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Two patients with intellectual disability, overlapping facial features, and overlapping deletions in 6p25.1p24.3

Bart C.W. Kuipers, Anneke T. Vulto-van Silfhout, Carlo Marcelis, Rolph Pfundt, Nicole de Leeuw, Bert B.A. de Vries
2013 Clinical Dysmorphology  
The clinical and molecular characterizations of two patients with a 1.4 Mb overlapping deletion in the 6p25.1p24.3 region are reported. In addition to the mild intellectual disability, they shared feeding problems in infancy and several dysmorphic facial features including a prominent forehead, almond-shaped eyes, a short philtrum, and low-set ears with square helices. The overlapping deleted region harbors six genes (RREB1, NRN1, CAGE1, LY86, SSR1, and F13A1), of which NRN1 and RREB1 are
more » ... ered as candidate genes for the intellectual disability and the overlapping dysmorphism, respectively.
doi:10.1097/mcd.0b013e32835b6e39 pmid:23183317 fatcat:a3tgtb3hafh2zc24qrmwojjeh4

1 in 38 individuals at risk of a dominant medically actionable disease

Lonneke Haer-Wigman, Vyne van der Schoot, Ilse Feenstra, Anneke T. Vulto-van Silfhout, Christian Gilissen, Han G. Brunner, Lisenka E. L. M. Vissers, Helger G. Yntema
2018 European Journal of Human Genetics  
Clinical genomic sequencing can identify pathogenic variants unrelated to the initial clinical question, but of medical relevance to the patients and their families. With ongoing discussions on the utility of disclosing or searching for such variants, it is of crucial importance to obtain unbiased insight in the prevalence of these incidental or secondary findings, in order to better weigh potential risks and benefits. Previous studies have reported a broad range of secondary findings ranging
more » ... om 1 to 9%, merely attributable to differences in study design, cohorts tested, sequence technology used and genes analyzed. Here, we analyzed WES data of 1640 anonymized healthy Dutch individuals to establish the frequency of medically actionable disease alleles in an outbred population of European descent. Our study shows that 1 in 38 healthy individuals (2.7%) has a (likely) pathogenic variant in one of 59 medically actionable dominant disease genes for which the American College of Medical Genetics and Genomics (ACMG) recommends disclosure. Additionally, we identified 36 individuals (2.2%) to be a carrier of a recessive pathogenic disease allele. Whereas these frequencies of secondary findings are in line with what has been reported in the East-Asian population, the pathogenic variants are differently distributed across the 59 ACMG genes. Our results contribute to the debate on genetic risk factor screening in healthy individuals and the discussion whether the potential benefits of this knowledge and related preventive options, outweigh the risk of the emotional impact of the test result and possible stigmatization.
doi:10.1038/s41431-018-0284-2 pmid:30291343 pmcid:PMC6336841 fatcat:vn3ahidzs5fzrouv3ixeywaidy

Mutations in MED12 Cause X-Linked Ohdo Syndrome

Anneke T. Vulto-van Silfhout, Bert B.A. de Vries, Bregje W.M. van Bon, Alexander Hoischen, Martina Ruiterkamp-Versteeg, Christian Gilissen, Fangjian Gao, Marloes van Zwam, Cornelis L. Harteveld, Anthonie J. van Essen, Ben C.J. Hamel, Tjitske Kleefstra (+6 others)
2013 American Journal of Human Genetics  
Asterisks denote statistically significant differences compared to WT FLAG-MED12 (Student's t test, *p < 0.05, **p < 0.01).  ...  No statistically significant differences in expression levels were observed (Student's t test; p values are given above the bars).  ... 
doi:10.1016/j.ajhg.2013.01.007 pmid:23395478 pmcid:PMC3591845 fatcat:sntgwsdqu5bdhciwktiky5ldqe

Pierpont syndrome: A collaborative study

Emma M.M. Burkitt Wright, Mohnish Suri, Susan M. White, Nicole de Leeuw, Anneke T. Vulto-van Silfhout, Fiona Stewart, Shane McKee, Sahar Mansour, Fiona C Connell, Maya Chopra, Edwin P. Kirk, Koen Devriendt (+3 others)
2011 American Journal of Medical Genetics. Part A  
doi:10.1002/ajmg.a.34147 pmid:21834056 pmcid:PMC4495254 fatcat:yckhl6ttvfdstaumnrnvl5srwe

Yunis-Varón Syndrome Is Caused by Mutations in FIG4, Encoding a Phosphoinositide Phosphatase

Philippe M. Campeau, Guy M. Lenk, James T. Lu, Yangjin Bae, Lindsay Burrage, Peter Turnpenny, Jorge Román Corona-Rivera, Lucia Morandi, Marina Mora, Heiko Reutter, Anneke T. Vulto-van Silfhout, Laurence Faivre (+4 others)
2013 American Journal of Human Genetics  
Protein-interaction do- main, blue; catalytic domain, yellow; P loop containing the catalytic CX 5 R(T/S) motif, orange.  ...  Above, YVS; below, CMT4J. 26 Protein-interaction domain, blue; catalytic domain, yellow; P loop containing the catalytic CX 5 R(T/S) motif, orange.  ... 
doi:10.1016/j.ajhg.2013.03.020 pmid:23623387 pmcid:PMC3644641 fatcat:ycpxvqsajrgw7b6vascszzaygu

