), Schot, R. (Rachel), Waterschoot, L. (Laura) van, Douben, H. (Hannie), Poddighe, P. (Pino), Leguin, M. (Maarten), Vries, L.S. (Linda) de, Terhal, P. (Paulien), Hahnemann, J.M.D. (Johanne), Coo, I.F.M. (René) de, Wit, M.C.Y. (Marie Claire) de, Wafelman, L.S. (Leontien), Garavelli, L. (Livia), Dobyns, W.B. (William), Spek, P.J. (Peter) van der, Klein, J.E.M.M. (Annelies) de, and Mancini, G.M.S. (Grazia)
Abstract: The combination of megalencephaly, perisylvian polymicrogyria, polydactyly and hydrocephalus (MPPH) is a rare syndrome of unknown cause. We observed two first cousins affected by an MPPH-like phenotype with a submicroscopic chromosome 5q35 deletion as a result of an unbalanced der(5)t(5;20)(q35.2;q13.3) translocation, including the NSD1 Sotos syndrome locus. We describe the phenotype and the deletion breakpoints of the two MPPH-li
Published: 2010
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44. The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes

Author: Paulussen, A.D.C. (Aimée), Schrander-Stumpel, C.T.R.M. (Constance), Tserpelis, D.C.J. (Demis), Spee, M.K.M. (Matteus), Stegmann, A.P.A. (Sander), Mancini, G.M.S. (Grazia), Brooks, A.S. (Alice), Colée, M. (Margriet), Maat-Kievit, A.A. (Anneke), Simon, M.E.H. (Marleen), Bever, Y. (Yolande) van, Stolte-Dijkstra, I. (Irene), Kerstjense-Frederikse, W.S. (Wilhelmina), Herkert, J.C. (Johanna), Essen, J.A. (Anthonie) van, Lichtenbelt, K.D. (Klaske), Haeringen, A. (Arie) van, Kwee, M.L. (Mei), Lachmeijer, A.M.A. (Augusta), Tan-Sindhunata, G.M.B. (Gita), Maarle, M.C. (Merel), Arens, Y.H.J.M. (Yvonne), Smeets, E.E.J.G.L. (Eric), Die-Smulders, C. (Christine) de, Engelen, J.J.M. (John), Smeets, H. (Hubert), Herbergs, J. (Jos), Paulussen, A.D.C. (Aimée), Schrander-Stumpel, C.T.R.M. (Constance), Tserpelis, D.C.J. (Demis), Spee, M.K.M. (Matteus), Stegmann, A.P.A. (Sander), Mancini, G.M.S. (Grazia), Brooks, A.S. (Alice), Colée, M. (Margriet), Maat-Kievit, A.A. (Anneke), Simon, M.E.H. (Marleen), Bever, Y. (Yolande) van, Stolte-Dijkstra, I. (Irene), Kerstjense-Frederikse, W.S. (Wilhelmina), Herkert, J.C. (Johanna), Essen, J.A. (Anthonie) van, Lichtenbelt, K.D. (Klaske), Haeringen, A. (Arie) van, Kwee, M.L. (Mei), Lachmeijer, A.M.A. (Augusta), Tan-Sindhunata, G.M.B. (Gita), Maarle, M.C. (Merel), Arens, Y.H.J.M. (Yvonne), Smeets, E.E.J.G.L. (Eric), Die-Smulders, C. (Christine) de, Engelen, J.J.M. (John), Smeets, H. (Hubert), and Herbergs, J. (Jos)
Abstract: Holoprosencephaly is a severe malformation of the brain characterized by abnormal formation and separation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, the live-born prevalence is 1:16 000. The etiology of HPE is extremely heterogeneous and can be teratogenic or genetic. We screened four known HPE genes in a Dutch cohort of 86 non-syndromic HPE index cases, including 53 family members. We detected 21 mutations (24.4%), 3 in SHH, 9 in ZIC2 and 9 in SIX3. Eight mutations involved amino-acid substitutions, 7 ins/del mutations, 1 frame-shift, 3 identical poly-alanine tract expansions and 2 gene deletions. Pathogenicity of mutations was presumed based on de novo character, predicted non-functionality of mutated proteins, segregation of mutations with affected family-members or combinations of these features. Two mutations were reported previously. SNP array confirmed detected deletions; one spanning the ZIC2/ZIC5 genes (approx. 100 kb) the other a 1.45 Mb
Published: 2010
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45. Distinctive phenotypic abnormalities associated with submicroscopic 21q22 deletion including DYRK1A

