Publications by authors named "Sandra Jansen"

54 Publications

Human disease genes website series: An international, open and dynamic library for up-to-date clinical information.

Am J Med Genet A 2021 04 13;185(4):1039-1046. Epub 2021 Jan 13.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands.

Since the introduction of next-generation sequencing, an increasing number of disorders have been discovered to have genetic etiology. To address diverse clinical questions and coordinate research activities that arise with the identification of these rare disorders, we developed the Human Disease Genes website series (HDG website series): an international digital library that records detailed information on the clinical phenotype of novel genetic variants in the human genome (https://humandiseasegenes.info/). Each gene website is moderated by a dedicated team of clinicians and researchers, focused on specific genes, and provides up-to-date-including unpublished-clinical information. The HDG website series is expanding rapidly with 424 genes currently adopted by 325 moderators from across the globe. On average, a gene website has detailed phenotypic information of 14.4 patients. There are multiple examples of added value, one being the ARID1B gene website, which was recently utilized in research to collect clinical information of 81 new patients. Additionally, several gene websites have more data available than currently published in the literature. In conclusion, the HDG website series provides an easily accessible, open and up-to-date clinical data resource for patients with pathogenic variants of individual genes. This is a valuable resource not only for clinicians dealing with rare genetic disorders such as developmental delay and autism, but other professionals working in diagnostics and basic research. Since the HDG website series is a dynamic platform, its data also include the phenotype of yet unpublished patients curated by professionals providing higher quality clinical detail to improve management of these rare disorders.
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http://dx.doi.org/10.1002/ajmg.a.62057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986414PMC
April 2021

KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.

Authors:
Laura Cif Diane Demailly Jean-Pierre Lin Katy E Barwick Mario Sa Lucia Abela Sony Malhotra Wui K Chong Dora Steel Alba Sanchis-Juan Adeline Ngoh Natalie Trump Esther Meyer Xavier Vasques Julia Rankin Meredith W Allain Carolyn D Applegate Sanaz Attaripour Isfahani Julien Baleine Bettina Balint Jennifer A Bassetti Emma L Baple Kailash P Bhatia Catherine Blanchet Lydie Burglen Gilles Cambonie Emilie Chan Seng Sandra Chantot Bastaraud Fabienne Cyprien Christine Coubes Vincent d'Hardemare Asif Doja Nathalie Dorison Diane Doummar Marisela E Dy-Hollins Ellyn Farrelly David R Fitzpatrick Conor Fearon Elizabeth L Fieg Brent L Fogel Eva B Forman Rachel G Fox William A Gahl Serena Galosi Victoria Gonzalez Tracey D Graves Allison Gregory Mark Hallett Harutomo Hasegawa Susan J Hayflick Ada Hamosh Marie Hully Sandra Jansen Suh Young Jeong Joel B Krier Sidney Krystal Kishore R Kumar Chloé Laurencin Hane Lee Gaetan Lesca Laurence Lion François Timothy Lynch Neil Mahant Julian A Martinez-Agosto Christophe Milesi Kelly A Mills Michel Mondain Hugo Morales-Briceno John R Ostergaard Swasti Pal Juan C Pallais Frédérique Pavillard Pierre-Francois Perrigault Andrea K Petersen Gustavo Polo Gaetan Poulen Tuula Rinne Thomas Roujeau Caleb Rogers Agathe Roubertie Michelle Sahagian Elise Schaefer Laila Selim Richard Selway Nutan Sharma Rebecca Signer Ariane G Soldatos David A Stevenson Fiona Stewart Michel Tchan Ishwar C Verma Bert B A de Vries Jenny L Wilson Derek A Wong Raghda Zaitoun Dolly Zhen Anna Znaczko Russell C Dale Claudio M de Gusmão Jennifer Friedman Victor S C Fung Mary D King Shekeeb S Mohammad Luis Rohena Jeff L Waugh Camilo Toro F Lucy Raymond Maya Topf Philippe Coubes Kathleen M Gorman Manju A Kurian

Brain 2020 12;143(11):3242-3261

Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.
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http://dx.doi.org/10.1093/brain/awaa304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719027PMC
December 2020

Successful Implementation of the Exercise First Approach for Intermittent Claudication in the Netherlands is Associated with Few Lower Limb Revascularisations.

