Raoul C.M. Hennekam

University of Amsterdam, Amsterdamo, North Holland, Netherlands

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Publications (520)2504.4 Total impact

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    ABSTRACT: Background: The combination of developmental delay, facial characteristics, hearing loss and abnormal fat distribution in the distal limbs is known as Pierpont syndrome. The aim of the present study was to detect and study the cause of Pierpont syndrome. Methods: We used whole-exome sequencing to analyse four unrelated individuals with Pierpont syndrome, and Sanger sequencing in two other unrelated affected individuals. Expression of mRNA of the wild-type candidate gene was analysed in human postmortem brain specimens, adipose tissue, muscle and liver. Expression of RNA in lymphocytes in patients and controls was additionally analysed. The variant protein was expressed in, and purified from, HEK293 cells to assess its effect on protein folding and function. Results: We identified a single heterozygous missense variant, c.1337A>C (p.Tyr446Cys), in transducin β-like 1 X-linked receptor 1 (TBL1XR1) as disease-causing in all patients. TBL1XR1 mRNA expression was demonstrated in pituitary, hypothalamus, white and brown adipose tissue, muscle and liver. mRNA expression is lower in lymphocytes of two patients compared with the four controls. The mutant TBL1XR1 protein assembled correctly into the nuclear receptor corepressor (NCoR)/ silencing mediator for retinoid and thyroid receptors (SMRT) complex, suggesting a dominant-negative mechanism. This contrasts with loss-of-function germline TBL1XR1 deletions and other TBL1XR1 mutations that have been implicated in autism. However, autism is not present in individuals with Pierpont syndrome. Conclusions: This study identifies a specific TBL1XR1 mutation as the cause of Pierpont syndrome. Deletions and other mutations in TBL1XR1 can cause autism. The marked differences between Pierpont patients with the p.Tyr446Cys mutation and individuals with other mutations and whole gene deletions indicate a specific, but as yet unknown, disease mechanism of the TBL1XR1 p.Tyr446Cys mutation.
    Preview · Article · Jan 2016 · Journal of Medical Genetics
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    ABSTRACT: The aim of the study was to evaluate the etiology, the role of pubertal timing and most useful criteria for diagnostic workup in adolescents with growth failure. Adolescents (n=182) aged 10.0–18.0 years underwent a standardized diagnostic protocol. Constitutional delay of growth and puberty (CDGP) was defined as late pubertal onset or a Tanner stage less than –2 SDS. Dutch and Finnish criteria for growth monitoring were retrospectively assessed. In 13 children (7.1%) a specific diagnosis could be established. CDGP was diagnosed in 10% of patients aged ≥13 (girls) or ≥14 years (boys). Sensitivity to detect pathologic causes was 85% and 62% for, respectively Dutch and Finnish criteria for growth monitoring as used in younger children, but specificity was low (55%–59%). In adolescents, pathological causes for growth failure and pubertal delay are common, and we recommend a combination of height SDS, distance to THSDS and growth deflection for deciding on further diagnostic testing.
    No preview · Article · Jan 2016 · Journal of pediatric endocrinology & metabolism: JPEM
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    ABSTRACT: Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases uracil, thymine and the antineoplastic agent 5-fluorouracil. Genetic variations in the gene encoding DPD (DPYD) have emerged as predictive risk alleles for 5FU-asscoiated toxicity. Here we report an in-depth analysis of genetic variants in DPYD and their consequences for DPD activity and pyrimidine metabolites in 100 Dutch healthy volunteers. 34 SNPs were detected in DPYD and 15 SNPs were associated with altered plasma concentrations of pyrimidine metabolites. DPD activity was significantly associated with the plasma concentrations of uracil, the presence of a specific DPYD mutation (c.1905 + 1G > A) and the combined presence of three risk variants in DPYD (c.1905 + 1G > A, c.1129-5923C > G, c.2846 A > T), but not with an altered uracil/dihydrouracil (U/UH2) ratio. Various haplotypes were associated with different DPD activities (haplotype D3, a decreased DPD activity; haplotype F2, an increased DPD activity). Functional analysis of eight recombinant mutant DPD enzymes showed a reduced DPD activity, ranging from 35% to 84% of the wild-type enzyme. Analysis of a DPD homology model indicated that the structural effect of the novel p.G401R mutation is most likely minor. The clinical relevance of the p.D949V mutation was demonstrated in a cancer patient heterozygous for the c.2846 A > T mutation and a novel nonsense mutation c.1681C > T (p.R561X), experiencing severe grade IV toxicity. Our studies showed that the endogenous levels of uracil and the U/UH2 ratio are poor predictors of an impaired DPD activity. Loading studies with uracil to identify patients with a DPD deficiency warrants further investigation.
    No preview · Article · Jan 2016 · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