Author: Oegema, R. (Renske), Klein, J.E.M.M. (Annelies) de, Verkerk, A., Schot, R. (Rachel), Dumee, B. (Belinda), Douben, H. (Hannie), Eussen, H.J.F.M.M. (Bert), Hulsman, L.O.M. (Lorette), Poddighe, P. (Pino), Laar, I.M.B.H. (Ingrid) van de, Dobyns, W.B. (William), Spek, P.J. (Peter) van der, Lequin, M.H. (Maarten), Coo, I.F.M. (René) de, Wit, M.C.Y. (Marie Claire) de, Wessels, M.W. (Marja), Mancini, G.M.S. (Grazia), Oegema, R. (Renske), Klein, J.E.M.M. (Annelies) de, Verkerk, A., Schot, R. (Rachel), Dumee, B. (Belinda), Douben, H. (Hannie), Eussen, H.J.F.M.M. (Bert), Hulsman, L.O.M. (Lorette), Poddighe, P. (Pino), Laar, I.M.B.H. (Ingrid) van de, Dobyns, W.B. (William), Spek, P.J. (Peter) van der, Lequin, M.H. (Maarten), Coo, I.F.M. (René) de, Wit, M.C.Y. (Marie Claire) de, Wessels, M.W. (Marja), and Mancini, G.M.S. (Grazia)
Abstract: Partial monosomy 21 has been reported, but the phenotypes described are variable with location and size of the deletion. We present 2 patients with a partially overlapping microdeletion of 21q22 and a striking phenotypic resemblance. They both presented with severe psychomotor delay, behavioral problems, no speech, microcephaly, feeding problems with frequent regurgit
Published: 2010

46. TUBA1A mutations cause wide spectrum lissencephaly (smooth brain) and suggest that multiple neuronal migration pathways converge on alpha tubulins

Author: Kumar, R.A. (Ravinesh), Pilz, D.T. (Daniela), Babatz, T.D. (Timothy), Cushion, T.D. (Thomas), Harvey, K. (Kirsten), Topf, M. (Maya), Yates, L. (Laura), Robb, S. (Stephanie), Uyanik, G. (Gökhan), Mancini, G.M.S. (Grazia), Rees, M.I. (Mark), Harvey, R.J. (Robert), Dobyns, W.B. (William), Kumar, R.A. (Ravinesh), Pilz, D.T. (Daniela), Babatz, T.D. (Timothy), Cushion, T.D. (Thomas), Harvey, K. (Kirsten), Topf, M. (Maya), Yates, L. (Laura), Robb, S. (Stephanie), Uyanik, G. (Gökhan), Mancini, G.M.S. (Grazia), Rees, M.I. (Mark), Harvey, R.J. (Robert), and Dobyns, W.B. (William)
Abstract: e previously showed that mutations in LIS1 and DCX account for ~85% of patients with the classic form of lissencephaly (LIS). Some rare forms of LIS are associated with a disproportionately small cerebellum, referred to as lissencephaly with cerebellar hypoplasia (LCH). Tubulin alpha1A (TUBA1A), encoding a critical structural subunit of microtubules, has recently been implicated in LIS. Here, we screen the largest cohort of unexplained LIS patients examined to date to determine: (i) the frequency of TUBA1A mutations in patients with lissencephaly, (ii) the spectrum of phenotypes associated with TUBA1A mutations and (iii) the functional consequences of different TUBA1A mutations on microtubule function. We identified novel and recurrent TUBA1A mutations in ~1% of children with classic LIS and in ~30% of children with LCH, making this the first major gene associated with the rare LCH phenotype. We also unexpectedly found a TUBA1A mutation in one child with agenesis of the corpus callosum and cerebellar hypoplasia without LIS. Thus, our data demonstrate a wider spectrum of phenotypes than previously reported and allow us to propose new recommendations for clinical testing. We also provide cellular and structural data suggesting that LIS-associated mutations of TUBA1A operate via diverse mechanisms that include disruption of binding sites for microtubule-associated proteins (MAPs).
Published: 2010
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47. Mutations in the nuclear localization sequence of the Aristaless related homeobox; Sequestration of mutant ARX with IPO13 disrupts normal subcellular distribution of the transcription factor and retards cell division

