Publications by authors named "Bregje W van Bon"

62 Publications

Clinical delineation of SETBP1 haploinsufficiency disorder.

Eur J Hum Genet 2021 Apr 19. Epub 2021 Apr 19.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

SETBP1 haploinsufficiency disorder (MIM#616078) is caused by haploinsufficiency of SETBP1 on chromosome 18q12.3, but there has not yet been any systematic evaluation of the major features of this monogenic syndrome, assessing penetrance and expressivity. We describe the first comprehensive study to delineate the associated clinical phenotype, with findings from 34 individuals, including 24 novel cases, all of whom have a SETBP1 loss-of-function variant or single (coding) gene deletion, confirmed by molecular diagnostics. The most commonly reported clinical features included mild motor developmental delay, speech impairment, intellectual disability, hypotonia, vision impairment, attention/concentration deficits, and hyperactivity. Although there is a mild overlap in certain facial features, the disorder does not lead to a distinctive recognizable facial gestalt. As well as providing insight into the clinical spectrum of SETBP1 haploinsufficiency disorder, this reports puts forward care recommendations for patient management.
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http://dx.doi.org/10.1038/s41431-021-00888-9DOI Listing
April 2021

SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.

Authors:
Francesca Clementina Radio Kaifang Pang Andrea Ciolfi Michael A Levy Andrés Hernández-García Lucia Pedace Francesca Pantaleoni Zhandong Liu Elke de Boer Adam Jackson Alessandro Bruselles Haley McConkey Emilia Stellacci Stefania Lo Cicero Marialetizia Motta Rosalba Carrozzo Maria Lisa Dentici Kirsty McWalter Megha Desai Kristin G Monaghan Aida Telegrafi Christophe Philippe Antonio Vitobello Margaret Au Katheryn Grand Pedro A Sanchez-Lara Joanne Baez Kristin Lindstrom Peggy Kulch Jessica Sebastian Suneeta Madan-Khetarpal Chelsea Roadhouse Jennifer J MacKenzie Berrin Monteleone Carol J Saunders July K Jean Cuevas Laura Cross Dihong Zhou Taila Hartley Sarah L Sawyer Fabíola Paoli Monteiro Tania Vertemati Secches Fernando Kok Laura E Schultz-Rogers Erica L Macke Eva Morava Eric W Klee Jennifer Kemppainen Maria Iascone Angelo Selicorni Romano Tenconi David J Amor Lynn Pais Lyndon Gallacher Peter D Turnpenny Karen Stals Sian Ellard Sara Cabet Gaetan Lesca Joset Pascal Katharina Steindl Sarit Ravid Karin Weiss Alison M R Castle Melissa T Carter Louisa Kalsner Bert B A de Vries Bregje W van Bon Marijke R Wevers Rolph Pfundt Alexander P A Stegmann Bronwyn Kerr Helen M Kingston Kate E Chandler Willow Sheehan Abdallah F Elias Deepali N Shinde Meghan C Towne Nathaniel H Robin Dana Goodloe Adeline Vanderver Omar Sherbini Krista Bluske R Tanner Hagelstrom Caterina Zanus Flavio Faletra Luciana Musante Evangeline C Kurtz-Nelson Rachel K Earl Britt-Marie Anderlid Gilles Morin Marjon van Slegtenhorst Karin E M Diderich Alice S Brooks Joost Gribnau Ruben G Boers Teresa Robert Finestra Lauren B Carter Anita Rauch Paolo Gasparini Kym M Boycott Tahsin Stefan Barakat John M Graham Laurence Faivre Siddharth Banka Tianyun Wang Evan E Eichler Manuela Priolo Bruno Dallapiccola Lisenka E L M Vissers Bekim Sadikovic Daryl A Scott Jimmy Lloyd Holder Marco Tartaglia

Am J Hum Genet 2021 03 16;108(3):502-516. Epub 2021 Feb 16.

Genetics and Rare Disease Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address:

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008487PMC
March 2021

Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders.

Nat Commun 2019 10 15;10(1):4679. Epub 2019 Oct 15.

Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USA.

Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.
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http://dx.doi.org/10.1038/s41467-019-12435-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794285PMC
October 2019

Deleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder.