  • No preview · Article · Dec 2015
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    ABSTRACT: Aims: To evaluate three guidelines for selecting short children for diagnostic workup in a general pediatric clinic. Methods: All patients (n = 131) aged 3.00-9.99 years who were referred for growth failure to a general pediatric clinic were evaluated for their medical history and growth and examined. All of them underwent the same standardized diagnostic workup. Retrospectively, the criteria for the diagnostic workup from three guidelines (proposed in the Netherlands, Finland and the UK) were applied, and their sensitivity was assessed. A Dutch reference sample (n = 958) was used for calculating population specificity. Results: In 23 patients (17.6%), a pathological cause of their growth failure was found. The sensitivity of the original Dutch, Finnish and British guidelines was 73.9, 78.3 and 56.5% and their specificity 98.5, 83.7 and 95.8%, respectively. When adding recent growth deflection to the Dutch guideline, sensitivity increased to 87%, but specificity decreased markedly (to 87%). Conclusion: The proposed cutoff values for height standard deviation score and distance to target height/mid-parental height, as used in the Netherlands and Finland, are effective for population growth monitoring, and superior to the monitoring algorithm in the UK. Growth deflection irrespective of height is an important sign of acquired growth disorders, but its specificity is too low for population screening.
    Full-text · Article · Oct 2015 · Hormone Research in Paediatrics
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    ABSTRACT: Background: Robin Sequence (RS) is usually defined as the combination of micrognathia, glossoptosis and upper airway obstruction. No objective criteria to diagnose RS exist. To compare management strategy results, a single RS definition using objective criteria is needed. The most frequently used primary diagnostic tool for glossoptosis is awake Flexible Fiberoptic Laryngoscopy (aFFL). Objectives: To determine the reliability of the aFFL videos as an independent diagnostic tool itself, rather than on the complete evaluation of a patient. Design, setting, participants: All RS individuals from an existing cohort with an available aFFL video were included retrospectively. Thirty age-matched patients without pathologic findings on aFFL were used as controls. aFFL videos were scored by six otolaryngologists as: a. Marked glossoptosis, b. Mild glossoptosis, c. Severity unknown, d. No glossoptosis, e. Insufficient video quality. Videos were anonymized and rated twice, in altered sequences, after a washout period of minimally 2 weeks. Main outcome measures: Inter-rater and intra-rater agreement. Results: 26 videos of 16 RS patients and 30 videos of controls were included. Inter-rater agreement was fair in the whole group (κ: 0.320) and RS group (κ: 0.226), and fair to moderate in determining presence of glossoptosis (total group κ: 0.430; RS κ: 0.302; controls κ: 0.212). The intra-rater agreement for presence of glossoptosis in RS was moderate (κ: 0.541). Conclusions: aFFL offers fair to moderate inter-rater agreement, with moderate intra-rater agreement, in evaluating glossoptosis in RS. Using aFFL as the single tool in choosing management strategies in RS seems insufficient. There is need for a more reliable, patient friendly diagnostic tool or an internationally accepted aFFL scoring system, to diagnose glossoptosis in RS. This article is protected by copyright. All rights reserved.
    No preview · Article · Oct 2015 · Clinical otolaryngology: official journal of ENT-UK; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery
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    ABSTRACT: We report on a sister and two brothers born to healthy Iranian parents with mild intellectual disability, progressive muscle weakness, and characteristic facies. including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries, and in one of them an inability to abduct the left eye. Electrophysiological studies showed signs of myopathy, and muscle biopsies demonstrated only nonspecific signs. Brain MRIs in two of the sibs showed leukencephalopathy with delayed myelination, frontal and parietal hyperintensities, and hippocampal atrophy in one. We have been unable to find a description of this association of features in literature. Based on the occurrence in siblings, no significant difference in phenotype between the brothers and sister, absence of manifestations in parents, and a likely consanguinity between parents we performed a homozygosity mapping. A single identical-by-descent bloc encompassing 57 genes located at 3p24.3-p25.3 was found to segregate within the family with this phenotype. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Jul 2015 · American Journal of Medical Genetics Part A
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    Dataset: OMIM 601559

    Full-text · Dataset · Jul 2015
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    Dataset: 601559[1]

