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45 results on '"Santen, G.W.E."'

1. ARID1B-related disorder in 87 adults: Natural history and self-sustainability

Author

van der Sluijs, P.J., Gösgens, M., Dingemans, A.J.M., Striano, P., Riva, A., Mignot, C., Faudet, A., Vasileiou, G., Walther, M., Schrier Vergano, S.A., Alders, M., Alkuraya, F.S., Alorainy, I., Alsaif, H.S., Anderlid, B., Bache, I., van Beek, I., Blanluet, M., van Bon, B.W., Brunet, T., Brunner, H., Carriero, M.L., Charles, P., Chatron, N., Coccia, E., Dubourg, C., Earl, R.K., Eichler, E.E., Faivre, L., Foulds, N., Graziano, C., Guerrot, A.M., Hashem, M.O., Heide, S., Heron, D., Hickey, S.E., Hopman, S.M.J., Kattentidt-Mouravieva, A., Kerkhof, J., Klein Wassink-Ruiter, J.S., Kurtz-Nelson, E.C., Kušíková, K., Kvarnung, M., Lecoquierre, F., Leszinski, G.S., Loberti, L., Magoulas, P.L., Mari, F., Maystadt, I., Merla, G., Milunsky, J.M., Moortgat, S., Nicolas, G., Leary, M.O.’, Odent, S., Ozmore, J.R., Parbhoo, K., Pfundt, R., Piccione, M., Pinto, A.M., Popp, B., Putoux, A., Rehm, H.L., Reis, A., Renieri, A., Rosenfeld, J.A., Rossi, M., Salzano, E., Saugier-Veber, P., Seri, M., Severi, G., Sonmez, F.M., Strobl-Wildemann, G., Stuurman, K.E., Uctepe, E., Van Esch, H., Vitetta, G., de Vries, B.B.A., Wahl, D., Wang, T., Zacher, P., Heitink, K.R., Ropers, F.G., Steenbeek, D., Rybak, T., and Santen, G.W.E.

Published
2024
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2. De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas

Author

Ambrose, J.C., Bleda, M., Boardman-Pretty, F., Boissiere, J.M., Boustred, C.R., Caulfield, M.J., Chan, G.C., Craig, C.E.H., Daugherty, L.C., de Burca, A., Devereau, A., Elgar, G., Foulger, R.E., Fowler, T., Furió-Tarí, P., Hackett, J.M., Halai, D., Holman, J.E., Hubbard, T.J.P., Kasperaviciute, D., Kayikci, M., Lahnstein, L., Lawson, K., Leigh, S.E.A., Leong, I.U.S., Lopez, F.J., Maleady-Crowe, F., Mason, J., McDonagh, E.M., Moutsianas, L., Mueller, M., Need, A.C., Odhams, C.A., Patch, C., Perez-Gil, D., Polychronopoulos, D., Pullinger, J., Rahim, T., Rendon, A., Rogers, T., Ryten, M., Savage, K., Scott, R.H., Siddiq, A., Sieghart, A., Smedley, D., Smith, K.R., Sosinsky, A., Spooner, W., Stevens, H.E., Stuckey, A., Thomas, E.R.A., Thompson, S.R., Tregidgo, C., Tucci, A., Walsh, E., Watters, S.A., Welland, M.J., Williams, E., Witkowska, K., Wood, S.M., Zarowiecki, M., Tolchin, Dara, Yeager, Jessica P., Prasad, Priya, Dorrani, Naghmeh, Russi, Alvaro Serrano, Martinez-Agosto, Julian A., Haseeb, Abdul, Angelozzi, Marco, Santen, G.W.E., Ruivenkamp, Claudia, Mercimek-Andrews, Saadet, Depienne, Christel, Kuechler, Alma, Mikat, Barbara, Ludecke, Hermann-Josef, Bilan, Frederic, Le Guyader, Gwenael, Gilbert-Dussardier, Brigitte, Keren, Boris, Heide, Solveig, Haye, Damien, Van Esch, Hilde, Keldermans, Liesbeth, Ortiz, Damara, Lancaster, Emily, Krantz, Ian D., Krock, Bryan L., Pechter, Kieran B., Arkader, Alexandre, Medne, Livija, DeChene, Elizabeth T., Calpena, Eduardo, Melistaccio, Giada, Wilkie, Andrew O.M., Suri, Mohnish, Foulds, Nicola, Begtrup, Amber, Henderson, Lindsay B., Forster, Cara, Reed, Patrick, McDonald, Marie T., McConkie-Rosell, Allyn, Thevenon, Julien, Le Tanno, Pauline, Coutton, Charles, Tsai, Anne C.H., Stewart, Sarah, Maver, Ales, Gorazd, Rudolf, Pichon, Olivier, Nizon, Mathilde, Cogné, Benjamin, Isidor, Bertrand, Martin-Coignard, Dominique, Stoeva, Radka, Lefebvre, Véronique, and Le Caignec, Cédric

Published
2020
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3. PhenoScore quantifies phenotypic variation for rare genetic diseases by combining facial analysis with other clinical features using a machine-learning framework

Author

Dingemans, A.J.M., Hinne, M., Truijen, K.M.G., Goltstein, C.M.J., Reeuwijk, J. van, Leeuw, N. de, Schuurs-Hoeijmakers, J.H.M., Pfundt, R.P., Diets, I.J., Hoed, J. den, Boer, E. de, Spek, J. van der, Bon, B.W.M. van, Ockeloen, C.W., Vulto-van Silfhout, A.T., Kleefstra, T., Koolen, D.A., Campeau, P.M., Palmer, E.E., Esch, H. van, Lyon, G.J., Alkuraya, F.S., Rauch, A., Marom, R., Baralle, D., Sluijs, P.J. van der, Santen, G.W.E., Kooy, R.F., Gerven, M.A.J. van, Vissers, L.E.L.M., Vries, L.B.A. de, Dingemans, A.J.M., Hinne, M., Truijen, K.M.G., Goltstein, C.M.J., Reeuwijk, J. van, Leeuw, N. de, Schuurs-Hoeijmakers, J.H.M., Pfundt, R.P., Diets, I.J., Hoed, J. den, Boer, E. de, Spek, J. van der, Bon, B.W.M. van, Ockeloen, C.W., Vulto-van Silfhout, A.T., Kleefstra, T., Koolen, D.A., Campeau, P.M., Palmer, E.E., Esch, H. van, Lyon, G.J., Alkuraya, F.S., Rauch, A., Marom, R., Baralle, D., Sluijs, P.J. van der, Santen, G.W.E., Kooy, R.F., Gerven, M.A.J. van, Vissers, L.E.L.M., and Vries, L.B.A. de

Abstract

07 augustus 2023, Item does not contain fulltext, Several molecular and phenotypic algorithms exist that establish genotype–phenotype correlations, including facial recognition tools. However, no unified framework that investigates both facial data and other phenotypic data directly from individuals exists. We developed PhenoScore: an open-source, artificial intelligence-based phenomics framework, combining facial recognition technology with Human Phenotype Ontology data analysis to quantify phenotypic similarity. Here we show PhenoScore’s ability to recognize distinct phenotypic entities by establishing recognizable phenotypes for 37 of 40 investigated syndromes against clinical features observed in individuals with other neurodevelopmental disorders and show it is an improvement on existing approaches. PhenoScore provides predictions for individuals with variants of unknown significance and enables sophisticated genotype–phenotype studies by testing hypotheses on possible phenotypic (sub)groups. PhenoScore confirmed previously known phenotypic subgroups caused by variants in the same gene for SATB1, SETBP1 and DEAF1 and provides objective clinical evidence for two distinct ADNP-related phenotypes, already established functionally.

Published
2023

4. Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals.

Author

Bosch, E., Popp, B., Güse, E., Skinner, C., Sluijs, P.J. van der, Maystadt, I., Pinto, Ameet J., Renieri, A., Bruno, L.P., Granata, S., Marcelis, C.L., Baysal, Ö., Hartwich, D., Holthöfer, L., Isidor, B., Cogne, B., Wieczorek, D., Capra, V., Scala, M., Marco, P. De, Ognibene, M., Jamra, R.A., Platzer, K., Carter, L.B., Kuismin, O., Haeringen, A. van, Maroofian, R., Valenzuela, I., Cuscó, I., Martinez-Agosto, J.A., Rabani, A.M., Mefford, H.C., Pereira, E.M., Close, C., Anyane-Yeboa, K., Wagner, M., Hannibal, M.C., Zacher, P., Thiffault, I., Beunders, G., Umair, M., Bhola, P.T., McGinnis, E., Millichap, J., Kamp, J.M. van de, Prijoles, E.J., Dobson, A., Shillington, A., Graham, B.H., Garcia, E.J., Galindo, M.K., Ropers, F.G., Nibbeling, E.A., Hubbard, G., Karimov, C., Goj, G., Bend, R., Rath, J., Morrow, M.M., Millan, F., Salpietro, V., Torella, A., Nigro, V., Kurki, M., Stevenson, R.E., Santen, G.W.E., Zweier, M., Campeau, P.M., Severino, M., Reis, A., Accogli, A., Vasileiou, G., Bosch, E., Popp, B., Güse, E., Skinner, C., Sluijs, P.J. van der, Maystadt, I., Pinto, Ameet J., Renieri, A., Bruno, L.P., Granata, S., Marcelis, C.L., Baysal, Ö., Hartwich, D., Holthöfer, L., Isidor, B., Cogne, B., Wieczorek, D., Capra, V., Scala, M., Marco, P. De, Ognibene, M., Jamra, R.A., Platzer, K., Carter, L.B., Kuismin, O., Haeringen, A. van, Maroofian, R., Valenzuela, I., Cuscó, I., Martinez-Agosto, J.A., Rabani, A.M., Mefford, H.C., Pereira, E.M., Close, C., Anyane-Yeboa, K., Wagner, M., Hannibal, M.C., Zacher, P., Thiffault, I., Beunders, G., Umair, M., Bhola, P.T., McGinnis, E., Millichap, J., Kamp, J.M. van de, Prijoles, E.J., Dobson, A., Shillington, A., Graham, B.H., Garcia, E.J., Galindo, M.K., Ropers, F.G., Nibbeling, E.A., Hubbard, G., Karimov, C., Goj, G., Bend, R., Rath, J., Morrow, M.M., Millan, F., Salpietro, V., Torella, A., Nigro, V., Kurki, M., Stevenson, R.E., Santen, G.W.E., Zweier, M., Campeau, P.M., Severino, M., Reis, A., Accogli, A., and Vasileiou, G.

Abstract

Contains fulltext : 299984.pdf (Publisher’s version ) (Open Access), PURPOSE: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort. METHODS: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays. RESULTS: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD. CONCLUSION: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated., 01 november 2023

Published
2023

6. Diagnostic Value of a Protocolized In-Depth Evaluation of Pediatric Bone Marrow Failure: A Multi-Center Prospective Cohort Study

Author

Atmar, K., Ruivenkamp, C.A.L., Hooimeijer, L., Nibbeling, E.A.R., Eckhardt, C.L., Huisman, E.J., Lankester, A.C., Bartels, M., Santen, G.W.E., Smiers, F.J., Burg, M. van der, Mohseny, A.B., Paediatric Haematology, ACS - Pulmonary hypertension & thrombosis, Faculteit Medische Wetenschappen/UMCG, and Pediatrics

Subjects
SEVERE APLASTIC-ANEMIA, DNA Copy Number Variations, aplastic anemia, Pancytopenia, PATHOPHYSIOLOGY, Immunology, NATURAL-KILLER-CELLS, BMF, MYELODYSPLASTIC SYNDROMES, MANAGEMENT, diagnostics, Humans, cytopenia, Immunology and Allergy, Prospective Studies, Child, GERM-LINE, Anemia, Aplastic, CLONAL HEMATOPOIESIS, Bone Marrow Failure Disorders, AA, DEFICIENCY, MANIFESTATIONS, next-generation sequencing, MUTATIONS CAUSE, bone marrow failure
Abstract

BackgroundSevere multilineage cytopenia in childhood caused by bone marrow failure (BMF) often represents a serious condition requiring specific management. Patients are at risk for invasive infections and bleeding complications. Previous studies report low rates of identifiable causes of pediatric BMF, rendering most patients with a descriptive diagnosis such as aplastic anemia (AA).MethodsWe conducted a multi-center prospective cohort study in which an extensive diagnostic approach for pediatric patients with suspected BMF was implemented. After exclusion of malignant and transient causes of BMF, patients entered thorough diagnostic evaluation including bone marrow analysis, whole exome sequencing (WES) including copy number variation (CNV) analysis and/or single nucleotide polymorphisms (SNP) array analysis. In addition, functional and immunological evaluation were performed. Here we report the outcomes of the first 50 patients (2017-2021) evaluated by this approach.ResultsIn 20 patients (40%) a causative diagnosis was made. In this group, 18 diagnoses were established by genetic analysis, including 14 mutations and 4 chromosomal deletions. The 2 remaining patients had short telomeres while no causative genetic defect was found. Of the remaining 30 patients (60%), 21 were diagnosed with severe aplastic anemia (SAA) based on peripheral multi-lineage cytopenia and hypoplastic bone marrow, and 9 were classified as unexplained cytopenia without bone marrow hypoplasia. In total 28 patients had undergone hematopoietic stem cell transplantation (HSCT) of which 22 patients with an unknown cause and 6 patients with an identified cause for BMF.ConclusionWe conclude that a standardized in-depth diagnostic protocol as presented here, can increase the frequency of identifiable causes within the heterogeneous group of pediatric BMF. We underline the importance of full genetic analysis complemented by functional tests of all patients as genetic causes are not limited to patients with typical (syndromal) clinical characteristics beyond cytopenia. In addition, it is of importance to apply genome wide genetic analysis, since defects in novel genes are frequently discovered in this group. Identification of a causal abnormality consequently has implications for the choice of treatment and in some cases prevention of invasive therapies.