Am J Hum Genet 2019 04 14;104(4):701-708. Epub 2019 Mar 14.

HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA. Electronic address:

Developmental delay and intellectual disability (DD and ID) are heterogeneous phenotypes that arise in many rare monogenic disorders. Because of this rarity, developing cohorts with enough individuals to robustly identify disease-associated genes is challenging. Social-media platforms that facilitate data sharing among sequencing labs can help to address this challenge. Through one such tool, GeneMatcher, we identified nine DD- and/or ID-affected probands with a rare, heterozygous variant in the gene encoding the serine/threonine-protein kinase BRSK2. All probands have a speech delay, and most present with intellectual disability, motor delay, behavioral issues, and autism. Six of the nine variants are predicted to result in loss of function, and computational modeling predicts that the remaining three missense variants are damaging to BRSK2 structure and function. All nine variants are absent from large variant databases, and BRSK2 is, in general, relatively intolerant to protein-altering variation among humans. In all six probands for whom parents were available, the mutations were found to have arisen de novo. Five of these de novo variants were from cohorts with at least 400 sequenced probands; collectively, the cohorts span 3,429 probands, and the observed rate of de novo variation in these cohorts is significantly higher than the estimated background-mutation rate (p = 2.46 × 10). We also find that exome sequencing provides lower coverage and appears less sensitive to rare variation in BRSK2 than does genome sequencing; this fact most likely reduces BRSK2's visibility in many clinical and research sequencing efforts. Altogether, our results implicate damaging variation in BRSK2 as a source of neurodevelopmental disease.
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http://dx.doi.org/10.1016/j.ajhg.2019.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451696PMC
April 2019

Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations.

Neuron 2018 12 15;100(6):1354-1368.e5. Epub 2018 Nov 15.

Research Institute of Molecular Pathology, Campus Vienna Biocenter 1, Vienna Biocenter (VBC), Vienna 1030, Austria. Electronic address:

Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule-associated protein that is predominantly expressed in post-mitotic neurons and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions, we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant-negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.
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http://dx.doi.org/10.1016/j.neuron.2018.10.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436622PMC
December 2018

The intellectual disability-associated CAMK2G p.Arg292Pro mutation acts as a pathogenic gain-of-function.

Hum Mutat 2018 12 19;39(12):2008-2024. Epub 2018 Sep 19.

Department of Neuroscience, Erasmus University Medical Center, Rotterdam, the Netherlands.

The abundantly expressed calcium/calmodulin-dependent protein kinase II (CAMK2), alpha (CAMK2A), and beta (CAMK2B) isoforms are essential for learning and memory formation. Recently, a de novo candidate mutation (p.Arg292Pro) in the gamma isoform of CAMK2 (CAMK2G) was identified in a patient with severe intellectual disability (ID), but the mechanism(s) by which this mutation causes ID is unknown. Here, we identified a second, unrelated individual, with a de novo CAMK2G p.Arg292Pro mutation, and used in vivo and in vitro assays to assess the impact of this mutation on CAMK2G and neuronal function. We found that knockdown of CAMK2G results in inappropriate precocious neuronal maturation. We further found that the CAMK2G p.Arg292Pro mutation acts as a highly pathogenic gain-of-function mutation, leading to increased phosphotransferase activity and impaired neuronal maturation as well as impaired targeting of the nuclear CAMK2G isoform. Silencing the catalytic site of the CAMK2G p.Arg292Pro protein reversed the pathogenic effect of the p.Arg292Pro mutation on neuronal maturation, without rescuing its nuclear targeting. Taken together, our results reveal an indispensable function of CAMK2G in neurodevelopment and indicate that the CAMK2G p.Arg292Pro protein acts as a pathogenic gain-of-function mutation, through constitutive activity toward cytosolic targets, rather than impaired targeting to the nucleus.
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http://dx.doi.org/10.1002/humu.23647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240363PMC
December 2018

Analysis of 182 cerebral palsy transcriptomes points to dysregulation of trophic signalling pathways and overlap with autism.

Transl Psychiatry 2018 04 23;8(1):88. Epub 2018 Apr 23.

Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.

Cerebral palsy (CP) is the most common motor disability of childhood. It is characterised by permanent, non-progressive but not unchanging problems with movement, posture and motor function, with a highly heterogeneous clinical spectrum and frequent neurodevelopmental comorbidities. The aetiology of CP is poorly understood, despite recent reports of a genetic contribution in some cases. Here we demonstrate transcriptional dysregulation of trophic signalling pathways in patient-derived cell lines from an unselected cohort of 182 CP-affected individuals using both differential expression analysis and weighted gene co-expression network analysis (WGCNA). We also show that genes differentially expressed in CP, as well as network modules significantly correlated with CP status, are enriched for genes associated with ASD. Combining transcriptome and whole exome sequencing (WES) data for this CP cohort likely resolves an additional 5% of cases separated to the 14% we have previously reported as resolved by WES. Collectively, these results support a convergent molecular abnormality in CP and ASD.
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http://dx.doi.org/10.1038/s41398-018-0136-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911435PMC
April 2018

WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.

Am J Hum Genet 2018 01 21;102(1):27-43. Epub 2017 Dec 21.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX 77030, USA. Electronic address:

Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, ∼70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered -1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.
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http://dx.doi.org/10.1016/j.ajhg.2017.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777383PMC
January 2018

A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency.

Eur J Hum Genet 2018 01 5;26(1):54-63. Epub 2017 Dec 5.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Genotype-first combined with reverse phenotyping has shown to be a powerful tool in human genetics, especially in the era of next generation sequencing. This combines the identification of individuals with mutations in the same gene and linking these to consistent (endo)phenotypes to establish disease causality. We have performed a MIP (molecular inversion probe)-based targeted re-sequencing study in 3,275 individuals with intellectual disability (ID) to facilitate a genotype-first approach for 24 genes previously implicated in ID.Combining our data with data from a publicly available database, we confirmed 11 of these 24 genes to be relevant for ID. Amongst these, PHIP was shown to have an enrichment of disruptive mutations in the individuals with ID (5 out of 3,275). Through international collaboration, we identified a total of 23 individuals with PHIP mutations and elucidated the associated phenotype. Remarkably, all 23 individuals had developmental delay/ID and the majority were overweight or obese. Other features comprised behavioral problems (hyperactivity, aggression, features of autism and/or mood disorder) and dysmorphisms (full eyebrows and/or synophrys, upturned nose, large ears and tapering fingers). Interestingly, PHIP encodes two protein-isoforms, PHIP/DCAF14 and NDRP, each involved in neurodevelopmental processes, including E3 ubiquitination and neuronal differentiation. Detailed genotype-phenotype analysis points towards haploinsufficiency of PHIP/DCAF14, and not NDRP, as the underlying cause of the phenotype.Thus, we demonstrated the use of large scale re-sequencing by MIPs, followed by reverse phenotyping, as a constructive approach to verify candidate disease genes and identify novel syndromes, highlighted by PHIP haploinsufficiency causing an ID-overweight syndrome.
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http://dx.doi.org/10.1038/s41431-017-0039-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839042PMC
January 2018

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

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

Am J Hum Genet 2017 Nov;101(5):768-788

CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes Cedex 1, France.

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.
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http://dx.doi.org/10.1016/j.ajhg.2017.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673671PMC
November 2017

Expanding the clinical spectrum of recessive truncating mutations of to a Bohring-Opitz-like phenotype.

J Med Genet 2017 12 26;54(12):830-835. Epub 2017 Oct 26.

Inserm UMR 1231 GAD Team, Genetics of Developmental Anomalies, Université de Bourgogne-Franche Comté, Dijon, France.

Background: Bohring-Opitz syndrome (BOS) is a rare genetic disorder characterised by a recognisable craniofacial appearance and a typical 'BOS' posture. BOS is caused by sporadic mutations of. However, several typical patients with BOS have no molecular diagnosis, suggesting clinical and genetic heterogeneity.

Objectives: To expand the phenotypical spectrum of autosomal recessive variants of , reported as causing Crisponi syndrome/cold-induced sweating syndrome type 1 (CS/CISS1)-like syndrome.