    Full-text · Dataset · Jul 2015

  • No preview · Article · Jul 2015
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    ABSTRACT: Maternal Uniparental Disomy of chromosome 14 (matUPD(14)) resembles Prader-Willi syndrome. Since positive effects of growth hormone (GH) are observed in individuals with PWS, treatment with GH may be useful in individuals with matUPD(14) as well. The aim of this study was to investigate the effect of GH treatment on growth and body composition in children with matUPD(14). Prospective observational study of GH treatment in two girls with matUPD(14) during 2 years, and spontaneous growth in another matUPD(14) girl of similar age. Three girls (patient A, B and C, aged 8.9, 11.4 and 12.7 years respectively) with matUPD(14). Patients A and B were treated with GH during two years. Patient C was not treated with GH, as she was diagnosed at an age at which she attained near-final height. Main outcome measures included height, weight, body proportions, IGF-1, bone age, DXA scan for body composition. In both treated girls a considerable increase in height (from -2.3SD and -1.2SD to -1.2SD and -0.6SD, respectively) and IGF-1 levels (from +0.1SD and -1.4SD to +1.3SD and +0.9SD, respectively), and in patient A a decrease in weight (+1.2 SD to -0.7SD), and improved body composition (fat percentage from 51.5% to 45.4%). Both experienced improved muscle strength. GH treatment in matUPD(14) cases can show beneficial effects on growth and body composition if started in time. Larger, international studies to determine detailed effectivity and side-effects are suggested. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jun 2015 · Clinical Endocrinology
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    ABSTRACT: Robin sequence (RS) can be defined as the combination of micrognathia and upper airway obstruction/glossoptosis causing neonatal respiratory problems, with or without a cleft palate and either isolated or non-isolated. Pathogenesis varies widely. We hypothesize that optimal treatment depends on pathogenesis and therefore patients should be stratified according to diagnosis. Here, we evaluate diagnoses and (presumed) pathogeneses in an RS cohort. Medical records of all RS patients presenting between 1995-2013 in three academic hospitals were evaluated. Four clinical geneticists re-evaluated all information, including initial diagnosis. Diagnoses were either confirmed, considered uncertain, or rejected. If uncertain or rejected, patients were re-evaluated. Subsequent results were re-discussed and a final conclusion was drawn. We included 191 RS patients. After re-evaluation and changing initial diagnoses in 48 of the 191 patients (25.1%), 37.7% of the cohort had isolated RS, 8.9% a chromosome anomaly, 29.3% a Mendelian disorder, and 24.1% no detectable cause. Twenty-two different Mendelian disorders were diagnosed, of which Stickler syndrome was most frequent. Stratification of diagnoses according to (presumed) pathogenic mechanism in 73 non-isolated patients with reliable diagnoses showed 43.9% to have a connective tissue dysplasia, 5.5% a neuromuscular disorder, 47.9% a multisystem disorder, and 2.7% an unknown mechanism. We diagnosed more non-isolated RS patients compared to other studies. Re-evaluation changed initial diagnosis in a quarter of patients. We suggest standardized re-evaluation of all RS patients. Despite the relatively high diagnostic yield pathogenesis could be determined in only 59.7% (71/119), due to limited insight in pathogenesis in diagnosed entities. Further studies into pathogenesis of entities causing RS are indicated. © 2015 Wiley Periodicals, Inc.
    No preview · Article · May 2015 · American Journal of Medical Genetics Part A
  • Elcke J Kranendonk · M Corrette Ploem · Raoul C M Hennekam
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    ABSTRACT: Many current paediatric studies concern relationships between genes and environment and discuss aetiology, treatment and prevention of Mendelian and multifactorial diseases. Many of these studies depend on collection and long-term storage of data and biological material from affected children in biobanks. Stored material is a source of personal information of the donor and his family and could be used in an undesirable context, potentially leading to discrimination and interfering with a child's right to an open future. Here, we address the normative framework regarding biobanking with residual tissue of children, protecting the privacy interests of young biobank donors (0-12 years). We analyse relevant legal documents concerning storage and use of children's material for research purposes. We explore the views of 17 Dutch experts involved in paediatric biobank research and focus on informed consent for donation of leftover tissue as well as disclosure of individual research findings resulting from biobank research. The results of this analysis show that experts have no clear consensus about the appropriate rules for storage of and research with children's material in biobanks. Development of a framework that provides a fair balance between fundamental paediatric research and privacy protection is necessary.European Journal of Human Genetics advance online publication, 15 April 2015; doi:10.1038/ejhg.2015.59.
    No preview · Article · Apr 2015 · European journal of human genetics: EJHG
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    ABSTRACT: Frontometaphyseal dysplasia (FMD) is a distinctive sclerosing skeletal dysplasia associated with a number of non-skeletal manifestations including hearing loss, cardiac malformations, and stenosis, particularly of the upper airway and urinary tract. Some, but not all, patients have mutations in FLNA causing the condition. Consonant with the X chromosomal location of FLNA males are generally more severely affected than females. FLNA mutations can be detected in 82% of affected males. We describe seven patients (one male, six females) all of whom have the major clinical and radiological features of FMD, but without detectable mutations in FLNA. The females in our cohort are affected to a similar degree as is usually found in males. In addition, all patients have marked keloid formation at various body sites, including the eye, from an early age. Other features that may indicate a different etiology in these patients are the increased frequency of cleft palate, Robin sequence, tracheal stenosis, and mild intellectual disability, which all occur in three of more patients in the present group. All patients are isolated. We hypothesize that the presently reported patients represent further evidence that phenotypes strongly resembling FMD exist that are not accounted for by mutations in FLNA. Since the frequency of several of the manifestations, their sporadic presentations, and the presence of keloid formation differ from the X-linked form of this condition we propose de novo autosomal dominant acting mutations in a gene functionally related to FLNA, underpin this disorder. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Apr 2015 · American Journal of Medical Genetics Part A