Published
2022
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7. Discovering a new part of the phenotypic spectrum of Coffin-Siris syndrome in a fetal cohort

Author

Sluijs, P.J. van der, Joosten, Marieke, Alby, C., Attié-Bitach, T., Gilmore, K., Dubourg, C., Fradin, M., Wang, T., Kurtz-Nelson, E.C., Ahlers, K.P., Arts, P., Barnett, C.P., Ashfaq, M., Baban, A., Born, M. van den, Borrie, S., Busa, T., Byrne, A., Carriero, M., Cesario, C., Chong, K., Cueto-González, A.M., Dempsey, J.C., Diderich, K.E.M., Doherty, D., Farholt, S., Gerkes, E.H., Gorokhova, S., Govaerts, L.C.P., Gregersen, P.A., Hickey, S.E., Lefebvre, M., Mari, F., Martinovic, Jelena, Northrup, H., O'Leary, M., Parbhoo, K., Patrier, S., Popp, B., Santos-Simarro, F., Stoltenburg, C., Thauvin-Robinet, C., Thompson, E., Vulto-van Silfhout, A.T., Zahir, F.R., Scott, H.S., Earl, R.K., Eichler, E.E., Vora, N.L., Wilnai, Y., Giordano, J.L., Wapner, R.J., Rosenfeld, J.A., Haak, M.C., Santen, G.W.E., Sluijs, P.J. van der, Joosten, Marieke, Alby, C., Attié-Bitach, T., Gilmore, K., Dubourg, C., Fradin, M., Wang, T., Kurtz-Nelson, E.C., Ahlers, K.P., Arts, P., Barnett, C.P., Ashfaq, M., Baban, A., Born, M. van den, Borrie, S., Busa, T., Byrne, A., Carriero, M., Cesario, C., Chong, K., Cueto-González, A.M., Dempsey, J.C., Diderich, K.E.M., Doherty, D., Farholt, S., Gerkes, E.H., Gorokhova, S., Govaerts, L.C.P., Gregersen, P.A., Hickey, S.E., Lefebvre, M., Mari, F., Martinovic, Jelena, Northrup, H., O'Leary, M., Parbhoo, K., Patrier, S., Popp, B., Santos-Simarro, F., Stoltenburg, C., Thauvin-Robinet, C., Thompson, E., Vulto-van Silfhout, A.T., Zahir, F.R., Scott, H.S., Earl, R.K., Eichler, E.E., Vora, N.L., Wilnai, Y., Giordano, J.L., Wapner, R.J., Rosenfeld, J.A., Haak, M.C., and Santen, G.W.E.

Abstract

Item does not contain fulltext, PURPOSE: Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS), we collected clinical data from patients with a prenatal phenotype and a pathogenic variant in one of the CSS-associated genes. METHODS: Clinical data was collected through an extensive web-based survey. RESULTS: We included 44 patients with a variant in a CSS-associated gene and a prenatal phenotype; 9 of these patients have been reported before. Prenatal anomalies that were frequently observed in our cohort include hydrocephalus, agenesis of the corpus callosum, hypoplastic left heart syndrome, persistent left vena cava, diaphragmatic hernia, renal agenesis, and intrauterine growth restriction. Anal anomalies were frequently identified after birth in patients with ARID1A variants (6/14, 43%). Interestingly, pathogenic ARID1A variants were much more frequently identified in the current prenatal cohort (16/44, 36%) than in postnatal CSS cohorts (5%-9%). CONCLUSION: Our data shed new light on the prenatal phenotype of patients with pathogenic variants in CSS genes.

Published
2022

8. Hearing loss, cleft palate, and congenital hip dysplasia in female carriers of an intragenic deletion of AMMECR1

Author

Koene, S., Knijnenburg, J., Hoffer, M.J.V., Zwanenburg, F., Haak, M.C., Locher, H., Beelen, E.S.A. van, Santen, G.W.E., and Rotteveel, L.J.C.

Subjects
congenital abnormalities, X-linked inheritance, Genetics, AMMECR1, Genetics (clinical), sensorineural hearing loss
Abstract

Previously, mutations in the AMMECR1 gene have been described in six males with developmental delay, sensorineural hearing loss (SNHL) and/or congenital abnormalities, including fetal nuchal edema, fetal pericardial effusion, talipes, congenital hip dysplasia, elliptocytosis and cleft palate. In this report, we present three female relatives of a male fetus with an intragenic deletion in this X-linked gene. All three women reported hearing loss and one was born with a soft cleft palate and hip dysplasia. The audiograms showed mild to moderate SNHL with a variable pattern of the affected frequencies. Immunohistochemical analysis of fetal cochlea was performed confirming the expression of AMMECR1 in the human inner ear. Since hearing loss, cleft palate and congenital hip dysplasia were reported before in male AMMECR1 point mutation carriers and AMMECR1 is expressed in fetal inner ear, we suggest that female carriers may display a partial phenotype in this X-linked condition.

Published
2022

9. Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood (vol 6, 92, 2021)

Author

Levy, M.A., Beck, D.B., Metcalfe, K., Douzgou, S., Sithambaram, S., Cottrell, T., Ansar, M., Kerkhof, J., Mignot, C., Nougues, M.C., Keren, B., Moore, H.W., Oegema, R., Giltay, J.C., Simon, M., Jaarsveld, R.H. van, Bos, J., Haelst, M. van, Motazacker, M.M., Boon, E.M.J., Santen, G.W.E., Ruivenkamp, C.A.L., Alders, M., Luperchio, T.R., Boukas, L., Ramsey, K., Narayanan, V., Schaefer, G.B., Bonasio, R., Doheny, K.F., Stevenson, R.E., Banka, S., Sadikovic, B., and Fahrner, J.A.

Published
2021

10. ZTTK syndrome: Clinical and molecular findings of 15 cases and a review of the literature

Author

Kushary, S.T., Revah-Politi, A., Barua, S., Ganapathi, M., Accogli, A., Aggarwal, V., Brunetti-Pierri, N., Cappuccio, G., Capra, V., Fagerberg, C.R., Gazdagh, G., Guzman, E., Hadonou, M., Harrison, V., Havelund, K., Iancu, D., Kraus, A., Lippa, N.C., Mansukhani, M., McBrian, D., McEntagart, M., Pacio-Miguez, M., Palomares-Bralo, M., Pottinger, C., Ruivenkamp, C.A.L., Sacco, O., Santen, G.W.E., Santos-Simarro, F., Scala, M., Short, J., Sorensen, K.P., Woods, C.G., Yeboa, K.A., DDD Study, TUDP Consortium, Kushary, S. T., Revah-Politi, A., Barua, S., Ganapathi, M., Accogli, A., Aggarwal, V., Brunetti Pierri, N., Cappuccio, G., Capra, V., Fagerberg, C. R., Gazdagh, G., Guzman, E., Hadonou, M., Harrison, V., Havelund, K., Iancu, D., Kraus, A., Lippa, N. C., Mansukhani, M., Mcbrian, D., Mcentagart, M., Pacio-Miguez, M., Palomares-Bralo, M., Pottinger, C., Ruivenkamp, C. A. L., Sacco, O., Santen, G. W. E., Santos-Simarro, F., Scala, M., Short, J., Sorensen, K. P., Woods, C. G., and Anyane Yeboa, K.

Subjects
Male, Genotype, Mutation, Missense, genotype-phenotype correlation, Article, Congenital Abnormalities, whole exome sequencing, Minor Histocompatibility Antigens, Neuroimaging, Seizures, Intellectual Disability, Intellectual disability, Exome Sequencing, Genetics, Medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Gene, Genetics (clinical), Exome sequencing, Genetic Association Studies, business.industry, Brain, genotype–phenotype correlation, medicine.disease, SON, DNA-Binding Proteins, Phenotype, Variable dysmorphic features, Female, business, multisystemic disorder
Abstract

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is caused by de novo loss-of-function variants in the SON gene (MIM #617140). This multisystemic disorder is characterized by intellectual disability, seizures, abnormal brain imaging, variable dysmorphic features, and various congenital anomalies. The wide application and increasing accessibility of whole exome sequencing (WES) has helped to identify new cases of ZTTK syndrome over the last few years. To date, there have been approximately 45 cases reported in the literature. Here, we describe 15 additional individuals with variants in the SON gene, including those with missense variants bringing the total number of known cases to 60. We have reviewed the clinical and molecular data of these new cases and all previously reported cases to further delineate the most common as well as emerging clinical findings related to this syndrome. Furthermore, we aim to delineate any genotype–phenotype correlations specifically for a recurring pathogenic four base pair deletion (c.5753_5756del) along with discussing the impact of missense variants seen in the SON gene.

Published
2021
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12. A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria

Author

Sluijs, Pleuntje J. van der, Alders, M., Dingemans, A.J.M., Parbhoo, Kareesma, Bon, B.W. van, Dempsey, J.C., Vries, B.B.A. de, Maystadt, I., Santen, G.W.E., Sluijs, Pleuntje J. van der, Alders, M., Dingemans, A.J.M., Parbhoo, Kareesma, Bon, B.W. van, Dempsey, J.C., Vries, B.B.A. de, Maystadt, I., and Santen, G.W.E.

Abstract

Contains fulltext : 237017.pdf (Publisher’s version ) (Open Access)

Published
2021

13. A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria

Author

Sluijs, P.J. van der, Alders, M., Dingemans, A.J.M., Parbhoo, Kareesma, Bon, B.W. van, Dempsey, J.C., Vries, B.B.A. de, Maystadt, I., Santen, G.W.E., Sluijs, P.J. van der, Alders, M., Dingemans, A.J.M., Parbhoo, Kareesma, Bon, B.W. van, Dempsey, J.C., Vries, B.B.A. de, Maystadt, I., and Santen, G.W.E.

Abstract

Contains fulltext : 237017.pdf (Publisher’s version ) (Open Access)

Published
2021

14. De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas

Author

Tolchin, Dara, primary, Yeager, Jessica P., additional, Prasad, Priya, additional, Dorrani, Naghmeh, additional, Russi, Alvaro Serrano, additional, Martinez-Agosto, Julian A., additional, Haseeb, Abdul, additional, Angelozzi, Marco, additional, Santen, G.W.E., additional, Ruivenkamp, Claudia, additional, Mercimek-Andrews, Saadet, additional, Depienne, Christel, additional, Kuechler, Alma, additional, Mikat, Barbara, additional, Ludecke, Hermann-Josef, additional, Bilan, Frederic, additional, Le Guyader, Gwenael, additional, Gilbert-Dussardier, Brigitte, additional, Keren, Boris, additional, Heide, Solveig, additional, Haye, Damien, additional, Van Esch, Hilde, additional, Keldermans, Liesbeth, additional, Ortiz, Damara, additional, Lancaster, Emily, additional, Krantz, Ian D., additional, Krock, Bryan L., additional, Pechter, Kieran B., additional, Arkader, Alexandre, additional, Medne, Livija, additional, DeChene, Elizabeth T., additional, Calpena, Eduardo, additional, Melistaccio, Giada, additional, Wilkie, Andrew O.M., additional, Suri, Mohnish, additional, Foulds, Nicola, additional, Begtrup, Amber, additional, Henderson, Lindsay B., additional, Forster, Cara, additional, Reed, Patrick, additional, McDonald, Marie T., additional, McConkie-Rosell, Allyn, additional, Thevenon, Julien, additional, Le Tanno, Pauline, additional, Coutton, Charles, additional, Tsai, Anne C.H., additional, Stewart, Sarah, additional, Maver, Ales, additional, Gorazd, Rudolf, additional, Pichon, Olivier, additional, Nizon, Mathilde, additional, Cogné, Benjamin, additional, Isidor, Bertrand, additional, Martin-Coignard, Dominique, additional, Stoeva, Radka, additional, Lefebvre, Véronique, additional, Le Caignec, Cédric, additional, Ambrose, J.C., additional, Bleda, M., additional, Boardman-Pretty, F., additional, Boissiere, J.M., additional, Boustred, C.R., additional, Caulfield, M.J., additional, Chan, G.C., additional, Craig, C.E.H., additional, Daugherty, L.C., additional, de Burca, A., additional, Devereau, A., additional, Elgar, G., additional, Foulger, R.E., additional, Fowler, T., additional, Furió-Tarí, P., additional, Hackett, J.M., additional, Halai, D., additional, Holman, J.E., additional, Hubbard, T.J.P., additional, Kasperaviciute, D., additional, Kayikci, M., additional, Lahnstein, L., additional, Lawson, K., additional, Leigh, S.E.A., additional, Leong, I.U.S., additional, Lopez, F.J., additional, Maleady-Crowe, F., additional, Mason, J., additional, McDonagh, E.M., additional, Moutsianas, L., additional, Mueller, M., additional, Need, A.C., additional, Odhams, C.A., additional, Patch, C., additional, Perez-Gil, D., additional, Polychronopoulos, D., additional, Pullinger, J., additional, Rahim, T., additional, Rendon, A., additional, Rogers, T., additional, Ryten, M., additional, Savage, K., additional, Scott, R.H., additional, Siddiq, A., additional, Sieghart, A., additional, Smedley, D., additional, Smith, K.R., additional, Sosinsky, A., additional, Spooner, W., additional, Stevens, H.E., additional, Stuckey, A., additional, Thomas, E.R.A., additional, Thompson, S.R., additional, Tregidgo, C., additional, Tucci, A., additional, Walsh, E., additional, Watters, S.A., additional, Welland, M.J., additional, Williams, E., additional, Witkowska, K., additional, Wood, S.M., additional, and Zarowiecki, M., additional

Published
2020
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17. Putting genome-wide sequencing in neonates into perspective (vol 24, pg 1074, 2019)

Author

Sluijs, P.J. van der, Aten, E., Barge-Schaapveld, D.Q.C.M., Bijlsma, E.K., Bokenkamp-Gramann, R., Kaat, L.D., Doorn, R. van, Putte, D.F. van de, Haeringen, A. van, Harkel, A.D.J. ten, Hilhorst-Hofstee, Y., Hoffer, M.J.V., Hollander, N.S. den, Ierland, Y. van, Koopmans, M., Kriek, M., Moghadasi, S., Nibbeling, E.A.R., Peeters-Scholte, C.M.P.C.D., Potjer, T.P., Rij, M. van, Ruivenkamp, C.A.L., Rutten, J.W., Steggerda, S.J., Suerink, M., Tan, R.N.G.B., Tuin, K. van der, Visser, R., Werf-'t Lam, A.S. van der, Williams, M., Witlox, R., and Santen, G.W.E.