Author: Shoubridge, C. (Cheryl), Tan, M. (May), Fullston, T. (Tod), Cloosterman, D. (Desiree), Coman, D. (David), McGillivray, G. (George), Mancini, G.M.S. (Grazia), Kleefstra, T. (Tjitske), Gecz, J. (Jozef), Shoubridge, C. (Cheryl), Tan, M. (May), Fullston, T. (Tod), Cloosterman, D. (Desiree), Coman, D. (David), McGillivray, G. (George), Mancini, G.M.S. (Grazia), Kleefstra, T. (Tjitske), and Gecz, J. (Jozef)
Abstract: Background. Aristaless related homeobox (ARX) is a paired-type homeobox gene. ARX function is frequently affected by naturally occurring mutations. Nonsense mutations, polyalanine tract expansions and missense mutations in ARX cause a range of intellectual disability and epilepsy phenotypes with or without additional features including hand dystonia, lissencephaly, autism or dysarthria. Severe malformation phenotypes, such as X-linked lissencephaly with ambiguous genitalia (XLAG), are frequently observed in individuals with protein truncating or missense mutations clustered in the highly conserved paired-type homeodomain. Results. We have identified two novel point mutations in the R379 residue of the ARX homeodomain; c.1135C>A, p.R379S in a patient with infantile spasms and intellectual disability and c.1136G>T, p.R379L in a patient with XLAG. We investigated these and other missense mutations (R332P, R332H, R332C, T333N: associated with XLAG and Proud syndrome) predicted to affect the nuclear localisation sequences (NLS) flanking either end of the ARX homeodomain. The NLS regions are required for correct nuclear import facilitated by Importin 13 (IPO13). We demonstrate that missense mutations in either the N- or C-terminal NLS regions of the homeodomain cause significant disruption to nuclear
Published: 2010
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48. Glucose transporter-1 deficiency syndrome: The expanding clinical and genetic spectrum of a treatable disorder

Author: Leen, W.G. (Wilhelmina), Klepper, J. (Joerg), Verbeek, M.M. (Marcel), Leferink, M. (Maike), Hofste, T. (Tom), Engelen, B.G.M. (Baziel) van, Wevers, R.A. (Ron), Arthur, T. (Todd), Bahi-Buisson, N. (Nadia), Ballhausen, D. (Diana), Bekhof, J. (Jolita), Bogaert, P. (Patrick) van, Carrilho, I. (Inês), Chabrol, B. (Brigitte), Champion, M.P. (Michael), Coldwell, J. (James), Clayton, P. (Peter), Donner, E. (Elizabeth), Evangeliou, A. (Athanasios), Ebinger, F. (Friedrich), Farrell, K. (Kevin), Forsyth, R.J. (Rob), Goede, C.G.E.L. (Christian) de, Gross, S. (Stephanie), Grünewald, S. (Sonja), Holthausen, H. (Hans), Jayawant, S. (Sandeep), Lachlan, K. (Katherine), Laugel, V. (Vincent), Leppig, K. (Kathy), Lim, M.J. (Ming), Mancini, G.M.S. (Grazia), Marina, A.D., Martorell, L. (Loreto), McMenamin, J. (Joe), Meuwissen, M.E.C. (Marije), Mundy, H. (Helen), Nilsson, N.O. (Nils), Panzer, A. (Axel), Poll-The, B.T., Rauscher, C. (Christian), Rouselle, C.M.R. (Christophe), Sandvig, I. (Inger), Scheffner, T. (Thomas), Sheridan, E. (Eamonn), Simpson, N. (Neil), Sykora, P. (Parol), Tomlinson, R. (Richard), Trounce, J. (John), Webb, D.W.M. (David), Weschke, B. (Bernhard), Scheffer, H. (Hans), Willemsen, M.A. (Michél), Leen, W.G. (Wilhelmina), Klepper, J. (Joerg), Verbeek, M.M. (Marcel), Leferink, M. (Maike), Hofste, T. (Tom), Engelen, B.G.M. (Baziel) van, Wevers, R.A. (Ron), Arthur, T. (Todd), Bahi-Buisson, N. (Nadia), Ballhausen, D. (Diana), Bekhof, J. (Jolita), Bogaert, P. (Patrick) van, Carrilho, I. (Inês), Chabrol, B. (Brigitte), Champion, M.P. (Michael), Coldwell, J. (James), Clayton, P. (Peter), Donner, E. (Elizabeth), Evangeliou, A. (Athanasios), Ebinger, F. (Friedrich), Farrell, K. (Kevin), Forsyth, R.J. (Rob), Goede, C.G.E.L. (Christian) de, Gross, S. (Stephanie), Grünewald, S. (Sonja), Holthausen, H. (Hans), Jayawant, S. (Sandeep), Lachlan, K. (Katherine), Laugel, V. (Vincent), Leppig, K. (Kathy), Lim, M.J. (Ming), Mancini, G.M.S. (Grazia), Marina, A.D., Martorell, L. (Loreto), McMenamin, J. (Joe), Meuwissen, M.E.C. (Marije), Mundy, H. (Helen), Nilsson, N.O. (Nils), Panzer, A. (Axel), Poll-The, B.T., Rauscher, C. (Christian), Rouselle, C.M.R. (Christophe), Sandvig, I. (Inger), Scheffner, T. (Thomas), Sheridan, E. (Eamonn), Simpson, N. (Neil), Sykora, P. (Parol), Tomlinson, R. (Richard), Trounce, J. (John), Webb, D.W.M. (David), Weschke, B. (Bernhard), Scheffer, H. (Hans), and Willemsen, M.A. (Michél)
Abstract: Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutation
Published: 2010
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49. Movement disorder and neuronal migration disorder due to ARFGEF2 mutation