DVL1 Frameshift Mutations Clustering in the Penultimate Exon Cause Autosomal-Dominant Robinow Syndrome

Janson White, Juliana F. Mazzeu, Alexander Hoischen, Shalini N. Jhangiani, Tomasz Gambin, Michele Calijorne Alcino, Samantha Penney, Jorge M. Saraiva, Hanne Hove, Flemming Skovby, Hülya Kayserili, Elicia Estrella (+9 others)
2015 American Journal of Human Genetics  
Robinow syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non-canonical signaling gene WNT5A underlie a subset of autosomal-dominant Robinow syndrome (DRS) cases, but most individuals with DRS remain without a molecular diagnosis. We performed whole-exome sequencing in four
more » ... unrelated DRS-affected individuals without coding mutations in WNT5A and found heterozygous DVL1 exon 14 mutations in three of them. Targeted Sanger sequencing in additional subjects with DRS uncovered DVL1 exon 14 mutations in five individuals, including a pair of monozygotic twins. In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1. In five families in which samples from unaffected parents were available, the variants were demonstrated to represent de novo mutations. All variant alleles are predicted to result in a premature termination codon within the last exon, escape nonsense-mediated decay (NMD), and most likely generate a C-terminally truncated protein with a distinct À1 reading-frame terminus. Study of the transcripts extracted from affected subjects' leukocytes confirmed expression of both wild-type and variant alleles, supporting the hypothesis that mutant mRNA escapes NMD. Genomic variants identified in our study suggest that truncation of the C-terminal domain of DVL1, a protein hypothesized to have a downstream role in the Wnt-5a non-canonical pathway, is a common cause of DRS.
doi:10.1016/j.ajhg.2015.02.015 pmid:25817016 pmcid:PMC4385180 fatcat:5wnmpxhgubhyfmuesroqst76pq

A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP

Céline Helsmoortel, Anneke T Vulto-van Silfhout, Bradley P Coe, Geert Vandeweyer, Liesbeth Rooms, Jenneke van den Ende, Janneke H M Schuurs-Hoeijmakers, Carlo L Marcelis, Marjolein H Willemsen, Lisenka E L M Vissers, Helger G Yntema, Madhura Bakshi (+13 others)
2014 Nature Genetics  
Whole-exome sequencing (WES) Patient 1 was detected in a family-based WES study (unpublished data (CH, GV, Filip Van Nieuwerburg, NVdA, RFK)).  ... 
doi:10.1038/ng.2899 pmid:24531329 pmcid:PMC3990853 fatcat:erv27ocuireelf5clvdffzauby

Homozygous SLC6A17 Mutations Cause Autosomal-Recessive Intellectual Disability with Progressive Tremor, Speech Impairment, and Behavioral Problems

Zafar Iqbal, Marjolein H. Willemsen, Marie-Amélie Papon, Luciana Musante, Marco Benevento, Hao Hu, Hanka Venselaar, Willemijn M. Wissink-Lindhout, Anneke T. Vulto-van Silfhout, Lisenka E.L.M. Vissers, Arjan P.M. de Brouwer, Sylviane Marouillat (+8 others)
2015 American Journal of Human Genetics  
We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of
more » ... l amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses.
doi:10.1016/j.ajhg.2015.01.010 pmid:25704603 pmcid:PMC4375531 fatcat:aev43jzmr5ckrntp3b22bv2ijm

Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency

Joe C H Sim, Susan M White, Elizabeth Fitzpatrick, Gabrielle R Wilson, Greta Gillies, Kate Pope, Hayley S Mountford, Pernille M Torring, Shane McKee, Anneke T Vulto-van Silfhout, Shalini N Jhangiani, Donna M Muzny (+4 others)
2014 Orphanet Journal of Rare Diseases  
The de novo heterozygous ARID1B mutation NM_020732.3(ARID1B):c.294 1C > T (p.  ...  T-Test was used to investigate the difference in relative ARID1B expression between samples. Each experiment was independently performed at least three times.  ... 
doi:10.1186/1750-1172-9-43 pmid:24674232 pmcid:PMC4022252 fatcat:ddjak6tcorffpmiek67q742jly

Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development

Raphael Bernier, Christelle Golzio, Bo Xiong, Holly A. Stessman, Bradley P. Coe, Osnat Penn, Kali Witherspoon, Jennifer Gerdts, Carl Baker, Anneke T. Vulto-van Silfhout, Janneke H. Schuurs-Hoeijmakers, Marco Fichera (+22 others)
2014 Cell  
., not significant; *p < 0.05; **p < 0.001; ***p < 0.0001 (Student's t test). Data are represented as mean ± SEM. See also Figures S4 and S5 .  ...  Cortical samples are organized in columns by lobe (f, frontal; p, parietal; t, temporal; o, occipital) and in rows by layer from basal to apical surfaces of the developing neocortex (SG, suprageniculate  ... 
doi:10.1016/j.cell.2014.06.017 pmid:24998929 pmcid:PMC4136921 fatcat:lcspkktohvdylg4gll7mm3qnre