Published
2019
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18. Letter regarding the article: 'Striking phenotypic overlap between Nicolaides-Baraitser and Coffin-Siris syndromes in monozygotic twins with ARID1B intragenic deletion'

Author

Sluijs, P.J. van der and Santen, G.W.E.

Subjects
Genetics, Micrognathism, Facies, General Medicine, Syndrome, Twins, Monozygotic, Biology, medicine.disease, Phenotype, DNA-Binding Proteins, Intellectual Disability, Intellectual disability, medicine, Humans, Coffin, Hand Deformities, Congenital, Genetics (clinical), Neck, Transcription Factors
Published
2019

19. The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome (vol 21, pg 1295, 2019)

Author

Sluijs, P.J. van der, Jansen, S., Vergano, S.A., Adachi-Fukuda, M., Alanay, Y., AlKindy, A., Baban, A., Bayat, A., Beck-Wodl, S., Berry, K., Bijlsma, E.K., Bok, L.A., Brouwer, A.F.J., Burgt, I. van der, Campeau, P.M., Canham, N., Chrzanowska, K., Chu, Y.W.Y., Chung, B.H.Y., Dahan, K., Rademaeker, M. de, Destree, A., Dudding-Byth, T., Earl, R., Elcioglu, N., Elias, E.R., Fagerberg, C., Gardham, A., Gener, B., Gerkes, E.H., Grasshoff, U., Haeringen, A. van, Heitink, K.R., Herkert, J.C., Hollander, N.S. den, Horn, D., Hunt, D., Kant, S.G., Kato, M., Kayserili, H., Kersseboom, R., Kilic, E., Krajewska-Walasek, M., Lammers, K., Laulund, L.W., Lederer, D., Lees, M., Lopez-Gonzalez, V., Maas, S., Mancini, G.M.S., Marcelis, C., Martinez, F., Maystadt, I., McGuire, M., Mckee, S., Mehta, S., Metcalfe, K., Milunsky, J., Mizuno, S., Moeschler, J.B., Netzer, C., Ockeloen, C.W., Oehl-Jaschkowitz, B., Okamoto, N., Olminkhof, S.N.M., Orellana, C., Pasquier, L., Pottinger, C., Riehmer, V., Robertson, S.P., Roifman, M., Rooryck, C., Ropers, F.G., Rosello, M., Ruivenkamp, C.A.L., Sagiroglu, M.S., Sallevelt, S.C.E.H., Calvo, A.S., Simsek-Kiper, P.O., Soares, G., Solaeche, L., Sonmez, F.M., Splitt, M., Steenbeek, D., Stegmann, A.P.A., Stumpel, C.T.R.M., Tanabe, S., Uctepe, E., Utine, G.E., Veenstra-Knol, H.E., Venkateswaran, S., Vilain, C., Vincent-Delorme, C., Vulto-van Silfhout, A.T., Wheeler, P., Wilson, G.N., Wilson, L.C., Wollnik, B., Kosho, T., Wieczorek, D., Eichler, E., Pfundt, R., Vries, B.B.A. de, Clayton-Smith, J., Santen, G.W.E., and Acibadem University Dspace

Abstract

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019

20. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Wang, T., Hoekzema, K., Vecchio, D., Wu, H., Sulovari, A., Coe, B.P., Gillentine, M.A., Wilfert, A.B., Perez-Jurado, L.A., Kvarnung, M., Sleyp, Y., Earl, R.K., Rosenfeld, J.A., Geisheker, M.R., Han, L., Du, B., Barnett, C., Thompson, E., Shaw, M., Carroll, R., Friend, K., Catford, R., Palmer, E.E., Zou, X., Ou, J., Li, H., Guo, H, Gerdts, J., Avola, E., Calabrese, G., Elia, M., Greco, D., Lindstrand, A., Nordgren, A., Anderlid, B.M., Vandeweyer, G., Dijck, A. Van, Aa, N. van der, McKenna, B., Hancarova, M., Bendova, S., Havlovicova, M., Malerba, G., Bernardina, B.D., Muglia, P., Haeringen, A. van, Hoffer, M.J.V., Franke, B., Cappuccio, G., Delatycki, M., Lockhart, P.J., Manning, M.A., Liu, P, Scheffer, I.E., Brunetti-Pierri, N., Rommelse, N.N.J., Amaral, D.G., Santen, G.W.E., Trabetti, E., Sedláček, Z., Michaelson, J.J., Pierce, K., Courchesne, E., Kooy, R.F., Nordenskjöld, M., Romano, C, Peeters, H, Bernier, R.A., Gecz, J., Xia, K., Eichler, E.E., Wang, T., Hoekzema, K., Vecchio, D., Wu, H., Sulovari, A., Coe, B.P., Gillentine, M.A., Wilfert, A.B., Perez-Jurado, L.A., Kvarnung, M., Sleyp, Y., Earl, R.K., Rosenfeld, J.A., Geisheker, M.R., Han, L., Du, B., Barnett, C., Thompson, E., Shaw, M., Carroll, R., Friend, K., Catford, R., Palmer, E.E., Zou, X., Ou, J., Li, H., Guo, H, Gerdts, J., Avola, E., Calabrese, G., Elia, M., Greco, D., Lindstrand, A., Nordgren, A., Anderlid, B.M., Vandeweyer, G., Dijck, A. Van, Aa, N. van der, McKenna, B., Hancarova, M., Bendova, S., Havlovicova, M., Malerba, G., Bernardina, B.D., Muglia, P., Haeringen, A. van, Hoffer, M.J.V., Franke, B., Cappuccio, G., Delatycki, M., Lockhart, P.J., Manning, M.A., Liu, P, Scheffer, I.E., Brunetti-Pierri, N., Rommelse, N.N.J., Amaral, D.G., Santen, G.W.E., Trabetti, E., Sedláček, Z., Michaelson, J.J., Pierce, K., Courchesne, E., Kooy, R.F., Nordenskjöld, M., Romano, C, Peeters, H, Bernier, R.A., Gecz, J., Xia, K., and Eichler, E.E.

Abstract

Contains fulltext : 229260.pdf (publisher's version ) (Open Access), Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

Published
2020

21. Repurposing of Diagnostic Whole Exome Sequencing Data of 1,583 Individuals for Clinical Pharmacogenetics

Author

Lee, M. van der, Allard, W.G., Bollen, S., Santen, G.W.E., Ruivenkamp, C.A.L., Hoffer, M.J.V., Kriek, M., Guchelaar, H.J., Anvar, S.Y., Swen, J.J., Lee, M. van der, Allard, W.G., Bollen, S., Santen, G.W.E., Ruivenkamp, C.A.L., Hoffer, M.J.V., Kriek, M., Guchelaar, H.J., Anvar, S.Y., and Swen, J.J.

Abstract

Contains fulltext : 229047.pdf (Publisher’s version ) (Open Access), For ~ 80 drugs, widely recognized pharmacogenetics dosing guidelines are available. However, the use of these guidelines in clinical practice remains limited as only a fraction of patients is subjected to pharmacogenetic screening. We investigated the feasibility of repurposing whole exome sequencing (WES) data for a panel of 42 variants in 11 pharmacogenes to provide a pharmacogenomic profile. Existing diagnostic WES-data from child-parent trios totaling 1,583 individuals were used. Results were successfully extracted for 39 variants. No information could be extracted for three variants, located in CYP2C19, UGT1A1, and CYP3A5, and for CYP2D6 copy number. At least one actionable phenotype was present in 86% of the individuals. Haplotype phasing proved relevant for CYP2B6 assignments as 1.5% of the phenotypes were corrected after phasing. In conclusion, repurposing WES-data can yield meaningful pharmacogenetic profiles for 7 of 11 important pharmacogenes, which can be used to guide drug treatment.

Published
2020

22. Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation

Author

Yan, K.Z., Rousseau, J., Littlejohn, R.O., Kiss, C., Lehman, A., Rosenfeld, J.A., Stumpel, C.T.R., Stegmann, A.P.A., Robak, L., Scaglia, F., Nguyen, T.T.M., Fu, H., Ajeawung, N.F., Camurri, M.V., Li, L., Gardham, A., Panis, B., Almannai, M., Sacoto, M.J.G., Baskin, B., Ruivenkamp, C., Xia, F., Bi, W., Cho, M.T., Potjer, T.P., Santen, G.W.E., Parker, M.J., Canham, N., McKinnon, M., Potocki, L., MacKenzie, J.J., Roeder, E.R., Campeau, P.M., Yang, X.J., DDD Study, CAUSES Study, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, and MUMC+: DA KG Lab Centraal Lab (9)

Subjects
0301 basic medicine, Male, Developmental Disabilities, PZP DOMAIN, HBO1 ACETYLTRANSFERASE, Histones, Mice, Intellectual disability, Global developmental delay, Child, Genetics (clinical), Histone Acetyltransferases, Genetics, Mice, Knockout, ZINC-FINGER PROTEIN, Nuclear Proteins, Acetylation, Syndrome, Chromatin, DNA-Binding Proteins, Histone, Muscle Hypotonia, Female, EXPRESSION, Adolescent, Biology, KAT6B, Article, 03 medical and health sciences, Histone H3, Intellectual Disability, medicine, Animals, Humans, HEMATOPOIETIC STEM-CELLS, Epigenetics, Histone H3 acetylation, Alleles, Adaptor Proteins, Signal Transducing, CAUSE GENITOPATELLAR SYNDROME, Lysine, PHD FINGER, medicine.disease, Bromodomain, Mice, Inbred C57BL, 030104 developmental biology, DE-NOVO MUTATIONS, Face, Mutation, biology.protein, Carrier Proteins, CAENORHABDITIS-ELEGANS
Abstract

Identification of over 500 epigenetic regulators in humans raises an interesting question regarding how chromatin dysregulation contributes to different diseases. Bromodomain and PHD finger-containing protein 1 (BRPF1) is a multivalent chromatin regulator possessing three histone-binding domains, one non-specific DNA-binding module, and several motifs for interacting with and activating three lysine acetyltransferases. Genetic analyses of fish brpf1 and mouse Brpf1 have uncovered an important role in skeletal, hematopoietic, and brain development, but it remains unclear how BRPF1 is linked to human development and disease. Here, we describe an intellectual disability disorder in ten individuals with inherited or de novo monoallelic BRPF1 mutations. Syrhptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms. Central nervous system and spinal abnormalities are also seen in some individuals. These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans. Functional assays showed that the resulting BRPF1 variants are pathogenic and impair acetylation of histone H3 at lysine 23, an abundant but poorly characterized epigenetic mark. We also found a similar deficiency in different lines of Brpf1-knockout mice. These data indicate that aberrations in the chromatin regulator gene BRPF1 cause histone H3 acetylation deficiency and a previously unrecognized intellectual disability syndrome.

Published
2017
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23. Exome sequencing in families with chronic central serous chorioretinopathy

Author

Schellevis, R.L., Dijk, Elon H.C. van, Breukink, M.B., Keunen, J.E., Santen, G.W.E., Hoyng, C.B., Jong, E.K. de, Boon, C.J.F., Hollander, A.I. den, Schellevis, R.L., Dijk, Elon H.C. van, Breukink, M.B., Keunen, J.E., Santen, G.W.E., Hoyng, C.B., Jong, E.K. de, Boon, C.J.F., and Hollander, A.I. den

Abstract

Contains fulltext : 203468.pdf (publisher's version ) (Open Access)

Published
2019

24. Skewed X-inactivation is common in the general female population

Author

Shvetsova, Ekaterina, Sofronova, Alina, Monajemi, R., Gagalova, Kristina, Draisma, H.H.M., White, S.J., Santen, G.W.E., Dunnen, J.T. den, Hoen, P.A.C. 't, Shvetsova, Ekaterina, Sofronova, Alina, Monajemi, R., Gagalova, Kristina, Draisma, H.H.M., White, S.J., Santen, G.W.E., Dunnen, J.T. den, and Hoen, P.A.C. 't

Abstract

Contains fulltext : 202141.pdf (publisher's version ) (Open Access)

Published
2019

25. The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome

Author

Sluijs, P.J. van der, Jansen, S, Vergano, Samantha A., Adachi-Fukuda, Miho, Alanay, Yasemin, AlKindy, Adila, Burgt, I. van der, Marcelis, C.L., Ockeloen, C.W., Vulto-van Silfhout, A.T., Pfundt, R.P., Vries, B.B.A. de, Clayton-Smith, Jill, Santen, G.W.E., Sluijs, P.J. van der, Jansen, S, Vergano, Samantha A., Adachi-Fukuda, Miho, Alanay, Yasemin, AlKindy, Adila, Burgt, I. van der, Marcelis, C.L., Ockeloen, C.W., Vulto-van Silfhout, A.T., Pfundt, R.P., Vries, B.B.A. de, Clayton-Smith, Jill, and Santen, G.W.E.