Methods: We performed whole-exome sequencing in two families with a suspected recessive mode of inheritance. We used the Matchmaker Exchange initiative to identify additional patients.

Results: Here, we report six patients with microcephaly, facial dysmorphism, including exophthalmos, nevus flammeus of the glabella and joint contractures with a suspected BOS posture in five out of six patients. We identified autosomal recessive truncating mutations in the gene. encodes a BTB-kelch protein implicated in the cell cycle and in protein degradation by the ubiquitin-proteasome pathway. Recently, biallelic mutations in the gene were reported in four families and associated with CS/CISS1, characterised by clinical features overlapping with our patients.

Conclusion: We have expanded the clinical spectrum of autosomal recessive variants by describing a syndrome with features overlapping CS/CISS1 and BOS.
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http://dx.doi.org/10.1136/jmedgenet-2017-104748DOI Listing
December 2017

YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction.

Am J Hum Genet 2017 Jun;100(6):907-925

Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address:

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.
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http://dx.doi.org/10.1016/j.ajhg.2017.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473733PMC
June 2017

Upstream SLC2A1 translation initiation causes GLUT1 deficiency syndrome.

Eur J Hum Genet 2017 06 5;25(6):771-774. Epub 2017 Apr 5.

Department of Human Genetics, Donders Centre for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a neurometabolic disorder with a complex phenotypic spectrum but simple biomarkers in cerebrospinal fluid. The disorder is caused by impaired glucose transport into the brain resulting from variants in SCL2A1. In 10% of GLUT1DS patients, a genetic diagnosis can not be made. Using whole-genome sequencing, we identified a de novo 5'-UTR variant in SLC2A1, generating a novel translation initiation codon, severely compromising SLC2A1 function. This finding expands our understanding of the disease mechanisms underlying GLUT1DS and encourages further in-depth analysis of SLC2A1 non-coding regions in patients without variants in the coding region.
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http://dx.doi.org/10.1038/ejhg.2017.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477372PMC
June 2017

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies.

PLoS Genet 2017 03 27;13(3):e1006683. Epub 2017 Mar 27.

Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.
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http://dx.doi.org/10.1371/journal.pgen.1006683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386295PMC
March 2017

Quantification of Phenotype Information Aids the Identification of Novel Disease Genes.

Hum Mutat 2017 05 2;38(5):594-599. Epub 2017 Feb 2.

Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.

Next-generation sequencing led to the identification of many potential novel disease genes. The presence of mutations in the same gene in multiple unrelated patients is, however, a priori insufficient to establish that these genes are truly involved in the respective disease. Here, we show how phenotype information can be incorporated within statistical approaches to provide additional evidence for the causality of mutations. We developed a broadly applicable statistical model that integrates gene-specific mutation rates, cohort size, mutation type, and phenotype frequency information to assess the chance of identifying de novo mutations affecting the same gene in multiple patients with shared phenotype features. We demonstrate our approach based on the frequency of phenotype features present in a unique cohort of 6,149 patients with intellectual disability. We show that our combined approach can decrease the number of patients required to identify novel disease genes, especially for patients with combinations of rare phenotypes. In conclusion, we show how integrating genotype-phenotype information can aid significantly in the interpretation of de novo mutations in potential novel disease genes.
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http://dx.doi.org/10.1002/humu.23176DOI Listing
May 2017

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.

