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1. Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects

Author

Duncan, A.R. (Anna R.), Vitobello, A. (Antonio), Collins, S.C. (Stephan C.), Vancollie, V.E. (Valerie E.), Lelliott, C.J. (Christopher J.), Rodan, L. (Lance), Shi, J. (Jiahai), Seman, A.R. (Ann R.), Agolini, E. (Emanuele), Novelli, A. (Antonio), Prontera, P. (Paolo), Guillen Sacoto, M.J. (Maria J.), Santiago-Sim, T. (Teresa), Trimouille, A. (Aurélien), Goizet, C. (Cyril), Nizon, M. (Mathilde), Bruel, A.-L. (Ange-Line), Philippe, C. (Christophe), Grant, P.E. (Patricia E.), Wojcik, M.H. (Monica H.), Stoler, J. (Joan), Genetti, C.A. (Casie A.), Dooren, M.F. (Marieke) van, Maas, S.M. (Saskia), Alders, M. (Mariëlle), Faivre, L. (Laurence), Sorlin, A. (Arthur), Yoon, G. (Grace), Yalcin, B. (Binnaz), Agrawal, P.B. (Pankaj B.), Duncan, A.R. (Anna R.), Vitobello, A. (Antonio), Collins, S.C. (Stephan C.), Vancollie, V.E. (Valerie E.), Lelliott, C.J. (Christopher J.), Rodan, L. (Lance), Shi, J. (Jiahai), Seman, A.R. (Ann R.), Agolini, E. (Emanuele), Novelli, A. (Antonio), Prontera, P. (Paolo), Guillen Sacoto, M.J. (Maria J.), Santiago-Sim, T. (Teresa), Trimouille, A. (Aurélien), Goizet, C. (Cyril), Nizon, M. (Mathilde), Bruel, A.-L. (Ange-Line), Philippe, C. (Christophe), Grant, P.E. (Patricia E.), Wojcik, M.H. (Monica H.), Stoler, J. (Joan), Genetti, C.A. (Casie A.), Dooren, M.F. (Marieke) van, Maas, S.M. (Saskia), Alders, M. (Mariëlle), Faivre, L. (Laurence), Sorlin, A. (Arthur), Yoon, G. (Grace), Yalcin, B. (Binnaz), and Agrawal, P.B. (Pankaj B.)

Abstract

KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In mice, lysine demethylase 4B is expressed during brain development with high levels in the hippocampus, a region important for learning and memory. To understand how KDM4B variants can lead to GDD in humans, we assessed the effect of KDM4B disruption on brain anatomy and behavior through an in vivo heterozygous mouse model (Kdm4b+/-), focusing on neuroanatomical changes. In mutant mice, the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. This report demonstrates that variants in KDM4B are associated with GDD/ intellectual disability and neuroanatomical defects. Our findings suggest that KDM4B variation leads to a chromatinopathy, broadening the spectrum of this group of Mendelian disorders caused by alterations in epigenetic machinery.

Published
2020
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2. 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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3. Identification of Variants in RET and IHH Pathway Members in a Large Family With History of Hirschsprung Disease

Author

Sribudiani, Y. (Yunia), Chauhan, R.K. (Rajendra), Alves, M.M. (Maria), Petrova, L. (Lucy), Brosens, E. (Erwin), Harrison, C. (Colin), Wabbersen, T.D. (Tara), Graaf, B.M. (Bianca) de, Rügenbrink, T. (Tim), Burzynski, G.M. (Grzegorz), Brouwer, R.W.W. (Rutger), IJcken, W.F.J. (Wilfred) van, Maas, S.M. (Saskia), Klein, A. (Annelies) de, Osinga, J. (Jan), Eggen, B.J. (Bart), Burns, A.J. (Alan), Brooks, A.S. (Alice), Shepherd, I.T. (Iain), Hofstra, R.M.W. (Robert), Sribudiani, Y. (Yunia), Chauhan, R.K. (Rajendra), Alves, M.M. (Maria), Petrova, L. (Lucy), Brosens, E. (Erwin), Harrison, C. (Colin), Wabbersen, T.D. (Tara), Graaf, B.M. (Bianca) de, Rügenbrink, T. (Tim), Burzynski, G.M. (Grzegorz), Brouwer, R.W.W. (Rutger), IJcken, W.F.J. (Wilfred) van, Maas, S.M. (Saskia), Klein, A. (Annelies) de, Osinga, J. (Jan), Eggen, B.J. (Bart), Burns, A.J. (Alan), Brooks, A.S. (Alice), Shepherd, I.T. (Iain), and Hofstra, R.M.W. (Robert)

Abstract

Background & Aims: Hirschsprung disease (HSCR) is an inherited congenital disorder characterized by absence of enteric ganglia in the distal part of the gut. Variants in ret proto-oncogene (RET) have been associated with up to 50% of familial and 35% of sporadic cases. We searched for variants that affect disease risk in a large, multigenerational family with history of HSCR in a linkage region previously associated with the disease (4q31.3–q32.3) and exome wide. Methods: We performed exome sequencing analyses of a family in the Netherlands with 5 members diagnosed with HSCR and 2 members diagnosed with functional constipation. We initially focused on variants in genes located in 4q31.3–q32.3; however, we also performed an exome-wide analysis in which known HSCR or HSCR-associated gene variants predicted to be deleterious were prioritized for further analysis. Candidate genes were expressed in HEK293, COS-7, and Neuro-2a cells and analyzed by luciferase and immunoblot assays. Morpholinos were designed to target exons of candidate genes and injected into 1-cell stage zebrafish embryos. Embryos were allowed to develop and stained for enteric neurons. Results: Within the linkage region, we identified 1 putative splice variant in the lipopolysaccharide responsive beige-like anchor protein gene (LRBA). Functional assays could not confirm its predicted effect on messenger RNA splicing or on expression of the mab-21 like 2 gene (MAB21L2), which is embedded in LRBA. Zebrafish that developed following injection of the lrba morpholino had a shortened body axis and subtle gut morphological defects, but no significant reduction in number of enteric neurons compared with controls. Outside the linkage region, members of 1 branch of the family carried a previously unidentified RET variant or an in-frame deletion in the glial cell line derived neurotrophic factor gene (GDNF), which encodes a ligand of RET. This deletion was located 6 base pairs before the last codon. We also found