Abstract

Contains fulltext : 204629.pdf (publisher's version ) (Open Access)

Published
2019

26. De Novo and Inherited Loss-of-Function Variants in TLK2 : Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder

Author

Reijnders, M.R.F., Miller, K.A., Alvi, M., Goos, J.A.C., Lees, M.M., Burca, A. de, Henderson, A., Kraus, A., Mikat, B., Vries, B.B.A. de, Isidor, B., Kerr, B., Marcelis, C.L.M., Schluth-Bolard, C., Deshpande, C., Ruivenkamp, C.A.L., Wieczorek, D., Baralle, D., Blair, E.M., Engels, H., Ludecke, H.J., Eason, J., Santen, G.W.E., Clayton-Smith, J., Chandler, K., Tatton-Brown, K., Payne, K., Helbig, K., Radtke, K., Nugent, K.M., Cremer, K., Strom, T.M., Bird, L.M., Sinnema, M., Bitner-Glindzicz, M., Dooren, M.F. van, Alders, M., Koopmans, M., Brick, L., Kozenko, M., Harline, M.L., Klaassens, M., Steinraths, M., Cooper, N.S., Edery, P., Yap, P., Terhal, P.A., Spek, P.J. van der, Lakeman, P., Taylor, R.L., Littlejohn, R.O., Pfundt, R.P., Mercimek-Andrews, S., Stegmann, A.P.A., Kant, S.G., McLean, S., Joss, S., Swagemakers, S.M.A., Douzgou, S., Wall, S.A., Kury, S., Calpena, E., Koelling, N., McGowan, S.J., Twigg, S.R.F., Mathijssen, I.M.J., Nellaker, C., Brunner, H.G., Wilkie, A.O.M., Plastic and Reconstructive Surgery and Hand Surgery, Clinical Genetics, and Pathology

Subjects
Tousled-like, Facial Averaging, Haploinsufficiency, Intellectual Disability, Kinase, Adult, Male, Adolescent, kinase, viruses, Inheritance Patterns, Medizin, Translocation, Genetic, Cell Line, Young Adult, Loss of Function Mutation, Report, Humans, RNA, Messenger, Child, Genetic Association Studies, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Base Sequence, Facies, Infant, haploinsufficiency, Neurodevelopmental Disorders, intellectual disability, Child, Preschool, Female, Protein Kinases, facial averaging, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Human adenovirus (HAdV) E1B-55K is a multifunctional regulator of productive viral replication and oncogenic transformation in nonpermissive mammalian cells. These functions depend on E1B-55K's posttranslational modification with the SUMO protein and its binding to HAdV E4orf6. Both early viral proteins recruit specific host factors to form an E3 ubiquitin ligase complex that targets antiviral host substrates for proteasomal degradation. Recently, we reported that the PML-NB associated factor Daxx represses efficient HAdV productive infection and is proteasomally degraded via a SUMO-E1B-55K-dependent, E4orf6-independent pathway, the details of which remained to be established. RNF4, a cellular SUMO-targeted ubiquitin ligase (STUbL), induces ubiquitinylation of specific SUMOy lated proteins and plays an essential role during DNA repair. Here, we show that E1B-55K recruits RNF4 to the insoluble nuclear matrix fraction of the infected cell to support RNF4/Daxx association, promoting Daxx PTM and thus inhibiting this antiviral factor. Removing RNF4 from infected cells using RNA interference resulted in blocking the proper establishment of viral replication centers and significantly diminished viral gene expression. These results provide a model for how HAdV antagonize the antiviral host responses by exploiting the functional capacity of cellular STUbLs. Thus, RNF4 and its STUbL function represent a positive factor during lytic infection and a novel candidate for future therapeutic antiviral intervention strategies.IMPORTANCE Daxx is a PML-NB-associated transcription factor that was recently shown to repress efficient HAdV productive infection. To counteract this antiviral measurement during infection, Daxx is degraded via a novel pathway including viral E1B-55K and host proteasomes. This virus-mediated degradation is independent of the classical HAdV E3 ubiquitin ligase complex, which is essential during viral infection to target other host antiviral substrates. To maintain a productive viral life cycle, HAdV E1B-55K early viral protein inhibits the chromatin-remodeling factor Daxx in a SUMO-dependent manner. In addition, viral E1B-55K protein recruits the STUbL RNF4 and sequesters it into the insoluble fraction of the infected cell. E1B-55K promotes complex formation between RNF4-and E1B-55K-targeted Daxx protein, supporting Daxx posttranslational modification prior to functional inhibition. Hence, RNF4 represents a novel host factor that is beneficial for HAdV gene expression by supporting Daxx counteraction. In this regard, RNF4 and other STUbL proteins might represent novel targets for therapeutic intervention.

Published
2018

27. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Author

Kury, S., Woerden, G.M. van, Besnard, T., Onori, M.P., Latypova, X., Towne, M.C., Cho, M.T., Prescott, T.E., Ploeg, M.A., Sanders, S., Stessman, H.A.F., Pujol, A., Distel, ben, Robak, L.A., Bernstein, J.A., Denomme-Pichon, A.S., Lesca, G., Sellars, E.A., Berg, J., Carre, W., Busk, O.L., Bon, B.W.M. van, Waugh, J.L., Deardorff, M., Hoganson, G.E., Bosanko, K.B., Johnson, D.S., Dabir, T., Holla, O.L., Sarkar, A., Tveten, K., Bellescize, J. de, Braathen, G.J., Terhal, P.A., Grange, D.K., Haeringen, A. van, Lam, C., Mirzaa, G., Burton, J., Bhoj, E.J., Douglas, J., Santani, A.B., Nesbitt, A.I., Helbig, K.L., Andrews, M.V., Begtrup, A., Tang, S., Gassen, K.L.I. van, Juusola, J., Foss, K., Enns, G.M., Moog, U., Hinderhofer, K., Paramasivam, N., Lincoln, S., Kusako, B.H., Lindenbaum, P., Charpentier, E., Nowak, C.B., Cherot, E., Simonet, T., Ruivenkamp, C.A.L., Hahn, S., Brownstein, C.A., Xia, F., Schmitt, S., Deb, W., Bonneau, D., Nizon, M., Quinquis, D., Chelly, J., Rudolf, G., Sanlaville, D., Parent, P., Gilbert-Dussardier, B., Toutain, A., Sutton, V.R., Thies, J., Peart-Vissers, L.E.L.M., Boisseau, P., Vincent, M., Grabrucker, A.M., Dubourg, C., Tan, W.H., Verbeek, N.E., Granzow, M., Santen, G.W.E., Shendure, J., Isidor, B., Pasquier, L., Redon, R., Yang, Y.P., State, M.W., Kleefstra, T., Cogne, B., Petrovski, S., Retterer, K., Eichler, E.E., Rosenfeld, J.A., Agrawal, P.B., Bezieau, S., Odent, S., Elgersma, Y., Mercier, S., Undiagnosed Dis Network, GEM HUGO, Deciphering Dev Dis Study, Service de génétique médicale [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Neuroscience [Rotterdam, the Netherlands], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Expertise Center for Neurodevelopmental Disorders [Rotterdam, the Netherlands] (ENCORE), Genomics Program and Division of Genetics [Boston, USA], Harvard Medical School [Boston] (HMS)-Boston Children's Hospital-The Manton Center for Orphan Disease Research, Gene Discovery Core [Boston, MA, USA] ( The Manton Center for Orphan Disease Research), Harvard Medical School [Boston] (HMS)-Boston Children's Hospital, GeneDx [Gaithersburg, MD, USA], Department of Medical Genetics [Skien, Norway], Telemark Hospital Trust [Skien, Norway], Department of Psychiatry [San Francisco, CA, USA], University of California [San Francisco] (UCSF), University of California-University of California, Department of Genome Sciences [Seattle] (GS), University of Washington [Seattle], Department of Pharmacology [Omaha, NE, USA], Creighton University Medical School [Omaha, NE, USA], Neurometabolic Diseases Laboratory [Barcelona, Spain], Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Centre for Biomedical Research on Rare Diseases [Barcelona, Spain] (CIBERER), Hospital Sant Joan de Déu [Barcelona], Institució Catalana de Recerca i Estudis Avançats (ICREA), Department of Medical Biochemistry [Amsterdam, the Netherlands] (Academic Medical Center), University of Amsterdam [Amsterdam] (UvA), Department of Molecular and Human Genetics [Houston, USA], Baylor College of Medecine, Department of Pediatrics [Stanford], Stanford Medicine, Stanford University-Stanford University, Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Service de Génétique [HCL, Lyon] (Centre de Référence des Anomalies du Développement), Hospices civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Section of Genetics and Metabolism [Little Rock, AR, USA], University of Arkansas for Medical Sciences (UAMS), Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Laboratoire de Génétique Moléculaire & Génomique [CHU Rennes], CHU Pontchaillou [Rennes], Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Pediatrics [Philadelphia, PA, USA] (Division of Genetics), Children’s Hospital of Philadelphia (CHOP ), Department of Pediatrics [Chicago, IL, USA] (College of Medicine), University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Sheffield Children's NHS Foundation Trust, Northern Ireland Regional Genetics Centre [Belfast, UK], Belfast City Hospital-Belfast Health and Social Care Trust, Nottingham Regional Genetics Service [Nottingham, UK], City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], Département d'Epilepsie, Sommeil et Neurophysiologie Pédiatrique [HCL, Lyon], Hospices Civils de Lyon (HCL), Department of Genetics [Utrecht, the Netherlands], University Medical Center [Utrecht], Department of Pediatrics [Saint Louis, MO, USA] (Division of Genetics and Genomic Medicine), Washington University in Saint Louis (WUSTL), Department of Clinical Genetics [Leiden, the Netherlands], Leiden University Medical Center (LUMC), Department of Pediatrics [Seattle, WA, USA] (Division of Genetic Medicine), University of Washington [Seattle]-Seattle Children’s Hospital, Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, The Center for Applied Genomics [Philadelphia, PA, USA], Division of Human Genetics [Philadelphia, PA, USA], Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA], University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA] (Perelman School of Medicine), Division of Clinical Genomics [Aliso Viejo, CA, USA], Ambry Genetics [Aliso Viejo, CA, USA], Division of Neurology [Philadelphia, PA, USA], Institute of Human Genetics [Heidelberg, Germany], Universität Heidelberg [Heidelberg], University of Heidelberg, Medical Faculty, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Service de Neurologie [CHU Strasbourg], Hôpital de Hautepierre [Strasbourg]-Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), Département de génétique médicale en pédiatrie [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de Génétique [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de Génétique [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Department of Biological Sciences [Limerick, Ireland], University of Limerick (UL), Bernal Institute [Limerick, Ireland], Howard Hughes Medical Institute [Seattle], Howard Hughes Medical Institute (HHMI), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de Génétique Clinique [CHU Rennes] (Réseau de Génétique et Génomique Médicale), Hôpitaux Universitaires du Grand Ouest, The Wellcome Trust Sanger Institute [Cambridge], Department of Medicine [Melbourne, Australia], University of Melbourne-Austin Health, Division of Newborn Medicine [Boston, MA, USA], Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Neurosciences, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Univ Angers, Okina, University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], Universiteit Leiden-Universiteit Leiden, Department of Pediatrics [Seattle, WA, USA], University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Universität Heidelberg [Heidelberg] = Heidelberg University, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Amsterdam Gastroenterology Endocrinology Metabolism, Medical Biochemistry, and Bernardo, Elizabeth

Subjects
0301 basic medicine, Male, de novo mutations, AMPAR, medicine.disease_cause, Inbred C57BL, Mice, 0302 clinical medicine, Intellectual disability, CAMK2A, Exome, Phosphorylation, Genetics (clinical), Genetics, Neurons, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Brain, Phenotype, NMDAR, intellectual disability, Female, Signal transduction, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Signal Transduction, Glutamic Acid, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, Cell Line, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Journal Article, Animals, Humans, Protein kinase A, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], synaptic plasticity, medicine.disease, Mice, Inbred C57BL, CAMK2, CAMK2B, 030104 developmental biology, HEK293 Cells, Synaptic plasticity, Calcium-Calmodulin-Dependent Protein Kinase Type 2, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Contains fulltext : 182539.pdf (Publisher’s version ) (Closed access) Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

Published
2017
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28. Genotype-phenotype correlation in ATAD3A deletions: not just of scientific relevance

Author

Santen, G.W.E., Adama van Scheltema, P.N., Peeters, C.M.P.C.D., Steggerda, S.J., Klumper, F.J.C.M., and Everwijn, S.M.P.

Abstract

Recently, Desai et al. described six subjects with deletions in the ATAD3 gene cluster (Desai et al. 2017). Most of these patients died within their first week of life and one died after 7 months, but one was still alive at 30 years of age. Harel et al. (2016) described three patients with biallellic variations in ATAD3A, one of whom died in the second week of life but the other two were alive at 24 and 26 years, respectively. For pre- and postnatal management it is important to understand why some patients die very early, whereas others seem to have a much milder clinical affect.

Published
2017

29. High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer

Author

Diets, I.J., Waanders, E., Ligtenberg, M.J.L., Bladel, D.A.G. van, Kamping, E.J., Hoogerbrugge, P.M., Hopman, S., Olderode-Berends, M.J., Gerkes, E.H., Koolen, D.A., Marcelis, C.L., Santen, G.W.E., Belzen, M.J. van, Mordaunt, D., McGregor, L., Thompson, E., Kattamis, A., Pastorczak, A., Mlynarski, W., Ilencikova, D., Vulto-van Silfhout, A.T., Gardeitchik, T., Bont, E.S. de, Loeffen, J., Wagner, A., Mensenkamp, A.R., Kuiper, R.P., Hoogerbrugge, N., Jongmans, M.C., Diets, I.J., Waanders, E., Ligtenberg, M.J.L., Bladel, D.A.G. van, Kamping, E.J., Hoogerbrugge, P.M., Hopman, S., Olderode-Berends, M.J., Gerkes, E.H., Koolen, D.A., Marcelis, C.L., Santen, G.W.E., Belzen, M.J. van, Mordaunt, D., McGregor, L., Thompson, E., Kattamis, A., Pastorczak, A., Mlynarski, W., Ilencikova, D., Vulto-van Silfhout, A.T., Gardeitchik, T., Bont, E.S. de, Loeffen, J., Wagner, A., Mensenkamp, A.R., Kuiper, R.P., Hoogerbrugge, N., and Jongmans, M.C.