Authors:
Claire Redin Harrison Brand Ryan L Collins Tammy Kammin Elyse Mitchell Jennelle C Hodge Carrie Hanscom Vamsee Pillalamarri Catarina M Seabra Mary-Alice Abbott Omar A Abdul-Rahman Erika Aberg Rhett Adley Sofia L Alcaraz-Estrada Fowzan S Alkuraya Yu An Mary-Anne Anderson Caroline Antolik Kwame Anyane-Yeboa Joan F Atkin Tina Bartell Jonathan A Bernstein Elizabeth Beyer Ian Blumenthal Ernie M H F Bongers Eva H Brilstra Chester W Brown Hennie T Brüggenwirth Bert Callewaert Colby Chiang Ken Corning Helen Cox Edwin Cuppen Benjamin B Currall Tom Cushing Dezso David Matthew A Deardorff Annelies Dheedene Marc D'Hooghe Bert B A de Vries Dawn L Earl Heather L Ferguson Heather Fisher David R FitzPatrick Pamela Gerrol Daniela Giachino Joseph T Glessner Troy Gliem Margo Grady Brett H Graham Cristin Griffis Karen W Gripp Andrea L Gropman Andrea Hanson-Kahn David J Harris Mark A Hayden Rosamund Hill Ron Hochstenbach Jodi D Hoffman Robert J Hopkin Monika W Hubshman A Micheil Innes Mira Irons Melita Irving Jessie C Jacobsen Sandra Janssens Tamison Jewett John P Johnson Marjolijn C Jongmans Stephen G Kahler David A Koolen Jerome Korzelius Peter M Kroisel Yves Lacassie William Lawless Emmanuelle Lemyre Kathleen Leppig Alex V Levin Haibo Li Hong Li Eric C Liao Cynthia Lim Edward J Lose Diane Lucente Michael J Macera Poornima Manavalan Giorgia Mandrile Carlo L Marcelis Lauren Margolin Tamara Mason Diane Masser-Frye Michael W McClellan Cinthya J Zepeda Mendoza Björn Menten Sjors Middelkamp Liya R Mikami Emily Moe Shehla Mohammed Tarja Mononen Megan E Mortenson Graciela Moya Aggie W Nieuwint Zehra Ordulu Sandhya Parkash Susan P Pauker Shahrin Pereira Danielle Perrin Katy Phelan Raul E Piña Aguilar Pino J Poddighe Giulia Pregno Salmo Raskin Linda Reis William Rhead Debra Rita Ivo Renkens Filip Roelens Jayla Ruliera Patrick Rump Samantha L P Schilit Ranad Shaheen Rebecca Sparkes Erica Spiegel Blair Stevens Matthew R Stone Julia Tagoe Joseph V Thakuria Bregje W van Bon Jiddeke van de Kamp Ineke van Der Burgt Ton van Essen Conny M van Ravenswaaij-Arts Markus J van Roosmalen Sarah Vergult Catharina M L Volker-Touw Dorothy P Warburton Matthew J Waterman Susan Wiley Anna Wilson Maria de la Concepcion A Yerena-de Vega Roberto T Zori Brynn Levy Han G Brunner Nicole de Leeuw Wigard P Kloosterman Erik C Thorland Cynthia C Morton James F Gusella Michael E Talkowski

Nat Genet 2017 01 14;49(1):36-45. Epub 2016 Nov 14.

Molecular Neurogenetics Unit, Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.
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http://dx.doi.org/10.1038/ng.3720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5307971PMC
January 2017

DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome.

Am J Hum Genet 2016 Mar 25;98(3):553-561. Epub 2016 Feb 25.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Robinow syndrome is a rare congenital disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features. Recent reports have identified, in individuals with dominant Robinow syndrome, a specific type of variant characterized by being uniformly located in the penultimate exon of DVL1 and resulting in a -1 frameshift allele with a premature termination codon that escapes nonsense-mediated decay. Here, we studied a cohort of individuals who had been clinically diagnosed with Robinow syndrome but who had not received a molecular diagnosis from variant studies of DVL1, WNT5A, and ROR2. Because of the uniform location of frameshift variants in DVL1-mediated Robinow syndrome and the functional redundancy of DVL1, DVL2, and DVL3, we elected to pursue direct Sanger sequencing of the penultimate exon of DVL1 and its paralogs DVL2 and DVL3 to search for potential disease-associated variants. Remarkably, targeted sequencing identified five unrelated individuals harboring heterozygous, de novo frameshift variants in DVL3, including two splice acceptor mutations and three 1 bp deletions. Similar to the variants observed in DVL1-mediated Robinow syndrome, all variants in DVL3 result in a -1 frameshift, indicating that these highly specific alterations might be a common cause of dominant Robinow syndrome. Here, we review the current knowledge of these peculiar variant alleles in DVL1- and DVL3-mediated Robinow syndrome and further elucidate the phenotypic features present in subjects with DVL1 and DVL3 frameshift mutations.
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http://dx.doi.org/10.1016/j.ajhg.2016.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800044PMC
March 2016

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila.

