Publications by authors named "Ton van Essen"

19 Publications

  • Page 1 of 1

De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia.

Am J Hum Genet 2019 08 25;105(2):283-301. Epub 2019 Jul 25.

Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, the Netherlands. Electronic address:

The RNA polymerase II complex (pol II) is responsible for transcription of all ∼21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly disease-causing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.
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http://dx.doi.org/10.1016/j.ajhg.2019.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699192PMC
August 2019

Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.

Nat Commun 2019 May 2;10(1):2079. Epub 2019 May 2.

CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada.

The HTML and PDF versions of this Article were updated after publication to remove images of one individual from Figure 1.
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http://dx.doi.org/10.1038/s41467-019-10161-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497626PMC
May 2019

Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.

Nat Commun 2019 02 15;10(1):883. Epub 2019 Feb 15.

CHU Sainte-Justine Research Center, Montreal, QC, H3T 1C5, Canada.

The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-019-08800-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377600PMC
February 2019

CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.

Nat Commun 2018 11 5;9(1):4619. Epub 2018 Nov 5.

CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada.

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.
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http://dx.doi.org/10.1038/s41467-018-06014-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218476PMC
November 2018

PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature.

J Med Genet 2018 02 2;55(2):104-113. Epub 2017 Nov 2.

Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.

Background: De novo mutations in have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia.

Objectives: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations.

Methods: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of -derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes.

Results: We report mutations in (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes.

Conclusion: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.
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http://dx.doi.org/10.1136/jmedgenet-2017-104946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800346PMC
February 2018

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

Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome.

Eur J Med Genet 2015 May 16;58(5):279-92. Epub 2015 Mar 16.

Department of Paediatrics, Academic Medical Centre, Amsterdam, The Netherlands; Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands. Electronic address:

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities, and subdivided in TRPS I, caused by mutations in TRPS1, and TRPS II, caused by a contiguous gene deletion affecting (amongst others) TRPS1 and EXT1. We performed a collaborative international study to delineate phenotype, natural history, variability, and genotype-phenotype correlations in more detail. We gathered information on 103 cytogenetically or molecularly confirmed affected individuals. TRPS I was present in 85 individuals (22 missense mutations, 62 other mutations), TRPS II in 14, and in 5 it remained uncertain whether TRPS1 was partially or completely deleted. Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella. The facial manifestations in patients with TRPS I and TRPS II do not show a significant difference. In the limbs the main findings are short hands and feet, hypermobility, and a tendency for isolated metacarpals and metatarsals to be shortened. Nails of fingers and toes are typically thin and dystrophic. The radiological hallmark are the cone-shaped epiphyses and in TRPS II multiple exostoses. Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally. Variability for all findings, also within a single family, can be marked. Morbidity mostly concerns joint problems, manifesting in increased or decreased mobility, pain and in a minority an increased fracture rate. The hips can be markedly affected at a (very) young age. Intellectual disability is uncommon in TRPS I and, if present, usually mild. In TRPS II intellectual disability is present in most but not all, and again typically mild to moderate in severity. Missense mutations are located exclusively in exon 6 and 7 of TRPS1. Other mutations are located anywhere in exons 4-7. Whole gene deletions are common but have variable breakpoints. Most of the phenotype in patients with TRPS II is explained by the deletion of TRPS1 and EXT1, but haploinsufficiency of RAD21 is also likely to contribute. Genotype-phenotype studies showed that mutations located in exon 6 may have somewhat more pronounced facial characteristics and more marked shortening of hands and feet compared to mutations located elsewhere in TRPS1, but numbers are too small to allow firm conclusions.
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http://dx.doi.org/10.1016/j.ejmg.2015.03.002DOI Listing
May 2015

Myhre and LAPS syndromes: clinical and molecular review of 32 patients.

Eur J Hum Genet 2014 Nov 15;22(11):1272-7. Epub 2014 Jan 15.

INSERM U781 Unit, Department of Genetics, Institut Imagine, Paris Descartes University-Sorbonne Paris Cité, Necker Enfants-Malades Hospital, Paris, France.