Abstract

Contains fulltext : 190442.pdf (publisher's version ) (Closed access), Purpose: In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole-exome sequencing on a selected cohort of children with cancer.Experimental Design: To identify mutations in known and novel cancer-predisposing genes, we performed trio-based whole-exome sequencing on germline DNA of 40 selected children and their parents. These children were diagnosed with cancer and had at least one of the following features: (1) intellectual disability and/or congenital anomalies, (2) multiple malignancies, (3) family history of cancer, or (4) an adult type of cancer. We first analyzed the sequence data for germline mutations in 146 known cancer-predisposing genes. If no causative mutation was found, the analysis was extended to the whole exome.Results: Four patients carried causative mutations in a known cancer-predisposing gene: TP53 and DICER1 (n = 3). In another 4 patients, exome sequencing revealed mutations causing syndromes that might have contributed to the malignancy (EP300-based Rubinstein-Taybi syndrome, ARID1A-based Coffin-Siris syndrome, ACTB-based Baraitser-Winter syndrome, and EZH2-based Weaver syndrome). In addition, we identified two genes, KDM3B and TYK2, which are possibly involved in genetic cancer predisposition.Conclusions: In our selected cohort of patients, pathogenic germline mutations causative or likely causative of the cancer phenotype were found in 8 patients, and two possible novel cancer-predisposing genes were identified. Therewith, our study shows the added value of sequencing beyond a cancer gene panel in selected patients, to recognize childhood cancer predisposition. Clin Cancer Res; 24(7); 1594-603. (c)2018 AACR.

Published
2018

30. 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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31. Correction to: Putting genome-wide sequencing in neonates into perspective

Author

Sluijs, P.J. (Pleuntje) van der, Aten, J.A. (Jacob), Barge-Schaapveld, D.Q.C.M. (Daniela), Bijlsma, E.K. (Emilia), Bökenkamp-Gramann, R. (Regina), Donker Kaat, L. (Laura), Doorn, R. (Remco) van, Putte, D.F. (Dietje Fransen) van de, Haeringen, A. (Arie) van, Harkel, A.D.J. (Arend) ten, Hilhorst-Hofstee, Y. (Yvonne), Hoffer, M.J.V. (Mariëtte), Hollander, N.S. (Nicolette) den, Ierland, Y. (Yvette) van, Koopmans, M. (Marije), Kriek, N. (Nadia), Moghadasi, S. (Setareh), Nibbeling, E.A.R. (Esther), Peeters-Scholte, C.M.P.C.D. (Cacha), Potjer, T.P. (Thomas P.), Rij, M.C. (Maartje) van, Ruivenkamp, C.A. (Claudia), Rutten, J.W. (Julie), Steggerda, S.J. (Sylke), Suerink, M. (Manon), Tan, R.N.G.B. (Ratna), van der Tuin, K. (Karin), Visser, R. (Remco), Werf –’t Lam, A.-S. (Anne-Sophie) van der, Williams, M. (Monique), Witlox, R. (Ruben), Santen, G.W.E. (Gijs), Sluijs, P.J. (Pleuntje) van der, Aten, J.A. (Jacob), Barge-Schaapveld, D.Q.C.M. (Daniela), Bijlsma, E.K. (Emilia), Bökenkamp-Gramann, R. (Regina), Donker Kaat, L. (Laura), Doorn, R. (Remco) van, Putte, D.F. (Dietje Fransen) van de, Haeringen, A. (Arie) van, Harkel, A.D.J. (Arend) ten, Hilhorst-Hofstee, Y. (Yvonne), Hoffer, M.J.V. (Mariëtte), Hollander, N.S. (Nicolette) den, Ierland, Y. (Yvette) van, Koopmans, M. (Marije), Kriek, N. (Nadia), Moghadasi, S. (Setareh), Nibbeling, E.A.R. (Esther), Peeters-Scholte, C.M.P.C.D. (Cacha), Potjer, T.P. (Thomas P.), Rij, M.C. (Maartje) van, Ruivenkamp, C.A. (Claudia), Rutten, J.W. (Julie), Steggerda, S.J. (Sylke), Suerink, M. (Manon), Tan, R.N.G.B. (Ratna), van der Tuin, K. (Karin), Visser, R. (Remco), Werf –’t Lam, A.-S. (Anne-Sophie) van der, Williams, M. (Monique), Witlox, R. (Ruben), and Santen, G.W.E. (Gijs)

Abstract

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2018
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32. Skewed X-inactivation is common in the general female population

Author

Shvetsova, E. (Ekaterina), Sofronova, A. (Alina), Monajemi, R. (Ramin), Gagalova, K. (Kristina), Draisma, G. (Gerrit), White, S.J. (Stefan), Santen, G.W.E. (Gijs), Chuva De Sousa Lopes, S.M. (Susana M.), Heijmans, B.T. (Bastiaan T.), van Meurs, J. (Joyce), Jansen, R. (Rick), Franke, L. (Lude), Kielbasa, S.M. (Szymon M.), Dunnen, J.T. (Johan) den, ‘t Hoen, P.A.C. (Peter A. C.), Heijmans, B.T. (Bastiaan T), Meurs, J.B.J. (Joyce) van, Boomsma, D.I. (Dorret), Pool, R. (Reńe), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Greevenbroek, M.M. van, Stehouwer, C.D. (Coen Da), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Wijmenga, C. (Cisca), Zhernakova, S. (Sasha), Tigchelaar, E.F. (Ettje F.), Slagboom, P.E. (Eline), Beekman, M. (Marian), Deelen, J. (Joris), Heemst, D. (Diana) van, Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Duijn, C.M. (Cornelia) van, Hofman, B.A. (Bert A), Uitterlinden, A.G. (André), Jhamai, P.M. (Mila), Verbiest, M.M.P.J. (Michael), Suchiman, H.E.D. (H Eka D), Verkerk, M. (Marijn), Breggen, R. (Ruud) van der, van Rooij, J. (Jeroen), Lakenberg, N. (Nico), Mei, S. (Shan), Bot, J. (Jan), Zhernakova, D.V. (Dasha V), van ’t Hof, P. (Peter), Deelen, P. (Patrick), Nooren, I. (Irene), Moed, H. (Heleen), Vermaat, M. (Martijn), Luijk, R. (René), Jan Bonder, M. (Marc), Iterson, M. (Maarten) van, van Dijk, F. (Freerk), Van Galen, M. (Michiel), Arindrarto, W. (Wibowo), Swertz, M.A. (Morris A), Zwet, E.W. (Erik) van, Isaacs, A.J. (Aaron), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara), Dijk, F. (Freerk) van, Palamara, P.F. (Pier Francesco), Elbers, C.C. (Clara), Neerincx, P.B.T. (Pieter B T), Ye, K. (K.), Guryev, V. (Victor), Kloosterman, W. (Wp), Abdellaoui, A. (Abdel), van Leeuwen, E. (Em), Oven, M. (Mannis) van, Li, M. (M.), Laros, J. (Jf), Karssen, L.C. (Lennart), Kanterakis, A. (Alexandros), Amin, N. (Najaf), Hottenga, J. (Jj), Lameijer, E. (Ew), Kattenberg, V.M. (Mathijs), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), Setten, J. (Jessica) van, van Schaik, B. (Bd), Bot, J.J. (Jan), Nijman, I. (Ij), Renkens, I. (Ivo), Marschall, T. (Tanja), Schönhuth, A. (A.), Hehir-Kwa, J. (Jayne), Handsaker, R.E. (Robert), Polak, P., Sohail, M. (Mashaal), Vuzman, D. (Dana), Hormozdiari, F. (Fereydoun), Enckevort, D. (David) van, Mei, H. (H.), Koval, V. (Vyacheslav), Moed, M. (Mh), van der Velde, K. (Kj), Rivadeneira Ramirez, F. (Fernando), Estrada Gil, K. (Karol), Medina-Gomez, M.C. (Carolina), McCarroll, S. (Sa), de Craen, A. (Aj), Suchiman, H. (He), Hofman, B. (Ba), Oostra, B.A. (Ben), Uitterlinden, A. (Ag), Willemsen, G.A.H.M. (Gonneke), Platteel, I. (Inge), Veldink, J. (Jh), van den Berg, L. (Lh), Pitts, S. (Sj), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D. (Dr), Sunyaev, S. (Sr), den Dunnen, J. (Jt), Stoneking, M. (Mark), Knijff, P. (Peter) de, Kayser, M.H. (Manfred), Li, Q. (Q.), Li, Y. (Y.), Du, Y. (Y.), Chen, R. (R.), Cao, H. (H.), Li, N. (N.), Cao, S. (Sherry), Wang, J. (J.), Bovenberg, J.A. (Jasper), Peer, I. (Itsik), Slagboom, P. (Pe), van Duijn, C. (Cm), Boomsma, D. (Di), van Ommen, G. (Gj), de Bakker, P. (Pi), Swertz, M. (Ma), Wijmenga, C. (C.), Shvetsova, E. (Ekaterina), Sofronova, A. (Alina), Monajemi, R. (Ramin), Gagalova, K. (Kristina), Draisma, G. (Gerrit), White, S.J. (Stefan), Santen, G.W.E. (Gijs), Chuva De Sousa Lopes, S.M. (Susana M.), Heijmans, B.T. (Bastiaan T.), van Meurs, J. (Joyce), Jansen, R. (Rick), Franke, L. (Lude), Kielbasa, S.M. (Szymon M.), Dunnen, J.T. (Johan) den, ‘t Hoen, P.A.C. (Peter A. C.), Heijmans, B.T. (Bastiaan T), Meurs, J.B.J. (Joyce) van, Boomsma, D.I. (Dorret), Pool, R. (Reńe), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Greevenbroek, M.M. van, Stehouwer, C.D. (Coen Da), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Wijmenga, C. (Cisca), Zhernakova, S. (Sasha), Tigchelaar, E.F. (Ettje F.), Slagboom, P.E. (Eline), Beekman, M. (Marian), Deelen, J. (Joris), Heemst, D. (Diana) van, Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Duijn, C.M. (Cornelia) van, Hofman, B.A. (Bert A), Uitterlinden, A.G. (André), Jhamai, P.M. (Mila), Verbiest, M.M.P.J. (Michael), Suchiman, H.E.D. (H Eka D), Verkerk, M. (Marijn), Breggen, R. (Ruud) van der, van Rooij, J. (Jeroen), Lakenberg, N. (Nico), Mei, S. (Shan), Bot, J. (Jan), Zhernakova, D.V. (Dasha V), van ’t Hof, P. (Peter), Deelen, P. (Patrick), Nooren, I. (Irene), Moed, H. (Heleen), Vermaat, M. (Martijn), Luijk, R. (René), Jan Bonder, M. (Marc), Iterson, M. (Maarten) van, van Dijk, F. (Freerk), Van Galen, M. (Michiel), Arindrarto, W. (Wibowo), Swertz, M.A. (Morris A), Zwet, E.W. (Erik) van, Isaacs, A.J. (Aaron), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara), Dijk, F. (Freerk) van, Palamara, P.F. (Pier Francesco), Elbers, C.C. (Clara), Neerincx, P.B.T. (Pieter B T), Ye, K. (K.), Guryev, V. (Victor), Kloosterman, W. (Wp), Abdellaoui, A. (Abdel), van Leeuwen, E. (Em), Oven, M. (Mannis) van, Li, M. (M.), Laros, J. (Jf), Karssen, L.C. (Lennart), Kanterakis, A. (Alexandros), Amin, N. (Najaf), Hottenga, J. (Jj), Lameijer, E. (Ew), Kattenberg, V.M. (Mathijs), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), Setten, J. (Jessica) van, van Schaik, B. (Bd), Bot, J.J. (Jan), Nijman, I. (Ij), Renkens, I. (Ivo), Marschall, T. (Tanja), Schönhuth, A. (A.), Hehir-Kwa, J. (Jayne), Handsaker, R.E. (Robert), Polak, P., Sohail, M. (Mashaal), Vuzman, D. (Dana), Hormozdiari, F. (Fereydoun), Enckevort, D. (David) van, Mei, H. (H.), Koval, V. (Vyacheslav), Moed, M. (Mh), van der Velde, K. (Kj), Rivadeneira Ramirez, F. (Fernando), Estrada Gil, K. (Karol), Medina-Gomez, M.C. (Carolina), McCarroll, S. (Sa), de Craen, A. (Aj), Suchiman, H. (He), Hofman, B. (Ba), Oostra, B.A. (Ben), Uitterlinden, A. (Ag), Willemsen, G.A.H.M. (Gonneke), Platteel, I. (Inge), Veldink, J. (Jh), van den Berg, L. (Lh), Pitts, S. (Sj), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D. (Dr), Sunyaev, S. (Sr), den Dunnen, J. (Jt), Stoneking, M. (Mark), Knijff, P. (Peter) de, Kayser, M.H. (Manfred), Li, Q. (Q.), Li, Y. (Y.), Du, Y. (Y.), Chen, R. (R.), Cao, H. (H.), Li, N. (N.), Cao, S. (Sherry), Wang, J. (J.), Bovenberg, J.A. (Jasper), Peer, I. (Itsik), Slagboom, P. (Pe), van Duijn, C. (Cm), Boomsma, D. (Di), van Ommen, G. (Gj), de Bakker, P. (Pi), Swertz, M. (Ma), and Wijmenga, C. (C.)

Abstract

X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants.