Eur J Vasc Endovasc Surg 2020 Dec 2;60(6):881-887. Epub 2020 Sep 2.

Department of Vascular Surgery and Clinical Epidemiology, OLVG, Amsterdam, the Netherlands.

Objective: A stepped care model, in which patients are primarily treated with supervised exercise therapy (SET), is recommended as the optimal strategy for intermittent claudication (IC). The aim of this study was to determine the primary treatment (SET, endovascular revascularisation [ER], or open surgery) in relation to secondary lower limb revascularisation and survival in patients with IC.

Methods: This study was a nationwide retrospective data analysis of health insurance claims of patients newly diagnosed with IC between January 2013 and December 2017. Exclusion criteria were the presence of diagnostic codes for critical limb ischaemia or for a diabetic foot. Study outcomes were distribution of primary treatment modalities, freedom from secondary lower limb revascularisation, and overall five year survival. Analysis included Kaplan-Meier method and Cox proportional hazards regression models with adjustment for multiple confounders (age, gender, socioeconomic status, use of diabetes medication, statins, platelet aggregation inhibitors or anticoagulants, presence of cardiac disease, chronic obstructive pulmonary disease, and pre-dialysis).

Results: The five year cohort included 54 504 patients with IC (primary SET n = 39 476, primary ER n = 11 769, and primary open surgery n = 3 259). SET as primary treatment increased from 63% in 2013 to 87% in 2017. Patients who underwent ER or open surgery as a primary treatment had a higher risk of secondary revascularisations (hazard ratio [HR] 1.44; 95% confidence interval [CI] 1.37-1.51; p < .001 and HR 1.45; 95% CI 1.34-1.57; p < .001, respectively) and a higher mortality risk compared with SET as a primary treatment (HR 1.38; 95% CI 1.29-1.48; p < .001 and HR 1.49; 95% CI 1.34-1.65; p < .001, respectively).

Conclusion: Guideline adherence improved to 87% in Dutch patients with IC. Patients receiving primary SET had fewer lower limb revascularisations and demonstrated better survival than patients undergoing primary ER or open surgery.
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http://dx.doi.org/10.1016/j.ejvs.2020.07.074DOI Listing
December 2020

Modes of exercise training for intermittent claudication.

Cochrane Database Syst Rev 2020 08 20;8:CD009638. Epub 2020 Aug 20.

Department of Vascular Surgery, Catharina Hospital, Eindhoven, Netherlands.

Background: According to international guidelines and literature, all patients with intermittent claudication should receive an initial treatment of cardiovascular risk modification, lifestyle coaching, and supervised exercise therapy. In the literature, supervised exercise therapy often consists of treadmill or track walking. However, alternative modes of exercise therapy have been described and yielded similar results to walking. This raises the following question: which exercise mode produces the most favourable results? This is the first update of the original review published in 2014.

Objectives: To assess the effects of alternative modes of supervised exercise therapy compared to traditional walking exercise in patients with intermittent claudication.

Search Methods: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 4 March 2019. We also undertook reference checking, citation searching and contact with study authors to identify additional studies. No language restriction was applied.

Selection Criteria: We included parallel-group randomised controlled trials comparing alternative modes of exercise training or combinations of exercise modes with a control group of supervised walking exercise in patients with clinically determined intermittent claudication. The supervised walking programme needed to be supervised at least twice a week for a consecutive six weeks of training.