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    ABSTRACT: 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. Copyright © 2015. Published by Elsevier Masson SAS.
    Full-text · Article · Mar 2015 · European journal of medical genetics
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    ABSTRACT: Hydrops fetalis is an excessive fluid accumulation within the fetal extra vascular compartments and body cavities. Non-immune hydrops fetalis (NIHF), due to causes other than Rh alloimmunization, is the cause in >85% of all affected individuals. Herein we present an update of our earlier systematic literature review [Bellini et al., 2009] using all publications between 2007 and 2013. We excluded most of the initial 31,783 papers by using strict selection criteria, thus resulting in 24 relevant NIHF publications describing 1,338 individuals with NIHF. We subdivided the affected individuals into 14 classification groups based on the cause of NIHF (percentage of the total group): Cardiovascular (20.1%), Hematologic (9.3%), Chromosomal (9.0%), Syndromic (5.5%), Lymphatic Dysplasia (15.0%), Inborn Errors of Metabolism (1.3%), Infections (7.0%), Thoracic (2.3%), Urinary Tract Malformations (0.9%), Extra Thoracic Tumors (0.7%), TTTF-Placental (4.1%), Gastrointestinal (1.3%), Miscellaneous (3.6%), Idiopathic (19.8%). We discuss the results of the review. There may be some shifts in the percentages of etiological categories as compared to the previous review, but the small numbers within each category make drawing firm conclusions hazardous. We highlight the need for multi-center series of NIHF cases collected and classified using the same schemes in diagnostic work-ups to allow for comparisons of larger numbers of cases. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Feb 2015 · American Journal of Medical Genetics Part A
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    ABSTRACT: Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s). Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Feb 2015 · The American Journal of Human Genetics
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    ABSTRACT: Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of sixteen patients with CdLS-like features caused by mutations in SMC3. Modelling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared to typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for ∼1-2% of CdLS-like phenotypes. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2015 · Human Mutation
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    ABSTRACT: Background Myoclonus-dystonia (M-D) is a hyperkinetic movement disorder with predominant myoclonic symptoms combined with dystonia of the upper part of the body. A proportion of M-D cases are caused by mutations in the epsilon-sarcoglycan gene. In remaining M-D patients, no genetic factor has been established, indicating genetic heterogeneity.Methods Patients were included in a prospective clinical database and recruited from referral centers and general neurology clinics in The Netherlands. To investigate new genetic causal factors in M-D syndrome, we performed homozygosity mapping combined with exome sequencing in a three-generation M-D family and genetically screened 24 additional patients with M-D.ResultsWe found co-segregation of the rare missense variant Thr1904Met in the RELN gene. By additional screening of an M-D cohort, we identified co-segregation of RELN variants in two families (Thr1904Met, Ile1217Met) and identified two sporadic RELN mutation carriers (Pro1703Arg, Leu411Ile). Taken together, five of 25 SGCE-negative M-D patients carried RELN rare missense variants.Conclusion We propose that RELN mutations contribute to the genetic heterogeneity of M-D. Reelin is a large secreted glycoprotein that plays essential roles in the cytoarchitecture of laminated brain structures and modulation of synaptic transmission and plasticity. © 2015 International Parkinson and Movement Disorder Society
    No preview · Article · Feb 2015 · Movement Disorders
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    ABSTRACT: Implementation of next-generation DNA sequencing (NGS) technology into routine diagnostic genome care requires strategic choices. Instead of theoretical discussions on the consequences of such choices, we compared NGS-based diagnostic practices in eight clinical genetic centers in the Netherlands, based on genetic testing of nine pre-selected patients with cardiomyopathy. We highlight critical implementation choices, including the specific contributions of laboratory and medical specialists, bioinformaticians and researchers to diagnostic genome care, and how these affect interpretation and reporting of variants. Reported pathogenic mutations were consistent for all but one patient. Of the two centers that were inconsistent in their diagnosis, one reported to have found 'no causal variant', thereby underdiagnosing this patient. The other provided an alternative diagnosis, identifying another variant as causal than the other centers. Ethical and legal analysis showed that informed consent procedures in all centers were generally adequate for diagnostic NGS applications that target a limited set of genes, but not for exome- and genome-based diagnosis. We propose changes to further improve and align these procedures, taking into account the blurring boundary between diagnostics and research, and specific counseling options for exome- and genome-based diagnostics. We conclude that alternative diagnoses may infer a certain level of 'greediness' to come to a positive diagnosis in interpreting sequencing results. Moreover, there is an increasing interdependence of clinic, diagnostics and research departments for comprehensive diagnostic genome care. Therefore, we invite clinical geneticists, physicians, researchers, bioinformatics experts and patients to reconsider their role and position in future diagnostic genome care.
    Full-text · Article · Jan 2015 · European Journal of HumanGenetics