Published
2018
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33. Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

Author

Ivanovski, I. (Ivan), Djuric, O. (Olivera), Caraffi, S.G. (Stefano Giuseppe), Santodirocco, D. (Daniela), Pollazzon, M. (Marzia), Rosato, S. (Simonetta), Cordelli, D.M. (Duccio M.), Abdalla, E. (Ebtesam), Accorsi, P. (Patrizia), Adam, M.P. (Margaret), Ajmone, P.F. (Paola Francesca), Badura-Stronka, M. (Magdalena), Baldo, C. (Chiara), Baldi, M. (Maddalena), Bayat, A. (Allan), Bigoni, S. (Stefania), Bonvicini, F. (Federico), Breckpot, J. (Jeroen), Callewaert, L., Cocchi, G. (Guido), Cuturilo, G. (Goran), De Brasi, D. (Daniele), Devriendt, K. (Koenraad), Dinulos, M.B. (Mary Beth), Hjortshøj, T.D. (Tina Duelund), Epifanio, R. (Roberta), Faravelli, F. (Francesca), Fiumara, A. (Agata), Formisano, D. (Debora), Giordano, L. (Lucio), Grasso, M. (Marina), Grønborg, S. (Sabine), Iodice, A. (Alessandro), Iughetti, L. (Lorenzo), Kuburovic, V. (Vladimir), Kutkowska-Kazmierczak, A. (Anna), Lacombe, D. (Didier), Lo Rizzo, C. (Caterina), Luchetti, A. (Anna), Malbora, B. (Baris), Mammi, I. (Isabella), Mari, F. (Francesca), Montorsi, G. (Giulia), Moutton, S. (Sebastien), Møller, R.S. (Rikke), Muschke, P. (Petra), Nielsen, J.E.K. (Jens Erik Klint), Obersztyn, E. (Ewa), Pantaleoni, C. (Chiara), Pellicciari, A. (Alessandro), Pisanti, M.A. (Maria Antonietta), Prpic, I. (Igor), Poch-Olive, M.L. (Maria Luisa), Raviglione, F. (Federico), Renieri, A. (Alessandra), Ricci, E. (Emilia), Rivieri, F. (Francesca), Santen, G.W.E. (Gijs), Savasta, S. (Salvatore), Scarano, G. (Gioacchino), Schanze, I. (Ina), Selicorni, A. (Angelo), Silengo, M.C., Smigiel, R. (Robert), Spaccini, L. (Luigina), Sorge, G. (Giovanni), Szczaluba, K. (Krzysztof), Tarani, L. (Luigi), Tone, L.G. (Luis Gonzaga), Toutain, A. (Annick), Trimouille, A. (Aurelien), Valera, E.T. (Elvis Terci), Vergano, S.S. (Samantha Schrier), Zanotta, N. (Nicoletta), Zenker, M. (Martin), Conidi, A. (Andrea), Zollino, M., Rauch, A., Zweier, C. (Christiane), Garavelli, L. (Livia), Ivanovski, I. (Ivan), Djuric, O. (Olivera), Caraffi, S.G. (Stefano Giuseppe), Santodirocco, D. (Daniela), Pollazzon, M. (Marzia), Rosato, S. (Simonetta), Cordelli, D.M. (Duccio M.), Abdalla, E. (Ebtesam), Accorsi, P. (Patrizia), Adam, M.P. (Margaret), Ajmone, P.F. (Paola Francesca), Badura-Stronka, M. (Magdalena), Baldo, C. (Chiara), Baldi, M. (Maddalena), Bayat, A. (Allan), Bigoni, S. (Stefania), Bonvicini, F. (Federico), Breckpot, J. (Jeroen), Callewaert, L., Cocchi, G. (Guido), Cuturilo, G. (Goran), De Brasi, D. (Daniele), Devriendt, K. (Koenraad), Dinulos, M.B. (Mary Beth), Hjortshøj, T.D. (Tina Duelund), Epifanio, R. (Roberta), Faravelli, F. (Francesca), Fiumara, A. (Agata), Formisano, D. (Debora), Giordano, L. (Lucio), Grasso, M. (Marina), Grønborg, S. (Sabine), Iodice, A. (Alessandro), Iughetti, L. (Lorenzo), Kuburovic, V. (Vladimir), Kutkowska-Kazmierczak, A. (Anna), Lacombe, D. (Didier), Lo Rizzo, C. (Caterina), Luchetti, A. (Anna), Malbora, B. (Baris), Mammi, I. (Isabella), Mari, F. (Francesca), Montorsi, G. (Giulia), Moutton, S. (Sebastien), Møller, R.S. (Rikke), Muschke, P. (Petra), Nielsen, J.E.K. (Jens Erik Klint), Obersztyn, E. (Ewa), Pantaleoni, C. (Chiara), Pellicciari, A. (Alessandro), Pisanti, M.A. (Maria Antonietta), Prpic, I. (Igor), Poch-Olive, M.L. (Maria Luisa), Raviglione, F. (Federico), Renieri, A. (Alessandra), Ricci, E. (Emilia), Rivieri, F. (Francesca), Santen, G.W.E. (Gijs), Savasta, S. (Salvatore), Scarano, G. (Gioacchino), Schanze, I. (Ina), Selicorni, A. (Angelo), Silengo, M.C., Smigiel, R. (Robert), Spaccini, L. (Luigina), Sorge, G. (Giovanni), Szczaluba, K. (Krzysztof), Tarani, L. (Luigi), Tone, L.G. (Luis Gonzaga), Toutain, A. (Annick), Trimouille, A. (Aurelien), Valera, E.T. (Elvis Terci), Vergano, S.S. (Samantha Schrier), Zanotta, N. (Nicoletta), Zenker, M. (Martin), Conidi, A. (Andrea), Zollino, M., Rauch, A., Zweier, C. (Christiane), and Garavelli, L. (Livia)

Abstract

Purpose: Mowat–Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype–phenotype correlations of MWS. Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluatio

Published
2018
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35. Mutations in TBL1X Are Associated With Central Hypothyroidism

Author

Heinen, C.A., Losekoot, M., Sun, Y., Watson, P.J., Fairall, L., Joustra, S.D., Zwaveling-Soonawala, N., Oostdijk, W., Akker, E.L.T. van den, Alders, M., Santen, G.W.E., Rijn, R.R. van, Dreschler, W.A., Surovtseva, O.V., Biermasz, N.R., Hennekam, R.C., Wit, J.M., Schwabe, J.W.R., Boelen, A., Fliers, E., Trotsenburg, A.S.P. van, ANS - Complex Trait Genetics, Paediatric Endocrinology, Other Research, ACS - Amsterdam Cardiovascular Sciences, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Human Genetics, Radiology and Nuclear Medicine, APH - Amsterdam Public Health, Ear, Nose and Throat, Paediatric Genetics, Endocrinology Laboratory, Endocrinology, and Pediatrics

Subjects
Adult, Male, Heterozygote, Adolescent, Hypothalamus, Infant, Original Articles, Middle Aged, Pedigree, Thyroxine, Young Adult, Hypothyroidism, Pituitary Gland, Mutation, Humans, Female, RNA, Messenger, Transducin, Child, Hearing Loss, hormones, hormone substitutes, and hormone antagonists
Abstract

Context: Isolated congenital central hypothyroidism (CeH) can result from mutations in TRHR, TSHB, and IGSF1, but its etiology often remains unexplained. We identified a missense mutation in the transducin β-like protein 1, X-linked (TBL1X) gene in three relatives diagnosed with isolated CeH. TBL1X is part of the thyroid hormone receptor-corepressor complex. Objective: The objectives of the study were the identification of TBL1X mutations in patients with unexplained isolated CeH, Sanger sequencing of relatives of affected individuals, and clinical and biochemical characterization; in vitro investigation of functional consequences of mutations; and mRNA expression in, and immunostaining of, human hypothalami and pituitary glands. Design: This was an observational study. Setting: The study was conducted at university medical centers. Patients: Nineteen individuals with and seven without a mutation participated in the study. Main Outcome Measures: Outcome measures included sequencing results, clinical and biochemical characteristics of mutation carriers, and results of in vitro functional and expression studies. Results: Sanger sequencing yielded five additional mutations. All patients (n = 8; six males) were previously diagnosed with CeH (free T4 [FT4] concentration below the reference interval, normal thyrotropin). Eleven relatives (two males) also carried mutations. One female had CeH, whereas 10 others had low-normal FT4 concentrations. As a group, adult mutation carriers had 20%–25% lower FT4 concentrations than controls. Twelve of 19 evaluated carriers had hearing loss. Mutations are located in the highly conserved WD40-repeat domain of the protein, influencing its expression and thermal stability. TBL1X mRNA and protein are expressed in the human hypothalamus and pituitary. Conclusions: TBL1X mutations are associated with CeH and hearing loss. FT4 concentrations in mutation carriers vary from low-normal to values compatible with CeH., By using DNA-analysis, clinical and biochemical phenotyping, and in vitro functional and expression studies, we show that TBL1X mutations are associated with central hypothyroidism and hearing loss.

Published
2016

36. PAPSS2 Deficiency Causes Androgen Excess via Impaired DHEA Sulfation-In Vitro and in Vivo Studies in a Family Harboring Two Novel PAPSS2 Mutations

Author

Oostdijk, W., Idkowiak, J., Mueller, J.W., House, P.J., Taylor, A.E., O'Reilly, M.W., Hughes, B.A., Vries, M.C. de, Kant, S.G., Santen, G.W.E., Verkerk, A.J.M.H., Uitterlinden, A.G., Wit, J.M., Losekoot, M., Arlt, W., and Internal Medicine

Subjects
polycyclic compounds, hormones, hormone substitutes, and hormone antagonists
Abstract

Context: PAPSS2 (PAPS synthase 2) provides the universal sulfate donor PAPS (3'-phospho-adenosine-5'-phosphosulfate) to all human sulfotransferases, including SULT2A1, responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone (DHEA). Impaired DHEA sulfation is thought to increase the conversion of DHEA toward active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations who presented with low serum DHEA sulfate and androgen excess, clinically manifesting with premature pubarche and early-onset polycystic ovary syndrome. Patients and Methods: We investigated a family harboring two novel PAPSS2 mutations, including two compound heterozygous brothers presenting with disproportionate short stature, low serum DHEA sulfate, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100 mg DHEA orally, with subsequent analysis of DHEA sulfation and androgen metabolism by mass spectrometry. The functional impact of the mutations was investigated in silico and in vitro. Results: We identified a novel PAPSS2 frameshift mutation, c. 1371del, p. W462Cfs*3, resulting in complete disruption, and a novel missense mutation, c. 809G>A, p. G270D, causing partial disruption of DHEA sulfation. Both patients and their mother, who was heterozygous for p. W462Cfs*3, showed increased 5 alpha-reductase activity at baseline and significantly increased production of active androgens after DHEA intake. The mother had a history of oligomenorrhea and chronic anovulation that required clomiphene for ovulation induction. Conclusions: We provide direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. Heterozygosity for PAPSS2 mutations can be associated with a phenotype resembling polycystic ovary syndrome.

Published
2015

37. Successful growth hormone therapy in Cornelia de Lange syndrome

Author

de Graaf, M. (Michael), Kant, S.G. (Sarina), Wit, J.M. (Jan), Redeker, E.J.W. (Egbert), Santen, G.W.E. (Gijs), Verkerk, A., Uitterlinden, A.G. (André), Losekoot, M. (Monique), Oostdijk, W. (Wilma), de Graaf, M. (Michael), Kant, S.G. (Sarina), Wit, J.M. (Jan), Redeker, E.J.W. (Egbert), Santen, G.W.E. (Gijs), Verkerk, A., Uitterlinden, A.G. (André), Losekoot, M. (Monique), and Oostdijk, W. (Wilma)

Abstract

Cornelia de Lange syndrome (CdLS) is a both clinically and genetically heterogeneous syndrome. In its classical form, it is characterised by distinctive facial features, intra-uterine growth retardation, short stature, developmental delay, and anomalies in multiple organ systems. NIPBL, SMC1A, SMC3, RAD21 and HDAC8, all involved in the cohesin pathway, have been identified to cause CdLS. Growth hormone (GH) secretion has been reported as normal, and to our knowledge, there are no reports on the effect of recombinant human GH treatment in CdLS patients. We present a patient born small for gestational age with persistent severe growth retardation [height -3.4 standard deviation score (SDS)] and mild dysmorphic features, who was treated with GH from 4.3 years of age onward and was diagnosed 6 years later with CdLS using whole-exome sequencing. Treatment led to a height gain of 1.6 SDS over 8 years. Treatment was interrupted shortly due to high serum insulin-like growth factor-1 serum values. In conclusion, GH therapy may be effective and safe for short children with CdLS.