Eur J Hum Genet 2016 08 13;24(8):1145-53. Epub 2016 Jan 13.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.
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http://dx.doi.org/10.1038/ejhg.2015.282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970694PMC
August 2016

Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems.

Hum Mol Genet 2015 Dec 6;24(25):7171-81. Epub 2015 Oct 6.

School of Medicine, and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5000, Australia,

Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals. We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.
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http://dx.doi.org/10.1093/hmg/ddv414DOI Listing
December 2015

Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling.

Am J Hum Genet 2015 Aug 30;97(2):343-52. Epub 2015 Jul 30.

Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address:

Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.
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http://dx.doi.org/10.1016/j.ajhg.2015.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573244PMC
August 2015

THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability.

Am J Hum Genet 2015 Aug 9;97(2):302-10. Epub 2015 Jul 9.

School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia; School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, SA 5005, Australia. Electronic address:

Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.
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http://dx.doi.org/10.1016/j.ajhg.2015.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573269PMC
August 2015

DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome.

Am J Hum Genet 2015 Apr 26;96(4):612-22. Epub 2015 Mar 26.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte MG 30190-002, Brazil. Electronic address:

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 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 -1 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.
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http://dx.doi.org/10.1016/j.ajhg.2015.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385180PMC
April 2015

Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations.

Eur J Hum Genet 2015 Sep 26;23(9):1176-85. Epub 2014 Nov 26.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.
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http://dx.doi.org/10.1038/ejhg.2014.253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538199PMC
September 2015

Refining analyses of copy number variation identifies specific genes associated with developmental delay.

Nat Genet 2014 10 14;46(10):1063-71. Epub 2014 Sep 14.

1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA. [2] Howard Hughes Medical Institute, Seattle, Washington, USA.

Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically large, and the underlying causative genes are unclear. We created an expanded CNV morbidity map from 29,085 children with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Follow-up of a subset of affected individuals identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. These genetic changes include haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and genes involved in neuropsychiatric disease despite extensive genetic heterogeneity.
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http://dx.doi.org/10.1038/ng.3092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177294PMC
October 2014

Genome sequencing identifies major causes of severe intellectual disability.

Nature 2014 Jul 4;511(7509):344-7. Epub 2014 Jun 4.

1] Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands [2] Department of Clinical Genetics, Maastricht University Medical Centre. Universiteitssingel 50, 6229 ER Maastricht, the Netherlands [3].

Severe intellectual disability (ID) occurs in 0.5% of newborns and is thought to be largely genetic in origin. The extensive genetic heterogeneity of this disorder requires a genome-wide detection of all types of genetic variation. Microarray studies and, more recently, exome sequencing have demonstrated the importance of de novo copy number variations (CNVs) and single-nucleotide variations (SNVs) in ID, but the majority of cases remain undiagnosed. Here we applied whole-genome sequencing to 50 patients with severe ID and their unaffected parents. All patients included had not received a molecular diagnosis after extensive genetic prescreening, including microarray-based CNV studies and exome sequencing. Notwithstanding this prescreening, 84 de novo SNVs affecting the coding region were identified, which showed a statistically significant enrichment of loss-of-function mutations as well as an enrichment for genes previously implicated in ID-related disorders. In addition, we identified eight de novo CNVs, including single-exon and intra-exonic deletions, as well as interchromosomal duplications. These CNVs affected known ID genes more frequently than expected. On the basis of diagnostic interpretation of all de novo variants, a conclusive genetic diagnosis was reached in 20 patients. Together with one compound heterozygous CNV causing disease in a recessive mode, this results in a diagnostic yield of 42% in this extensively studied cohort, and 62% as a cumulative estimate in an unselected cohort. These results suggest that de novo SNVs and CNVs affecting the coding region are a major cause of severe ID. Genome sequencing can be applied as a single genetic test to reliably identify and characterize the comprehensive spectrum of genetic variation, providing a genetic diagnosis in the majority of patients with severe ID.
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http://dx.doi.org/10.1038/nature13394DOI Listing
July 2014

Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems.