Myhre syndrome is characterized by short stature, brachydactyly, facial features, pseudomuscular hypertrophy, joint limitation and hearing loss. We identified SMAD4 mutations as the cause of Myhre syndrome. SMAD4 mutations have also been identified in laryngotracheal stenosis, arthropathy, prognathism and short stature syndrome (LAPS). This study aimed to review the features of Myhre and LAPS patients to define the clinical spectrum of SMAD4 mutations. We included 17 females and 15 males ranging in age from 8 to 48 years. Thirty were diagnosed with Myhre syndrome and two with LAPS. SMAD4 coding sequence was analyzed by Sanger sequencing. Clinical and radiological features were collected from a questionnaire completed by the referring physicians. All patients displayed a typical facial gestalt, thickened skin, joint limitation and muscular pseudohypertrophy. Growth retardation was common (68.7%) and was variable in severity (from -5.5 to -2 SD), as was mild-to-moderate intellectual deficiency (87.5%) with additional behavioral problems in 56.2% of the patients. Significant health concerns like obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis, pericarditis and early death occurred in four. Twenty-nine patients had a de novo heterozygous SMAD4 mutation, including both patients with LAPS. In 27 cases mutation affected Ile500 and in two cases Arg496. The three patients without SMAD4 mutations had typical findings of Myhre syndrome. Myhre-LAPS syndrome is a clinically homogenous condition with life threatening complications in the course of the disease. Our identification of SMAD4 mutations in 29/32 cases confirms that SMAD4 is the major gene responsible for Myhre syndrome.
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http://dx.doi.org/10.1038/ejhg.2013.288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200423PMC
November 2014

A 3-base pair deletion, c.9711_9713del, in DMD results in intellectual disability without muscular dystrophy.

Eur J Hum Genet 2014 Apr 31;22(4):480-5. Epub 2013 Jul 31.

1] Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands [2] Institute of Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands [3] Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands.

We have identified a deletion of 3 base pairs in the dystrophin gene (DMD), c.9711_9713del, in a family with nonspecific X-linked intellectual disability (ID) by sequencing of the exons of 86 known X-linked ID genes. This in-frame deletion results in the deletion of a single-amino-acid residue, Leu3238, in the brain-specific isoform Dp71 of dystrophin. Linkage analysis supported causality as the mutation was present in the 7.6 cM linkage interval on Xp22.11-Xp21.1 with a maximum positive LOD score of 2.41 (MRX85 locus). Molecular modeling predicts that the p.(Leu3238del) deletion results in the destabilization of the C-terminal domain of dystrophin and hence reduces the ability to interact with β-dystroglycan. Correspondingly, Dp71 protein levels in lymphoblastoid cells from the index patient are 6.7-fold lower than those in control cell lines (P=0.08). Subsequent determination of the creatine kinase levels in blood of the index patient showed a mild but significant elevation in serum creatine kinase, which is in line with impaired dystrophin function. In conclusion, we have identified the first DMD mutation in Dp71 that results in ID without muscular dystrophy.
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http://dx.doi.org/10.1038/ejhg.2013.169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953899PMC
April 2014

Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are risk factors for colorectal cancer.

Gastroenterology 2013 Sep 5;145(3):544-7. Epub 2013 Jun 5.

Department of Human Genetics, Radboud University Medical Centre and Research Institute for Oncology, Nijmegen, The Netherlands.

The spindle assembly checkpoint controls proper chromosome segregation during mitosis and prevents aneuploidy-an important feature of cancer cells. We performed genome-wide and targeted copy number and mutation analyses of germline DNA from 208 patients with familial or early-onset (40 years of age or younger) colorectal cancer; we identified haploinsufficiency or heterozygous mutations in the spindle assembly checkpoint genes BUB1 and BUB3 in 2.9% of them. Besides colorectal cancer, these patients had variegated aneuploidies in multiple tissues and variable dysmorphic features. These results indicate that mutations in BUB1 and BUB3 cause mosaic variegated aneuploidy and increase the risk of colorectal cancer at a young age.
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http://dx.doi.org/10.1053/j.gastro.2013.06.001DOI Listing
September 2013

Parental insertional balanced translocations are an important cause of apparently de novo CNVs in patients with developmental anomalies.

Eur J Hum Genet 2012 Feb 14;20(2):166-70. Epub 2011 Sep 14.

Department of Human Genetics, KU Leuven, Leuven, Belgium.