Data Collection And Analysis: Two review authors independently selected studies, extracted data, and assessed the risk of bias for each study. As we included studies with different treadmill test protocols and different measuring units (metres, minutes, or seconds), the standardised mean difference (SMD) approach was used for summary statistics of mean walking distance (MWD) and pain-free walking distance (PFWD). Summary estimates were obtained for all outcome measures using a random-effects model. We used the GRADE approach to assess the certainty of the evidence.

Main Results: For this update, five additional studies were included, making a total of 10 studies that randomised a total of 527 participants with intermittent claudication (IC). The alternative modes of exercise therapy included cycling, lower-extremity resistance training, upper-arm ergometry, Nordic walking, and combinations of exercise modes. Besides randomised controlled trials, two quasi-randomised trials were included. Overall risk of bias in included studies varied from high to low. According to GRADE criteria, the certainty of the evidence was downgraded to low, due to the relatively small sample sizes, clinical inconsistency, and inclusion of three studies with risk of bias concerns. Overall, comparing alternative exercise modes versus walking showed no clear differences for MWD at 12 weeks (standardised mean difference (SMD) -0.01, 95% confidence interval (CI) -0.29 to 0.27; P = 0.95; 6 studies; 274 participants; low-certainty evidence); or at the end of training (SMD -0.11, 95% CI -0.33 to 0.11; P = 0.32; 9 studies; 412 participants; low-certainty evidence). Similarly, no clear differences were detected in PFWD at 12 weeks (SMD -0.01, 95% CI -0.26 to 0.25; P = 0.97; 5 studies; 249 participants; low-certainty evidence); or at the end of training (SMD -0.06, 95% CI -0.30 to 0.17; P = 0.59; 8 studies, 382 participants; low-certainty evidence). Four studies reported on health-related quality of life (HR-QoL) and three studies reported on functional impairment. As the studies used different measurements, meta-analysis was only possible for the walking impairment questionnaire (WIQ) distance score, which demonstrated little or no difference between groups (MD -5.52, 95% CI -17.41 to 6.36; P = 0.36; 2 studies; 96 participants; low-certainty evidence).

Authors' Conclusions: This review found no clear difference between alternative exercise modes and supervised walking exercise in improving the maximum and pain-free walking distance in patients with intermittent claudication. The certainty of this evidence was judged to be low, due to clinical inconsistency, small sample size and risk of bias concerns. The findings of this review indicate that alternative exercise modes may be useful when supervised walking exercise is not an option. More RCTs with adequate methodological quality and sufficient power are needed to provide solid evidence for comparisons between each alternative exercise mode and the current standard of supervised treadmill walking. Future RCTs should investigate outcome measures on walking behaviour, physical activity, cardiovascular risk, and HR-QoL, using standardised testing methods and reporting of outcomes to allow meaningful comparison across studies.
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http://dx.doi.org/10.1002/14651858.CD009638.pub3DOI Listing
August 2020

The Effect of Arterial Disease Level on Outcomes of Supervised Exercise Therapy for Intermittent Claudication: A Prospective Cohort Study.

Ann Surg 2020 Jul 24. Epub 2020 Jul 24.

Catharina Hospital, Department of Surgery, Eindhoven, The Netherlands.

Objective: To assess whether level of arterial obstruction determines the effectiveness of SET in patients with IC.

Background Data: Guidelines advocate SET before invasive treatment for IC, but early revascularization remains widespread, especially in patients with aortoiliac disease.

Methods: Patients were recruited from 10 Dutch centers between October 2017 and October 2018. Participants received SET first, followed by endovascular or open revascularization in case of insufficient effect. They were grouped according to level of stenosis (aortoiliac, femoropopliteal, multilevel, or rest group with no significant stenosis). Changes from baseline walking performance (maximal and functional walking distance on a treadmill test, 6-minute walk test) and vascular quality of life questionnaire-6 at 3 and 6 months were compared, after multivariate adjustment for possible confounders. Freedom from revascularization was estimated with Kaplan-Meier analysis.