Published
2018
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4. The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in the Netherlands

Author

Seco, C.Z. (Celia Zazo), Wesdorp, M. (Mieke), Feenstra, I. (Ilse), Pfundt, R. (Rolph), Hehir-Kwa, J. (Jayne), Lelieveld, S.H. (Stefan H.), Castelein, S. (Steven), Gilissen, C. (Christian), Wijs, I.J. (Ilse) de, Admiraal, R.J. (Ronald), Pennings, R.J.E. (Ronald J.E.), Kunst, H.P.M. (Henricus P.M.), van de Kamp, J.M. (Jiddeke M.), Tamminga, S. (Saskia), Houweling, A.C. (Arjan), Plomp, A. (Astrid), Maas, S.M. (Saskia), de Koning Gans, P.A.M. (P. A M), Kant, S.G. (Sarina), De Geus, C.M. (Christa M.), Frints, S.G.M. (Suzanna), Vanhoutte, E.K. (Els), Dooren, M.F. (Marieke) van, Boogaard, M.H. (Marie-José Henriëtte) van den, Scheffer, H. (Hans), Nelen, M.R. (Marcel), Kremer, H. (Hannie), Hoefsloot, E.H. (Lies), Schraders, M. (Margit), Yntema, H.G., Seco, C.Z. (Celia Zazo), Wesdorp, M. (Mieke), Feenstra, I. (Ilse), Pfundt, R. (Rolph), Hehir-Kwa, J. (Jayne), Lelieveld, S.H. (Stefan H.), Castelein, S. (Steven), Gilissen, C. (Christian), Wijs, I.J. (Ilse) de, Admiraal, R.J. (Ronald), Pennings, R.J.E. (Ronald J.E.), Kunst, H.P.M. (Henricus P.M.), van de Kamp, J.M. (Jiddeke M.), Tamminga, S. (Saskia), Houweling, A.C. (Arjan), Plomp, A. (Astrid), Maas, S.M. (Saskia), de Koning Gans, P.A.M. (P. A M), Kant, S.G. (Sarina), De Geus, C.M. (Christa M.), Frints, S.G.M. (Suzanna), Vanhoutte, E.K. (Els), Dooren, M.F. (Marieke) van, Boogaard, M.H. (Marie-José Henriëtte) van den, Scheffer, H. (Hans), Nelen, M.R. (Marcel), Kremer, H. (Hannie), Hoefsloot, E.H. (Lies), Schraders, M. (Margit), and Yntema, H.G.

Abstract

Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.

Published
2017
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5. Lessons from BWS twins: Complex maternal and paternal hypomethylation and a common source of haematopoietic stem cells

Author

Bliek, J. (Jet), Alders, M. (Mariëlle), Maas, S.M. (Saskia), Oostra, R.J. (Roelof-Jan), Mackay, D.M. (Deborah), Lip, K. (Karin) van der, Callaway, J.L. (Johnatan), Brooks, A.S. (Alice), Padje, S. (Sandra) van't, Westerveld, A. (Andries), Leschot, N.J. (Nico), Mannens, M.M.A.M. (Marcel), Bliek, J. (Jet), Alders, M. (Mariëlle), Maas, S.M. (Saskia), Oostra, R.J. (Roelof-Jan), Mackay, D.M. (Deborah), Lip, K. (Karin) van der, Callaway, J.L. (Johnatan), Brooks, A.S. (Alice), Padje, S. (Sandra) van't, Westerveld, A. (Andries), Leschot, N.J. (Nico), and Mannens, M.M.A.M. (Marcel)

Abstract

The Beckwith-Wiedemann syndrome (BWS) is a growth disorder for which an increased frequency of monozygotic (MZ) twinning has been reported. With few exceptions, these twins are discordant for BWS and for females. Here, we describe the molecular and phenotypic analysis of 12 BWS twins and a triplet; seven twins are MZ, monochorionic and diamniotic, three twins are MZ, dichorionic and diamniotic and three twins are dizygotic. Twelve twins are female. In the majority of the twin pairs (11 of 13), the defect on chromosome 11p15 was hypomethylation of the paternal allele of DMR2. In 5 of 10 twins, there was additional hypomethylation of imprinted loci; in most cases, the loci affected were maternally methylated, but in two cases, hypomethylation of the paternally methylated DLK1 and H19 DMRs was detected, a novel finding in BWS. In buccal swabs of the MZ twins who share a placenta, the defect was present only in the affected twin; comparable hypomethylation in lymphocytes was detected in both the twins. The level of hypomethylation reached levels below 25%. The exchange of blood cells through vascular connections cannot fully explain the degree of hypomethylation found in the blood cell of the non-affected twin. We propose an additional mechanism through which sharing of aberrant methylation patterns in discordant twins, limited to blood cells, might occur. In a BWS-discordant MZ triplet, an intermediate level of demethylation was found in one of the non-affected sibs; this child showed mild signs of BWS. This finding supports the theory that a methylation error proceeds and possibly triggers the twinning process.

Published
2009
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