In several laboratories, genome-wide array analysis has been implemented as the first tier diagnostic test for the identification of copy number changes in patients with mental retardation and/or congenital anomalies. The identification of a pathogenic copy number variant (CNV) is not only important to make a proper diagnosis but also to enable the accurate estimation of the recurrence risk to family members. Upon the identification of a de novo interstitial loss or gain, the risk recurrence is considered very low. However, this risk is 50% if one of the parents is carrier of a balanced insertional translocation (IT). The apparently de novo imbalance in a patient is then the consequence of the unbalanced transmission of a derivative chromosome involved in an IT. To determine the frequency with which insertional balanced translocations would be the origin of submicroscopic imbalances, we investigated the potential presence of an IT in a consecutive series of 477 interstitial CNVs, in which the parental origin has been tested by FISH, among 14,293 patients with developmental abnormalities referred for array. We demonstrate that ITs underlie ~2.1% of the apparently de novo, interstitial CNVs, indicating that submicroscopic ITs are at least sixfold more frequent than cytogenetically visible ITs. This risk estimate should be taken into account during counseling, and warrant parental and proband FISH testing wherever possible in patients with an apparently de novo, interstitial aberration.
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http://dx.doi.org/10.1038/ejhg.2011.157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260932PMC
February 2012

Clinical features and respiratory complications in Myhre syndrome.

Eur J Med Genet 2011 Nov-Dec;54(6):e553-9. Epub 2011 Jul 21.

Ferguson-Smith Dept. of Clinical Genetics, Yorkhill Hospital, Glasgow, UK.

We describe the clinical characteristics of 4 singleton cases, 3 males and 1 female, with Myhre Syndrome (OMIM 139210), who were born to non-consanguineous parents. Three cases had no family history of similarly affected individuals but 1 male's mother had short stature, some facial features suggestive of Myhre syndrome and evidence of skewed X-chromosome inactivation in her blood DNA. Short stature, deafness, learning difficulties, skeletal anomalies and facial dysmorphisms were evident in all cases. Arthralgia and stiff joints with limited movement were also present. The facial appearance, thickened skin, a 'muscular' habitus are memorable features. The female patient was least affected: this patient and one affected male displayed streaky skin with areas of patchy thickening, suggestive of genetic mosaicism. One patient developed sleep apnoea, a restrictive ventilatory defect and died following a choking episode. Another affected male developed recurrent, progressive, proximal, tracheal stenosis requiring partial tracheal resection, laser treatment and eventually tracheotomy. Review of Myhre syndrome patients in the literature and syndromes in the differential diagnosis, suggests heterogeneity in Myhre syndrome and clinical overlap with Laryngotracheal stenosis, Arthropathy, Prognathism and Short stature syndrome.
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http://dx.doi.org/10.1016/j.ejmg.2011.07.001DOI Listing
January 2012

Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances.

Eur J Med Genet 2009 Mar-Jun;52(2-3):108-15. Epub 2009 Mar 27.

Beatrix Children's Hospital, University Medical Centre Groningen, University of Groningen, The Netherlands.

Behavioural differences have been described in patients with type I deletions (between breakpoints 1 and 3 (BP1-BP3)) or type II deletions (between breakpoints 2 and 3) of the 15q11.2 Prader-Willi/Angelman region. The larger type I deletions appear to coincide with more severe behavioural problems (autism, ADHD, obsessive-compulsive disorder). The non-imprinted chromosomal segment between breakpoints 1 and 2 involves four highly conserved genes, TUBGCP5, NIPA1, NIPA2, and CYFIP1; the latter three are widely expressed in the central nervous system, while TUBGCP5 is expressed in the subthalamic nuclei. These genes might explain the more severe behavioural problems seen in type I deletions. We describe nine cases with a microdeletion at 15q11.2 between BP1-BP2, thus having a haploinsufficiency for TUBGCP5, NIPA1, NIPA2, and CYFIP1 without Prader-Willi/Angelman syndrome. The clinical significance of a pure BP1-BP2 microdeletion has been debated, however, our patients shared several clinical features, including delayed motor and speech development, dysmorphisms and behavioural problems (ADHD, autism, obsessive-compulsive behaviour). Although the deletion often appeared to be inherited from a normal or mildly affected parent, it was de novo in two cases and we did not find it in 350 healthy unrelated controls. Our results suggest a pathogenic nature for the BP1-BP2 microdeletion and, although there obviously is an incomplete penetrance, they support the existence of a novel microdeletion syndrome in 15q11.2.
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http://dx.doi.org/10.1016/j.ejmg.2009.03.010DOI Listing
September 2009

Identification of copy number variants associated with BPES-like phenotypes.