Results: Some 267 patients were eligible for analysis (aortoiliac n = 70, 26%; femoropopliteal n = 115, 43%; multilevel n = 69, 26%; rest n = 13, 5%). No between group differences in walking performance or vascular quality of life questionnaire-6 were found. Mean improvement in maximal walking distance after 6 months was 439 m [99% confidence interval (CI) 297-581], 466 m (99% CI 359-574), 353 m (99% CI 210-496), and 403 m (99% CI 58-749), respectively (P = 0.40). Freedom from intervention was 73.9% for aortoiliac disease and 88.6% for femoropopliteal disease (hazard ratio 2.46, 99% CI 0.96 - 6.30, P = 0.013).

Conclusions: Short-term effectiveness of SET for IC is not determined by the location of stenosis. Although aortoiliac disease patients improved walking performance and health-related quality of life similarly compared to other arterial disease level groups, they underwent revascularization more often.
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http://dx.doi.org/10.1097/SLA.0000000000004073DOI Listing
July 2020

Overrepresentation of genetic variation in the AnkyrinG interactome is related to a range of neurodevelopmental disorders.

Eur J Hum Genet 2020 12 10;28(12):1726-1733. Epub 2020 Jul 10.

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.

Upon the discovery of numerous genes involved in the pathogenesis of neurodevelopmental disorders, several studies showed that a significant proportion of these genes converge on common pathways and protein networks. Here, we used a reversed approach, by screening the AnkyrinG protein-protein interaction network for genetic variation in a large cohort of 1009 cases with neurodevelopmental disorders. We identified a significant enrichment of de novo potentially disease-causing variants in this network, confirming that this protein network plays an important role in the emergence of several neurodevelopmental disorders.
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http://dx.doi.org/10.1038/s41431-020-0682-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785003PMC
December 2020

Primrose syndrome: Characterization of the phenotype in 42 patients.

Clin Genet 2020 06 20;97(6):890-901. Epub 2020 Apr 20.

Department of Pediatrics, Amsterdam UMC, Amsterdam, The Netherlands.

Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.
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http://dx.doi.org/10.1111/cge.13749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384157PMC
June 2020

Exploring associations between older adults' demographic characteristics and their perceptions of self-care actions for communicating with healthcare professionals in southern United States.

Nurs Open 2019 Jul 17;6(3):1133-1142. Epub 2019 Jun 17.

Taiwan History Research Foundation Taipei Taiwan.

Aims: This study examined associations between older adults' demographic factors and their perceived importance of, desire to and ability to perform seven self-care behaviours for communicating with healthcare professionals.

Design: This cross-sectional survey study analysed subset data of 123 older adults 65 years and older, living in southern United States.

Methods: The (57 items, grouped into 11 categories) was used to collect self-reported self-care data. Demographic characteristics were also collected. Descriptive statistics and logistic regression analyses were used to tests for relationships between the variables relevant to the research objective.

Results: Regression findings showed that separated older adults felt less able to share ideas about their healthcare experiences compared to married older adults. Male older adults reported less desire to list issues to discuss and less desire to share ideas about their care experience with their healthcare professionals compared to their female counterparts.
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http://dx.doi.org/10.1002/nop2.315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650656PMC
July 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

Protocol for a prospective, longitudinal cohort study on the effect of arterial disease level on the outcomes of supervised exercise in intermittent claudication: the ELECT Registry.

BMJ Open 2019 02 19;9(2):e025419. Epub 2019 Feb 19.

Department of Vascular Surgery, Catharina Hospital, Eindhoven, The Netherlands.

Introduction: Despite guideline recommendations advocating conservative management before invasive treatment in intermittent claudication, early revascularisation remains widespread in patients with favourable anatomy. The aim of the Effect of Disease Level on Outcomes of Supervised Exercise in Intermittent Claudication Registry is to determine the effect of the location of stenosis on the outcomes of supervised exercise in patients with intermittent claudication due to peripheral arterial disease.