Mutations in DDHD2, Encoding an Intracellular Phospholipase A1, Cause a Recessive Form of Complex Hereditary Spastic Paraplegia

Janneke H.M. Schuurs-Hoeijmakers, Michael T. Geraghty, Erik-Jan Kamsteeg, Salma Ben-Salem, Susanne T. de Bot, Bonnie Nijhof, Ilse I.G.M. van de Vondervoort, Marinette van der Graaf, Anna Castells Nobau, Irene Otte-Höller, Sascha Vermeer, Amanda C. Smith (+28 others)
2012 American Journal of Human Genetics  
(C) Consanguineous family 3 has seven affected individuals and homozygous mutation c.1546C>T (p.Arg516*).  ...  This homozygous C-to-T substitution in exon 9 at c.859 introduces a PTC at amino acid position 287 of the protein (family 4, Figure 1D ).  ... 
doi:10.1016/j.ajhg.2012.10.017 pmid:23176823 pmcid:PMC3516595 fatcat:26b4v6guunehrdw56bolxouwtq

Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features

Valter Tucci, Tjitske Kleefstra, Andrea Hardy, Ines Heise, Silvia Maggi, Marjolein H. Willemsen, Helen Hilton, Chris Esapa, Michelle Simon, Maria-Teresa Buenavista, Liam J. McGuffin, Lucie Vizor (+24 others)
2014 Journal of Clinical Investigation  
We would like to thank all patients and their relatives for their participation in these studies and Willemijn Wissink-Lindhout, Saskia van der Velde-Visser, Gaby van de Ven-Schobers, and Marga Schepens  ...  Tucci), and grants from the Consortium "Stronger on your own feet" (to T. Kleefstra and M.H. Willemsen), the Netherlands Organization for Health Research and Development (ZonMw) (907-00-365 to T.  ...  Statistical significance was determined using unpaired Student's t test (GraphPad Prism 5.0).  ... 
doi:10.1172/jci70372 pmid:24614104 pmcid:PMC3973091 fatcat:mrbvshcojve6tkf5eocuc5ucay

De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

Illja J. Diets, Roos van der Donk, Kristina Baltrunaite, Esmé Waanders, Margot R.F. Reijnders, Alexander J.M. Dingemans, Rolph Pfundt, Anneke T. Vulto-van Silfhout, Laurens Wiel, Christian Gilissen, Julien Thevenon, Laurence Perrin (+26 others)
2019 American Journal of Human Genetics  
p.Arg45* de novo 0 4.08 38 NA NA NA 2 c.277G>T p.Glu93* maternal 0 4.00 35 NA NA NA 3 b c.277G>T p.Glu93* ND 0 4.00 35 NA NA NA 4 c.349T>C p.Trp117Arg de novo 0 3.35  ...  To determine whether a facial gestalt is present in individuals with a variant in KDM3B, we used a hybrid model recently developed and described by van der Donk et al. 20 This hybrid model combines the  ... 
doi:10.1016/j.ajhg.2019.02.023 pmid:30929739 pmcid:PMC6451728 fatcat:woon44gpdbfwvcba5hzmlp3bde

Variants inCUL4Bare Associated with Cerebral Malformations

Anneke T. Vulto-van Silfhout, Tadashi Nakagawa, Nadia Bahi-Buisson, Stefan A. Haas, Hao Hu, Melanie Bienek, Lisenka E.L.M. Vissers, Christian Gilissen, Andreas Tzschach, Andreas Busche, Jörg Müsebeck, Patrick Rump (+33 others)
2014 Human Mutation  
For c.1906+1G>T, the MAXENT score was reduced from 8.60 to 0.10 and the NNSPLICE donor site prediction score from 0.92 to zero.  ...  Impaired chromatin remodeling, more specifically also increased H3K4 methylation, is a common mechanism underlying ID [van Bokhoven, 2011], for example, in patients with KDM5C variants [Iwase et al.,  ... 
doi:10.1002/humu.22718 pmid:25385192 pmcid:PMC4608231 fatcat:77xtlglz5zclfobxwqxi7w7lum

Mutations Affecting the SAND Domain of DEAF1 Cause Intellectual Disability with Severe Speech Impairment and Behavioral Problems

Anneke T. Vulto-van Silfhout, Shivakumar Rajamanickam, Philip J. Jensik, Sarah Vergult, Nina de Rocker, Kathryn J. Newhall, Ramya Raghavan, Sara N. Reardon, Kelsey Jarrett, Tara McIntyre, Joseph Bulinski, Stacy L. Ownby (+24 others)
2015 American Journal of Human Genetics  
Late in the review process, an additional SCN2A mutation (c.1570C > T [p.Arg524*]) leading to a truncating allele was identified in one of the four subjects (individual 3) and was added to Table 1 .  ... 
doi:10.1016/j.ajhg.2014.12.019 fatcat:ywftfik6yvakdgrrjsykwhvwk4
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