Hum Genet 2008 Dec 25;124(5):489-98. Epub 2008 Oct 25.

Center for Human and Clinical Genetics, Leiden University Medical Center, Postzone S-6-P, Einthovenweg 20, 2333 CZ, Leiden, The Netherlands.

Blepharophimosis-Ptosis-Epicanthus inversus syndrome (BPES) is a well-characterized rare syndrome that includes an eyelid malformation associated with (type I) or without premature ovarian failure (type II). Patients with typical BPES have four major characteristics: blepharophimosis, ptosis, epicanthus inversus and telecanthus. Mutations in the FOXL2 gene, encoding a forkhead transcription factor, are responsible for the majority of both types of BPES. However, many patients with BPES-like features, i.e., having at least two major characteristics of BPES, have an unidentified cause. Here, we report on a group of 27 patients with BPES-like features, but without an identified genetic defect in the FOXL2 gene or flanking region. These patients were analyzed with whole-genome high-density arrays in order to identify copy number variants (CNVs) that might explain the BPES-like phenotype. In nine out of 27 patients (33%) CNVs not previously described as polymorphisms were detected. Four of these patients displayed psychomotor retardation as an additional clinical characteristic. In conclusion, we demonstrate that BPES-like phenotypes are frequently caused by CNVs, and we emphasize the importance of whole-genome copy number screening to identify the underlying genetic causes of these phenotypes.
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http://dx.doi.org/10.1007/s00439-008-0574-9DOI Listing
December 2008

Missense mutations to the TSC1 gene cause tuberous sclerosis complex.

Eur J Hum Genet 2009 Mar 1;17(3):319-28. Epub 2008 Oct 1.

Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene on chromosome 9q34 or the TSC2 gene on chromosome 16p13.3. The TSC1 and TSC2 gene products, TSC1 and TSC2, interact to form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). Here we investigate the effects of putative TSC1 missense mutations identified in individuals with signs and/or symptoms of TSC on TSC1-TSC2 complex formation and mTOR signalling. We show that specific amino-acid substitutions close to the N-terminal of TSC1 reduce steady-state levels of TSC1, resulting in the activation of mTOR signalling and leading to the symptoms of TSC.
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http://dx.doi.org/10.1038/ejhg.2008.170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986174PMC
March 2009

FISH and array-CGH analysis of a complex chromosome 3 aberration suggests that loss of CNTN4 and CRBN contributes to mental retardation in 3pter deletions.

Am J Med Genet A 2006 Nov;140(22):2482-7

Department of Clinical Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Imbalances of 3p telomeric sequences cause 3p- and trisomy 3p syndrome, respectively, showing distinct, but also shared clinical features. No causative genes have been identified in trisomy 3p patients, but for the 3p- syndrome, there is growing evidence that monosomy for one or more of four genes at 3pter, CHL1, CNTN4, CRBN, and MEGAP/srGAP3, may play a causative role. We describe here an analysis of a complex chromosome 3p aberration in a severely mentally retarded patient that revealed two adjacent segments with different copy number gains and a distal deletion. The deletion in this patient included the loci for CHL1, CNTN4, and CRBN, and narrowed the critical segment associated with the 3p- syndrome to 1.5 Mb, including the loci for CNTN4 and CRBN. We speculate that the deletion contributes more to this patient's phenotype than the gains that were observed. We suggest that 3p- syndrome associated features are primarily caused by loss of CNTN4 and CRBN, with loss of CHL1 probably having an additional detrimental effect on the cognitive functioning of the present patient.
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http://dx.doi.org/10.1002/ajmg.a.31487DOI Listing
November 2006

Application of a comprehensive subtelomere array in clinical diagnosis of mental retardation.

Eur J Med Genet 2005 Jul-Sep;48(3):250-62

Department of Clinical Genetics, University Medical Centre Groningen, Antonius Deusinglaan 4, 9713 AW Groningen, The Netherlands.