Author: Wit, M.C.Y. (Marie Claire) de, Coo, I.F.M. (René) de, Halley, D. (Dicky), Leguin, M. (Maarten), Mancini, G.M.S. (Grazia), Wit, M.C.Y. (Marie Claire) de, Coo, I.F.M. (René) de, Halley, D. (Dicky), Leguin, M. (Maarten), and Mancini, G.M.S. (Grazia)
Abstract: We report a child with a severe choreadystonic movement disorder, bilateral periventricular nodular heterotopia (BPNH), and secondary microcephaly based on compound heterozygosity for two new ARFGEF2 mutations (c.2031_2038dup and c.3798_3802del), changing the limited knowledge about the phenotype. The brain MRI shows bilateral hyperintensity of the putamen, BPNH, and generalized atrophy. Loss of ARFGEF2 function affects vesicle trafficking, proliferation/apoptosis, and neurotransmitter receptor function. This can explain BPNH and microcephaly. We hypothesize that the movement disorder and the preferential damage to the basal ganglia, specifically to the putamen, may be caused by an increased sensitivity to degeneration, a dynamic dysfunction due to neurotransmitter receptor mislocalization or a combination of both.
Published: 2009
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50. Detection of low-level somatic and germline mosaicism by denaturing high-performance liquid chromatography in a EURO-MRX family with SLC6A8 deficiency

Author: Betsalel, O.T. (Ofir), van de Kamp, J.M. (Jiddeke M.), Martínez-Muñoz, C. (Cristina), Rosenberg, E.H. (Efraim), Brouwer, A.P.M. (Arjan) de, Pouwels, P.J.W. (Petra), Knaap, M.S. (Marjo) van der, Mancini, G.M.S. (Grazia), Jakobs, C. (Cornelis), Hamel, B.C. (Ben), Salomons, G.S. (Gajja), Betsalel, O.T. (Ofir), van de Kamp, J.M. (Jiddeke M.), Martínez-Muñoz, C. (Cristina), Rosenberg, E.H. (Efraim), Brouwer, A.P.M. (Arjan) de, Pouwels, P.J.W. (Petra), Knaap, M.S. (Marjo) van der, Mancini, G.M.S. (Grazia), Jakobs, C. (Cornelis), Hamel, B.C. (Ben), and Salomons, G.S. (Gajja)
Abstract: Creatine transporter deficiency is an X-linked mental retardation disorder caused by mutations in the creatine transporter gene, SLC6A8. In a European Mental Retardation Consortium panel of 66 patients, we identified a male with mental retardation, caused by a c.1059_1061delCTT; p.Phe354del mutation in the SLC6A8 gene. With the use of direct DNA sequencing, the mutation was also found in the brother of the proband, but not in their mother. However, by analyzing EDTA blood of the mother with denaturing high-performance liquid chromatography (DHPLC), we could show that the mother displays low-level somatic mosaicism for the three base-pair deletion. This study indicates DHPLC as an important tool in the detection of low-level mosaicism, as does it illustrate the importance of considering somatic and germline mosaicism in the case of apparent de novo mutation.
Published: 2008
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