Published
2017
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38. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Author

Küry, S. (Sébastien), Woerden, G.M. (Geeske) van, Besnard, T. (Thomas), Proietti-Onori, M. (Martina), Latypova, X. (Xénia), Towne, M.C. (Meghan C.), Cho, M.T. (Megan T.), Prescott, T. (Trine), Ploeg, M.A. (Melissa), Sanders, S. (Stephan), Stessman, H.A.F. (Holly A F), Pujol, A. (Aurora), Distel, B. (Ben), Robak, L.A. (Laurie A.), Bernstein, J.A. (Jonathan A.), Denommé-Pichon, A.-S. (Anne-Sophie), Lesca, G. (Gaëtan), Sellars, E.A. (Elizabeth A.), Berg, J. (Jonathan), Carré, W. (Wilfrid), Busk, ØL. (Øyvind Løvold), Bon, B. (Bregje) van, Waugh, J.L. (Jeff L.), Deardorff, M.A. (Matthew), Hoganson, G.E. (George E.), Bosanko, K.B. (Katherine B.), Johnson, D.S. (Diana S.), Dabir, T. (Tabib), Holla, ØL. (Øystein Lunde), Sarkar, A. (Ajoy), Tveten, K. (Kristian), de Bellescize, J. (Julitta), Braathen, G.J. (Geir J.), Terhal, P. (Paulien), Grange, D.K. (Dorothy K.), Haeringen, A. (Arie) van, Lam, C. (Christina), Mirzaa, G.M. (Ghayda), Burton, J. (Jennifer), Bhoj, E.J. (Elizabeth J.), Douglas, J. (Jessica), Santani, A.B. (Avni B.), Nesbitt, A.I. (Addie I.), Helbig, K.L. (Katherine L.), Andrews, M.V. (Marisa V.), Begtrup, A. (Amber), Tang, S. (Sha), van Gassen, K.L.I. (Koen L.I.), Juusola, J. (Jane), Foss, K. (Kimberly), Enns, G. (Gregory), Moog, U. (Ute), Hinderhofer, K. (Katrin), Paramasivam, N. (Nagarajan), Lincoln, S. (Sharyn), Kusako, B.H. (Brandon H.), Lindenbaum, P. (Pierre), Charpentier, E. (Eric), Nowak, C.B. (Catherine B.), Cherot, E. (Elouan), Simonet, T. (Thomas), Ruivenkamp, C.A. (Claudia), Hahn, S. (Sihoun), Brownstein, C.A. (Catherine A.), Xia, F. (Fan), Schmitt, S. (Sébastien), Deb, W. (Wallid), Bonneau, D. (Dominique), Nizon, M. (Mathilde), Quinquis, D. (Delphine), Chelly, J. (Jamel), Rudolf, G. (Gabrielle), Sanlaville, D. (Damien), Parent, P. (Philippe), Gilbert-Dussardier, B. (Brigitte), Toutain, A. (Annick), Sutton, V.R. (V. Reid), Thies, J. (Jenny), Peart-Vissers, L.E.L.M. (Lisenka E L M), Boisseau, P. (Pierre), Vincent, M. (Marie), Grabrucker, A.M. (Andreas M.), Dubourg, C. (Christèle), Tan, W.-H. (Wen-Hann), Verbeek, N.E. (Nienke), Granzow, M. (Martin), Santen, G.W.E. (Gijs), Shendure, J. (Jay), Isidor, B. (Bertrand), Pasquier, L. (Laurent), Redon, R. (Richard), Yang, Y. (Yaping), State, M.W. (Matthew), Kleefstra, T. (Tjitske), Cogné, B. (Benjamin), Petrovski, S. (Slavé), Retterer, K. (Kyle), Eichler, E.E. (Evan), Rosenfeld, J.A. (Jill), Agrawal, P.B. (Pankaj B.), Bézieau, S. (Stéphane), Odent, S. (Sylvie), Elgersma, Y. (Ype), Mercier, S. (Sandra), Küry, S. (Sébastien), Woerden, G.M. (Geeske) van, Besnard, T. (Thomas), Proietti-Onori, M. (Martina), Latypova, X. (Xénia), Towne, M.C. (Meghan C.), Cho, M.T. (Megan T.), Prescott, T. (Trine), Ploeg, M.A. (Melissa), Sanders, S. (Stephan), Stessman, H.A.F. (Holly A F), Pujol, A. (Aurora), Distel, B. (Ben), Robak, L.A. (Laurie A.), Bernstein, J.A. (Jonathan A.), Denommé-Pichon, A.-S. (Anne-Sophie), Lesca, G. (Gaëtan), Sellars, E.A. (Elizabeth A.), Berg, J. (Jonathan), Carré, W. (Wilfrid), Busk, ØL. (Øyvind Løvold), Bon, B. (Bregje) van, Waugh, J.L. (Jeff L.), Deardorff, M.A. (Matthew), Hoganson, G.E. (George E.), Bosanko, K.B. (Katherine B.), Johnson, D.S. (Diana S.), Dabir, T. (Tabib), Holla, ØL. (Øystein Lunde), Sarkar, A. (Ajoy), Tveten, K. (Kristian), de Bellescize, J. (Julitta), Braathen, G.J. (Geir J.), Terhal, P. (Paulien), Grange, D.K. (Dorothy K.), Haeringen, A. (Arie) van, Lam, C. (Christina), Mirzaa, G.M. (Ghayda), Burton, J. (Jennifer), Bhoj, E.J. (Elizabeth J.), Douglas, J. (Jessica), Santani, A.B. (Avni B.), Nesbitt, A.I. (Addie I.), Helbig, K.L. (Katherine L.), Andrews, M.V. (Marisa V.), Begtrup, A. (Amber), Tang, S. (Sha), van Gassen, K.L.I. (Koen L.I.), Juusola, J. (Jane), Foss, K. (Kimberly), Enns, G. (Gregory), Moog, U. (Ute), Hinderhofer, K. (Katrin), Paramasivam, N. (Nagarajan), Lincoln, S. (Sharyn), Kusako, B.H. (Brandon H.), Lindenbaum, P. (Pierre), Charpentier, E. (Eric), Nowak, C.B. (Catherine B.), Cherot, E. (Elouan), Simonet, T. (Thomas), Ruivenkamp, C.A. (Claudia), Hahn, S. (Sihoun), Brownstein, C.A. (Catherine A.), Xia, F. (Fan), Schmitt, S. (Sébastien), Deb, W. (Wallid), Bonneau, D. (Dominique), Nizon, M. (Mathilde), Quinquis, D. (Delphine), Chelly, J. (Jamel), Rudolf, G. (Gabrielle), Sanlaville, D. (Damien), Parent, P. (Philippe), Gilbert-Dussardier, B. (Brigitte), Toutain, A. (Annick), Sutton, V.R. (V. Reid), Thies, J. (Jenny), Peart-Vissers, L.E.L.M. (Lisenka E L M), Boisseau, P. (Pierre), Vincent, M. (Marie), Grabrucker, A.M. (Andreas M.), Dubourg, C. (Christèle), Tan, W.-H. (Wen-Hann), Verbeek, N.E. (Nienke), Granzow, M. (Martin), Santen, G.W.E. (Gijs), Shendure, J. (Jay), Isidor, B. (Bertrand), Pasquier, L. (Laurent), Redon, R. (Richard), Yang, Y. (Yaping), State, M.W. (Matthew), Kleefstra, T. (Tjitske), Cogné, B. (Benjamin), Petrovski, S. (Slavé), Retterer, K. (Kyle), Eichler, E.E. (Evan), Rosenfeld, J.A. (Jill), Agrawal, P.B. (Pankaj B.), Bézieau, S. (Stéphane), Odent, S. (Sylvie), Elgersma, Y. (Ype), and Mercier, S. (Sandra)

Abstract

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

Published
2017
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39. Mutations in TBL1X are associated with central hypothyroidism

Author

Heinen, C.A. (Charlotte A.), Losekoot, M. (Monique), Sun, Y. (Yu), Watson, P.J. (Peter J.), Fairall, L. (Louise), Joustra, S.D. (Sjoerd), Zwaveling-Soonawala, N. (Nitash), Oostdijk, W. (Wilma), Akker, E.L.T. (Erica) van den, Alders, M. (Mariëlle), Santen, G.W.E. (Gijs), Rijn, R.R. (Rick) van, Dreschler, W.A. (Wouter), Surovtseva, O.V. (Olga V.), Biermasz, N.R., Hennekam, R.C.M. (Raoul), Wit, J.M. (Jan), Schwabe, J.W.R. (John W.R.), Boelen, A. (Anita), Fliers, E. (Eric), Trotsenburg, A.S.P. (Paul) van, Heinen, C.A. (Charlotte A.), Losekoot, M. (Monique), Sun, Y. (Yu), Watson, P.J. (Peter J.), Fairall, L. (Louise), Joustra, S.D. (Sjoerd), Zwaveling-Soonawala, N. (Nitash), Oostdijk, W. (Wilma), Akker, E.L.T. (Erica) van den, Alders, M. (Mariëlle), Santen, G.W.E. (Gijs), Rijn, R.R. (Rick) van, Dreschler, W.A. (Wouter), Surovtseva, O.V. (Olga V.), Biermasz, N.R., Hennekam, R.C.M. (Raoul), Wit, J.M. (Jan), Schwabe, J.W.R. (John W.R.), Boelen, A. (Anita), Fliers, E. (Eric), and Trotsenburg, A.S.P. (Paul) van

Abstract

Context: Isolated congenital central hypothyroidism (CeH) can result from mutations in TRHR, TSHB, and IGSF1, but its etiology often remains unexplained. We identified a missense mutation in the transducin X-like protein 1, X-linked (TBL1X) gene in three relatives diagnosed with isolated CeH. TBL1X is part of the thyroid hormone receptor-corepressor complex. Objective: The objectives of the study were the identification of TBL1X mutations in patients with unexplained isolated CeH, Sanger sequencing of relatives of affected individuals, and clinical and biochemical characterization; in vitro investigation of functional consequences of mutations; and mRNA expression in, and immunostaining of, human hypothalami and pituitary glands. Design: This was an observational study. Setting: The study was conducted at university medical centers. Patients: Nineteen individuals with and seven without a mutation participated in the study. Main Outcome Measures: Outcome measures included sequencing results, clinical and biochemical characteristics of mutation carriers, and results of in vitro functional and expression studies. Results: Sanger sequencing yielded five additional mutations. All patients (n = 8; six males) were previously diagnosed with CeH (free T4 [FT4] concentration below the reference interval, normal thyrotropin). Eleven relatives (two males) also carried mutations. One female had CeH, whereas 10 others had low-normal FT4 concentrations. As a group, adult mutation carriers had 20%-25% lower FT4 concentrations than controls. Twelve of 19 evaluated carriers had hearing loss. Mutations are located in the highly conserved WD40-repeat domain of the protein, influencing its expression and thermal stability. TBL1X mRNA and protein are expressed in the human hypothalamus and pituitary. Conclusions: TBL1X mutations are associated with CeH and hearing loss. FT4 concentrations in mutation carriers vary from low-normal to values compatible with CeH.

Published
2016
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40. Next-generation sequencing-based genome diagnostics across clinical genetics centers: Implementation choices and their effects

Author

Vrijenhoek, T. (T.), Kraaijeveld, K. (Ken), Elferink, M.G. (Martin), Ligt, J. (Joep) de, Kranendonk, E. (Elcke), Santen, G.W.E. (Gijs), Nijman, I.J. (Isaac ), Butler, D. (Derek), Claes, G. (Godelieve), Costessi, A. (Adalberto), Dorlijn, W. (Wim), Van Eyndhoven, W. (Winfried), Halley, D.J.J. (Dicky), Van Den Hout, M.C.G.N. (Mirjam C.G.N.), Van Hove, S. (Steven), Johansson, L.F. (Lennart F.), Jongbloed, J.D.H. (Jan), Kamps, R. (Rick), Kockx, C. (Christel), De Koning, B. (Bart), Kriek, N. (Nadia), Lekanne Dit Deprez, R.H., Lunstroo, H. (Hans), Mannens, M.M.A.M. (Marcel), Mook, O. (Olaf), Nelen, M.R. (Marcel), Ploem, C. (Corrette), Rijnen, M. (Marco), Saris, J.J. (Jasper), Sinke, R.J. (Richard J), Sistermans, E. (Erik), Slegtenhorst, M.A. (Marjon) van, Sleutels, F. (Frank), Stoep, N. (Nienke) van der, Tienhoven, M. (Marianne) van, Vermaat, M. (Martijn), Vogel, M.J. (Maartje), Waisfisz, Q. (Quinten), Weiss, J.M. (Janneke), Wijngaard, A. (Arthur) van den, Workum, W. (W) van, Ijntema, H. (Helger), Zwaag, B. (Bert) van der, IJcken, W.F.J. (Wilfred) van, Dunnen, J.T. (Johan) den, Veltman, J.A. (Joris), Hennekam, R.C.M. (Raoul), Cuppen, E. (Edwin), Vrijenhoek, T. (T.), Kraaijeveld, K. (Ken), Elferink, M.G. (Martin), Ligt, J. (Joep) de, Kranendonk, E. (Elcke), Santen, G.W.E. (Gijs), Nijman, I.J. (Isaac ), Butler, D. (Derek), Claes, G. (Godelieve), Costessi, A. (Adalberto), Dorlijn, W. (Wim), Van Eyndhoven, W. (Winfried), Halley, D.J.J. (Dicky), Van Den Hout, M.C.G.N. (Mirjam C.G.N.), Van Hove, S. (Steven), Johansson, L.F. (Lennart F.), Jongbloed, J.D.H. (Jan), Kamps, R. (Rick), Kockx, C. (Christel), De Koning, B. (Bart), Kriek, N. (Nadia), Lekanne Dit Deprez, R.H., Lunstroo, H. (Hans), Mannens, M.M.A.M. (Marcel), Mook, O. (Olaf), Nelen, M.R. (Marcel), Ploem, C. (Corrette), Rijnen, M. (Marco), Saris, J.J. (Jasper), Sinke, R.J. (Richard J), Sistermans, E. (Erik), Slegtenhorst, M.A. (Marjon) van, Sleutels, F. (Frank), Stoep, N. (Nienke) van der, Tienhoven, M. (Marianne) van, Vermaat, M. (Martijn), Vogel, M.J. (Maartje), Waisfisz, Q. (Quinten), Weiss, J.M. (Janneke), Wijngaard, A. (Arthur) van den, Workum, W. (W) van, Ijntema, H. (Helger), Zwaag, B. (Bert) van der, IJcken, W.F.J. (Wilfred) van, Dunnen, J.T. (Johan) den, Veltman, J.A. (Joris), Hennekam, R.C.M. (Raoul), and Cuppen, E. (Edwin)

Abstract

Implementation of next-generation DNA sequencing (NGS) technology into routine diagnostic genome care requires strategic choices. Instead of theoretical discussions on the consequences of such choices, we compared NGS-based diagnostic practices in eight clinical genetic centers in the Netherlands, based on genetic testing of nine pre-selected patients with cardiomyopathy. We highlight critical implementation choices, including the specific contributions of laboratory and medical specialists, bioinformaticians and researchers to diagnostic genome care, and how these affect interpretation and reporting of variants. Reported pathogenic mutations were consistent for all but one patient. Of the two centers that were inconsistent in their diagnosis, one reported to have found 'no causal variant', thereby underdiagnosing this patient. The other provided an alternative diagnosis, identifying another variant as causal than the other centers. Ethical and legal analysis showed that informed consent procedures in all centers were generally adequate for diagnostic NGS applications that target a limited set of genes, but not for exome- and genome-based diagnosis. We propose changes to further improve and align these procedures, taking into account the blurring boundary between diagnostics and research, and specific counseling options for exome- and genome-based diagnostics. We conclude that alternative diagnoses may infer a certain level of 'greediness' to come to a positive diagnosis in interpreting sequencing results. Moreover, there is an increasing interdependence of clinic, diagnostics and research departments for comprehensive diagnostic genome care. Therefore, we invite clinical geneticists, physicians, researchers, bioinformatics experts and patients to reconsider their role and position in future diagnostic genome care.