In 2-8% of patients with mental retardation, small copy number changes in the subtelomeric region are thought to be the underlying cause. As detection of these genomic rearrangements is labour intensive using FISH, we constructed and validated a high-density BAC/PAC array covering the first 5 Mb of all subtelomeric regions and applied it in our routine screening of patients with idiopathic mental retardation for submicroscopic telomeric rearrangements. The present study shows the efficiency of this comprehensive subtelomere array in detecting terminal deletions and duplications but also small interstitial subtelomeric rearrangements, starting from small amounts of DNA. With our array, the size of the affected segments, at least those smaller than 5 Mb, can be determined simultaneously in the same experiment. In the first 100 patient samples analysed in our diagnostic practice by the use of this comprehensive telomere array, we found three patients with deletions in 3p, 10q and 15q, respectively, four patients with duplications in 9p, 12p, 21q and Xp, respectively, and one patient with a del 6q/dup 16q. The patients with del 3p and 10q and dup 12p had interstitial rearrangements that would have been missed with techniques using one probe per subtelomeric region chosen close to the telomere.
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http://dx.doi.org/10.1016/j.ejmg.2005.04.007DOI Listing
November 2005

Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy.

Hum Mol Genet 2004 Oct 18;13(20):2493-503. Epub 2004 Aug 18.

Inserm U491, Génétique Médicale et Développement, Faculté de Médecine de Marseille, Hôpital d'enfants de la Timone, Marseille, France.

Restrictive dermopathy (RD), also called tight skin contracture syndrome (OMIM 275210), is a rare disorder mainly characterized by intrauterine growth retardation, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, facial features (small mouth, small pinched nose and micrognathia), sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures and an early neonatal lethal course. Liveborn children usually die within the first week of life. The overall prevalence of consanguineous cases suggested an autosomal recessive inheritance. We explored nine fetuses/newborns children with RD. Two were found to have an heterozygous splicing mutation in the LMNA gene, leading to the complete or partial loss of exon 11 in mRNAs encoding Lamin A and resulting in a truncated Prelamin A protein. Lamins are major constituents of the nuclear lamina, a filamentous meshwork underlying the inner nuclear envelope. In the other seven patients, a unique heterozygous insertion leading to the creation of a premature termination codon was identified in the gene ZMPSTE24, also known as FACE-1 in human. This gene encodes a metalloproteinase specifically involved in the post-translational processing of Lamin A precursor. In all patients carrying a ZMPSTE24 mutation, loss of expression of Lamin A as well as abnormal patterns of nuclear sizes and shapes and mislocalization of Lamin-associated proteins was evidenced. Our results indicate that a common pathogenetic pathway, involving defects of the nuclear lamina and matrix, is involved in all RD cases. RD is thus one of the most deleterious laminopathies identified so far in humans caused by (primary or secondary) A-type Lamin defects and nuclear structural and functional alterations.
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http://dx.doi.org/10.1093/hmg/ddh265DOI Listing
October 2004

Hereditary fetal brain degeneration resembling fetal brain disruption sequence in two sibships.

Am J Med Genet A 2004 Jun;127A(2):172-82

Department of Clinical Genetics, University Hospital Groningen, 9700 RB Groningen, The Netherlands.

We present two families with sib recurrence of a phenotype which was originally diagnosed as fetal brain disruption sequence (FBDS). In the first family from the Hindu population of Surinam, two brothers were affected. In the second family of Dutch descent a brother and sister were affected. Periodic ultrasonic sound examinations of brain development of the girl in the second family appeared normal until 26 weeks of gestation after which progressive destruction of her brain was seen. Recurrence of the FBDS in a family is noteworthy as it is usually considered a sporadic disorder. Suggested causes in the literature are viral infections or early vascular interruption of the fetal brain with subsequent massive destruction of cerebral neurons. In 1995 the first familial case of FBDS was described, indicating a genetic cause. Recently Kavaslar et al. [2000: Am J Hum Genet 66:1705-1709.] found a locus on chromosome 16 in a large inbred Anatolian family with a phenotype resembling FBDS. Our experience and the literature show that the cause of the phenotype "FBDS" is heterogeneous. In case of sib recurrence the term FBDS should be avoided since a disruption sequence indicates an exogenous and sporadic cause of the disorder.
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http://dx.doi.org/10.1002/ajmg.a.20645DOI Listing
June 2004