Am J Hum Genet 2014 May 10;94(5):649-61. Epub 2014 Apr 10.

Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address:

Recently, we identified in two individuals with intellectual disability (ID) different de novo mutations in DEAF1, which encodes a transcription factor with an important role in embryonic development. To ascertain whether these mutations in DEAF1 are causative for the ID phenotype, we performed targeted resequencing of DEAF1 in an additional cohort of over 2,300 individuals with unexplained ID and identified two additional individuals with de novo mutations in this gene. All four individuals had severe ID with severely affected speech development, and three showed severe behavioral problems. DEAF1 is highly expressed in the CNS, especially during early embryonic development. All four mutations were missense mutations affecting the SAND domain of DEAF1. Altered DEAF1 harboring any of the four amino acid changes showed impaired transcriptional regulation of the DEAF1 promoter. Moreover, behavioral studies in mice with a conditional knockout of Deaf1 in the brain showed memory deficits and increased anxiety-like behavior. Our results demonstrate that mutations in DEAF1 cause ID and behavioral problems, most likely as a result of impaired transcriptional regulation by DEAF1.
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http://dx.doi.org/10.1016/j.ajhg.2014.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067565PMC
May 2014

Cantú syndrome resulting from activating mutation in the KCNJ8 gene.

Hum Mutat 2014 Jul 6;35(7):809-13. Epub 2014 May 6.

Department of Cell Biology and Physiology, and Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri.

ATP-sensitive potassium (KATP ) channels, composed of inward-rectifying potassium channel subunits (Kir6.1 and Kir6.2, encoded by KCNJ8 and KCNJ11, respectively) and regulatory sulfonylurea receptor (SUR1 and SUR2, encoded by ABCC8 and ABCC9, respectively), couple metabolism to excitability in multiple tissues. Mutations in ABCC9 cause Cantú syndrome (CS), a distinct multiorgan disease, potentially via enhanced KATP channel activity. We screened KCNJ8 in an ABCC9 mutation-negative patient who also exhibited clinical hallmarks of CS (hypertrichosis, macrosomia, macrocephaly, coarse facial appearance, cardiomegaly, and skeletal abnormalities). We identified a de novo missense mutation encoding Kir6.1[p.Cys176Ser] in the patient. Kir6.1[p.Cys176Ser] channels exhibited markedly higher activity than wild-type channels, as a result of reduced ATP sensitivity, whether coexpressed with SUR1 or SUR2A subunits. Our results identify a novel causal gene in CS, but also demonstrate that the cardinal features of the disease result from gain of KATP channel function, not from a Kir6-independent SUR2 function.
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http://dx.doi.org/10.1002/humu.22555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277879PMC
July 2014

Early presentation of cystic kidneys in a family with a homozygous INVS mutation.

Am J Med Genet A 2014 Jul 26;164A(7):1627-34. Epub 2014 Mar 26.

Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.

Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that is the most frequent monogenic cause of end-stage renal disease in children. Infantile NPHP, often in combination with other features like situs inversus, are commonly caused by mutations in the INVS gene. INVS encodes the ciliary protein inversin, and mutations induce dysfunction of the primary cilia. In this article, we present a family with two severely affected fetuses that were aborted after discovery of grossly enlarged cystic kidneys by ultrasonography before 22 weeks gestation. Exome sequencing showed that the fetuses were homozygous for a previously unreported nonsense mutation, resulting in a truncation in the IQ1 domain of inversin. This mutation induces nonsense-mediated RNA decay, as suggested by a reduced RNA level in fibroblasts derived from the fetus. However, a significant amount of mutant INVS RNA was present in these fibroblasts, yielding mutant inversin protein that was mislocalized. In control fibroblasts, inversin was present in the ciliary axoneme as well as at the basal body, whereas in the fibroblasts from the fetus, inversin could only be detected at the basal body. The phenotype of both fetuses is partly characteristic of infantile NPHP and Potter sequence. We also identified that the fetuses had mild skeletal abnormalities, including shortening and bowing of long bones, which may expand the phenotypic spectrum associated with INVS mutations.
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http://dx.doi.org/10.1002/ajmg.a.36501DOI Listing
July 2014