Published
2015
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41. PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation-in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations

Author

Oostdijk, W. (Wilma), Idkowiak, J. (Jan), Mueller, J.W. (Jonathan W.), House, P.J. (Philip J.), Taylor, A.E. (A.), O'Reilly, M.W. (Michael W.), Hughes, B.A. (Beverly A.), Vries, M.C. (Martine) de, Kant, S.G. (Sarina), Santen, G.W.E. (Gijs), Verkerk, A., Uitterlinden, A.G. (André), Wit, J.M. (Jan), Losekoot, M. (Monique), Arlt, W. (Wiebke), Oostdijk, W. (Wilma), Idkowiak, J. (Jan), Mueller, J.W. (Jonathan W.), House, P.J. (Philip J.), Taylor, A.E. (A.), O'Reilly, M.W. (Michael W.), Hughes, B.A. (Beverly A.), Vries, M.C. (Martine) de, Kant, S.G. (Sarina), Santen, G.W.E. (Gijs), Verkerk, A., Uitterlinden, A.G. (André), Wit, J.M. (Jan), Losekoot, M. (Monique), and Arlt, W. (Wiebke)

Abstract

Copyright

Published
2015
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42. P24 Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signalling

Author

Sharpe, J.A., primary, Logan, C.V., additional, Szabadkai, G., additional, Parry, D.A., additional, Torelli, S., additional, Childs, A.-M., additional, Kriek, M., additional, Phadke, R., additional, Johnson, C.A., additional, Roberts, N.Y., additional, Bonthron, D.T., additional, Pysden, K.A., additional, Whyte, T., additional, Munteanu, I., additional, Foley, A.R., additional, Wheway, G., additional, Szymanska, K., additional, Natarajan, S., additional, Abdelhamed, Z.A., additional, Morgan, J.E., additional, Roper, H., additional, Santen, G.W.E., additional, Niks, E.H., additional, van der Pol, W.L., additional, Lindhout, D., additional, Raffaello, A., additional, De Stefani, D., additional, den Dunnen, J.T., additional, Sun, Y., additional, Ginjaar, I., additional, Sewry, C.A., additional, Hurles, M., additional, Rizzuto, R., additional, Duchen, M.R., additional, Muntoni, F., additional, and Sheridan, E., additional

Published
2014
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43. An activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities

Author

Hannema, S.E. (Sabine), Duyvenvoorde, H.A. (Hermine) van, Thomas, P. (Premsler), Yang, R.-B. (Ruey-Bing), Mueller, T.D. (Thomas), Gassner, I.J. (Ingrid), Oberwinkler, H. (Heike), Roelfsema, F. (Ferdinand), Santen, G.W.E. (Gijs), Prickett, T. (Timothy), Kant, S.G. (Sarina), Verkerk, A., Uitterlinden, A.G. (André), Espiner, E. (Eric), Ruivenkamp, C.A. (Claudia), Oostdijk, W. (Wilma), Pereira, A.M. (Alberto), Losekoot, M. (Monique), Kuhn, M. (Michael), Wit, J.M. (Jan), Hannema, S.E. (Sabine), Duyvenvoorde, H.A. (Hermine) van, Thomas, P. (Premsler), Yang, R.-B. (Ruey-Bing), Mueller, T.D. (Thomas), Gassner, I.J. (Ingrid), Oberwinkler, H. (Heike), Roelfsema, F. (Ferdinand), Santen, G.W.E. (Gijs), Prickett, T. (Timothy), Kant, S.G. (Sarina), Verkerk, A., Uitterlinden, A.G. (André), Espiner, E. (Eric), Ruivenkamp, C.A. (Claudia), Oostdijk, W. (Wilma), Pereira, A.M. (Alberto), Losekoot, M. (Monique), Kuhn, M. (Michael), and Wit, J.M. (Jan)

Abstract

Background: C-type natriuretic peptide (CNP)/natriuretic peptide receptor 2 (NPR2) signaling is essential for long bone growth. Enhanced CNP production caused by chromosomal translocations results in tall stature, a Marfanoid phenotype, and skeletal abnormalities.Asimilar phenotype was described in a family with an activating NPR2 mutation within the guanylyl cyclase domain. Case: Here we describe an extremely tall male without skeletal deformities, with a novel NPR2 mutation (p.Arg655Cys) located in the kinase homology domain. Objectives: The objective of the study was to investigate the functional and structural effects of the NPR2 mutation. Methods: Guanylyl cyclase activities of wild-type vs mutant NPR2 were analyzed in transfected human embryonic kidney 293 cells and in skin fibroblasts. The former were also used to study possible interactions between both isoforms. Homology modeling was performed to understand the molecular impact of the mutation. Results: CNP-stimulated cGMP production by the mutant NPR2 was markedly increased in patient skin fibroblasts and transfected human embryonic kidney 293 cells. The stimulatory effects of ATP on CNP-dependent guanylyl cyclase activity were augmented, suggesting that this novel mutation enhances both the responsiveness of NPR2 to CNP and its allosteric modulation/stabilization by ATP. Coimmunoprecipitation showed that wild-type and mutant NPR2 can form stable heterodimers, suggesting a dominant-positive effect. In accordance with augmented endogenous receptor activity, plasma N-terminal pro-CNP (a marker of CNP production in tissues) was reduced in the proband. Conclusions:Wereport the first activating mutation within the kinase homology domain of NPR2, resulting in extremely tall stature. Our observations emphasize the important role of this domain in the regulation of guanylyl cyclase activity and bone growth in response to CNP.

Published
2013
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44. G.P.91 A new syndrome characterized by demyelinating neuropathy and hydrocephalus caused by a heterozygous mutation in one of the aminoacyl-tRNA synthetase genes

Author

Niks, E.H., primary, Potjer, T.P., additional, Al Momani, R., additional, Sun, Y., additional, Koot, R.W., additional, van Dijk, J.G., additional, Haring, D.A.J., additional, Aten, E., additional, Kriek, M., additional, Santen, G.W.E., additional, and Lesnik Oberstein, S.A.M., additional

Published
2012
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45. Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders

Author

Michael A. Levy, Raissa Relator, Haley McConkey, Erinija Pranckeviciene, Jennifer Kerkhof, Mouna Barat‐Houari, Sara Bargiacchi, Elisa Biamino, María Palomares Bralo, Gerarda Cappuccio, Andrea Ciolfi, Angus Clarke, Barbara R. DuPont, Mariet W. Elting, Laurence Faivre, Timothy Fee, Marco Ferilli, Robin S. Fletcher, Florian Cherick, Aidin Foroutan, Michael J. Friez, Cristina Gervasini, Sadegheh Haghshenas, Benjamin A. Hilton, Zandra Jenkins, Simranpreet Kaur, Suzanne Lewis, Raymond J. Louie, Silvia Maitz, Donatella Milani, Angela T. Morgan, Renske Oegema, Elsebet Østergaard, Nathalie R. Pallares, Maria Piccione, Astrid S. Plomp, Cathryn Poulton, Jack Reilly, Rocio Rius, Stephen Robertson, Kathleen Rooney, Justine Rousseau, Gijs W. E. Santen, Fernando Santos‐Simarro, Josephine Schijns, Gabriella M. Squeo, Miya St John, Christel Thauvin‐Robinet, Giovanna Traficante, Pleuntje J. van der Sluijs, Samantha A. Vergano, Niels Vos, Kellie K. Walden, Dimitar Azmanov, Tugce B. Balci, Siddharth Banka, Jozef Gecz, Peter Henneman, Jennifer A. Lee, Marcel M. A. M. Mannens, Tony Roscioli, Victoria Siu, David J. Amor, Gareth Baynam, Eric G. Bend, Kym Boycott, Nicola Brunetti‐Pierri, Philippe M. Campeau, Dominique Campion, John Christodoulou, David Dyment, Natacha Esber, Jill A. Fahrner, Mark D. Fleming, David Genevieve, Delphine Heron, Thomas Husson, Kristin D. Kernohan, Alisdair McNeill, Leonie A. Menke, Giuseppe Merla, Paolo Prontera, Cheryl Rockman‐Greenberg, Charles Schwartz, Steven A. Skinner, Roger E. Stevenson, Marie Vincent, Antonio Vitobello, Marco Tartaglia, Marielle Alders, Matthew L. Tedder, Bekim Sadikovic, Human genetics, Amsterdam Reproduction & Development (AR&D), Pediatrics, Levy M.A., Relator R., McConkey H., Pranckeviciene E., Kerkhof J., Barat-Houari M., Bargiacchi S., Biamino E., Palomares Bralo M., Cappuccio G., Ciolfi A., Clarke A., DuPont B.R., Elting M.W., Faivre L., Fee T., Ferilli M., Fletcher R.S., Cherick F., Foroutan A., Friez M.J., Gervasini C., Haghshenas S., Hilton B.A., Jenkins Z., Kaur S., Lewis S., Louie R.J., Maitz S., Milani D., Morgan A.T., Oegema R., Ostergaard E., Pallares N.R., Piccione M., Plomp A.S., Poulton C., Reilly J., Rius R., Robertson S., Rooney K., Rousseau J., Santen G.W.E., Santos-Simarro F., Schijns J., Squeo G.M., John M.S., Thauvin-Robinet C., Traficante G., van der Sluijs P.J., Vergano S.A., Vos N., Walden K.K., Azmanov D., Balci T.B., Banka S., Gecz J., Henneman P., Lee J.A., Mannens M.M.A.M., Roscioli T., Siu V., Amor D.J., Baynam G., Bend E.G., Boycott K., Brunetti-Pierri N., Campeau P.M., Campion D., Christodoulou J., Dyment D., Esber N., Fahrner J.A., Fleming M.D., Genevieve D., Heron D., Husson T., Kernohan K.D., McNeill A., Menke L.A., Merla G., Prontera P., Rockman-Greenberg C., Schwartz C., Skinner S.A., Stevenson R.E., Vincent M., Vitobello A., Tartaglia M., Alders M., Tedder M.L., Sadikovic B., Levy, Michael A, Relator, Raissa, Mcconkey, Haley, Pranckeviciene, Erinija, Kerkhof, Jennifer, Barat-Houari, Mouna, Bargiacchi, Sara, Biamino, Elisa, Bralo, María Palomare, Cappuccio, Gerarda, Ciolfi, Andrea, Clarke, Angu, Dupont, Barbara R, Elting, Mariet W, Faivre, Laurence, Fee, Timothy, Ferilli, Marco, Fletcher, Robin S, Cherick, Florian, Foroutan, Aidin, Friez, Michael J, Gervasini, Cristina, Haghshenas, Sadegheh, Hilton, Benjamin A, Jenkins, Zandra, Kaur, Simranpreet, Lewis, Suzanne, Louie, Raymond J, Maitz, Silvia, Milani, Donatella, Morgan, Angela T, Oegema, Renske, Østergaard, Elsebet, Pallares, Nathalie Ruiz, Piccione, Maria, Plomp, Astrid S, Poulton, Cathryn, Reilly, Jack, Rius, Rocio, Robertson, Stephen, Rooney, Kathleen, Rousseau, Justine, Santen, Gijs W E, Santos-Simarro, Fernando, Schijns, Josephine, Squeo, Gabriella Maria, John, Miya St, Thauvin-Robinet, Christel, Traficante, Giovanna, van der Sluijs, Pleuntje J, Vergano, Samantha A, Vos, Niel, Walden, Kellie K, Azmanov, Dimitar, Balci, Tugce B, Banka, Siddharth, Gecz, Jozef, Henneman, Peter, Lee, Jennifer A, Mannens, Marcel M A M, Roscioli, Tony, Siu, Victoria, Amor, David J, Baynam, Gareth, Bend, Eric G, Boycott, Kym, Brunetti-Pierri, Nicola, Campeau, Philippe M, Campion, Dominique, Christodoulou, John, Dyment, David, Esber, Natacha, Fahrner, Jill A, Fleming, Mark D, Genevieve, David, Heron, Delphine, Husson, Thoma, Kernohan, Kristin D, Mcneill, Alisdair, Menke, Leonie A, Merla, Giuseppe, Prontera, Paolo, Rockman-Greenberg, Cheryl, Schwartz, Charle, Skinner, Steven A, Stevenson, Roger E, Vincent, Marie, Vitobello, Antonio, Tartaglia, Marco, Alders, Marielle, Tedder, Matthew L, Sadikovic, Bekim, Human Genetics, General Paediatrics, Graduate School, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ARD - Amsterdam Reproduction and Development, ANS - Cellular & Molecular Mechanisms, ANS - Complex Trait Genetics, and ACS - Pulmonary hypertension & thrombosis

Subjects
DNA methylation, clinical diagnostics, Syndrome, DNA methylation, clinical diagnostics, episignatures, neurodevelopmental syndromes, neurodevelopmental syndromes, Epigenesis, Genetic, Neurodevelopmental Disorders, Genetics, Humans, CpG Islands, DNA, Intergenic, episignatures, Episignature, Genetics (clinical)
Abstract

An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes which can share significant overlap amongst different conditions. In this study we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders. This article is protected by copyright. All rights reserved.

Published
2022
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