Publication Stats

18k Citations
2,504.40 Total Impact Points


  • 1994-2016
    • University of Amsterdam
      • • Department of Paediatrics
      • • Faculty of Medicine AMC
      Amsterdamo, North Holland, Netherlands
  • 2015
    • VU University Medical Center
      • Department of Clinical Genetics
      Amsterdamo, North Holland, Netherlands
  • 2014
    • Cedars-Sinai Medical Center
      • Medical Genetics Institute
      Los Angeles, California, United States
  • 1993-2014
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • • Department of Clinical Genetics
      • • Department of Paediatrics
      • • Academic Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2006-2012
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands
    • University of the Ryukyus
      Okinawa, Okinawa, Japan
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • Leiden University Medical Centre
      • Department of Molecular Cell Biology
      Leyden, South Holland, Netherlands
  • 2005-2011
    • Great Ormond Street Hospital for Children NHS Foundation Trust
      • Department of Clinical Genetics
      Londinium, England, United Kingdom
    • Institute of Child Health Calcutta
      Kolkata, West Bengal, India
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • University of Utah
      • Department of Pediatrics
      Salt Lake City, Utah, United States
  • 2010
    • Maastricht University
      Maestricht, Limburg, Netherlands
    • Ghent University
      • Department of Molecular Biotechnology
      Gent, VLG, Belgium
  • 2009
    • IRCCS Ospedale Casa Sollievo della Sofferenza
      Giovanni Rotondo, Apulia, Italy
  • 2006-2009
    • Institute for Child Health Policy (ICHP)
      Florida, United States
  • 2005-2009
    • National Human Genome Research Institute
      Maryland, United States
  • 2008
    • University of London
      Londinium, England, United Kingdom
    • Hospital Egas Moniz
      Lisboa, Lisbon, Portugal
    • Clinical Molecular Genetics Society
      Londinium, England, United Kingdom
  • 2007-2008
    • University College London
      • Institute of Child Health
      Londinium, England, United Kingdom
    • St. James University
      Сент-Джеймс, New York, United States
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
    • University of California, San Francisco
      • Department of Neurology
      San Francisco, California, United States
  • 1989-2005
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands
  • 2004
    • Universitair Ziekenhuis Ghent
      • Centre for Medical Genetics
      Gand, Flanders, Belgium
  • 2000
    • Utrecht University
      Utrecht, Utrecht, Netherlands
    • Université de Versailles Saint-Quentin
      Versailles, Île-de-France, France
  • 1995-1998
    • Leiden University
      • Molecular Cell Biology Group
      Leyden, South Holland, Netherlands
  • 1996
    • Accare – Kinder- en Jeugdpsychiatrie
      Assen, Drenthe, Netherlands