Methods And Analysis: This multicentre prospective cohort study aims to enrol 320 patients in 10 vascular centres across the Netherlands. All patients diagnosed with intermittent claudication (peripheral arterial disease: Fontaine II/Rutherford 1-3), who are considered candidates for supervised exercise therapy by their own physicians are appropriate to participate. Participants will receive standard care, meaning supervised exercise therapy first, with endovascular or open revascularisation in case of insufficient effect (at the discretion of patient and vascular surgeon). For the primary objectives, patients are grouped according to anatomical characteristics of disease (aortoiliac, femoropopliteal or multilevel disease) as apparent on the preferred imaging modality in the participating centre (either duplex, CT angiography or magnetic resonance angiography). Changes in walking performance (treadmill tests, 6 min walk test) and quality of life (QoL; Vascular QoL Questionnaire-6, WHO QoL Questionnaire-Bref) will be compared between groups, after multivariate adjustment for possible confounders. Freedom from revascularisation and major adverse cardiovascular disease events, and attainment of the treatment goal between anatomical groups will be compared using Kaplan-Meier survival curves.

Ethics And Dissemination: This study has been exempted from formal medical ethical approval by the Medical Research Ethics Committees United 'MEC-U' (W17.071). Results are intended for publication in peer-reviewed journals and for presentation to stakeholders nationally and internationally.

Trial Registration Number: NTR7332; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-025419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367988PMC
February 2019

A systematic review and meta-analysis of the effects of supervised exercise therapy on modifiable cardiovascular risk factors in intermittent claudication.

J Vasc Surg 2019 Apr 15;69(4):1293-1308.e2. Epub 2019 Feb 15.

Department of Vascular Surgery, Erasmus University Medical Centre, Rotterdam, The Netherlands.

Objective: Cardiovascular events, such as myocardial infarction and stroke, contribute significantly to the prognosis of patients with peripheral artery disease. Therefore cardiovascular risk reduction is a vital element of treatment in patients with intermittent claudication (IC). The cardiovascular risk is largely determined by modifiable risk factors, which can be treated with medical care and lifestyle adjustments, such as increasing physical activity. The objective of this study was to determine the effects of supervised exercise therapy (SET) on modifiable cardiovascular risk factors in IC patients.

Methods: This is a systematic review and meta-analysis of prospective studies on the effects of SET on cardiovascular risk factors in symptomatic IC patients. Studies were eligible if they presented baseline and follow-up values for at least one of the following risk factors: blood pressure (systolic or diastolic), heart rate, lipid profile (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol), glucose, glycated hemoglobin, body weight, body mass index, or cigarette smoking. Pooled mean differences between follow-up and baseline were analyzed using a random-effects model. Data were classified into short-term results (6 weeks-3 months) and midterm results (6-12 months). Statistical heterogeneity was presented as I and Q statistic.

Results: Twenty-seven studies with a total of 808 patients were included in this review. In the short term, SET resulted in significant improvements of systolic blood pressure (decrease of 4 mm Hg; 10 studies; 95% confidence interval [CI], -6.40 to -1.76; I, 0%) and diastolic blood pressure (decrease of 2 mm Hg; 8 studies; 95% CI, -3.64 to -0.22; I, 35%). In the midterm, SET contributed to significant lowering of levels of low-density lipoprotein cholesterol (decrease of 0.2 mmol/L; four studies; 95% CI, -0.30 to -0.12; I, 29%) and total cholesterol (decrease of 0.2 mmol/L, four studies; 95% CI, -0.38 to -0.10; I, 36%). No significant effects of SET were identified for heart rate, triglycerides, high-density lipoprotein cholesterol, glucose, glycated hemoglobin, body weight, body mass index, or cigarette smoking.

Conclusions: This systematic review and meta-analysis shows favorable effects of SET on modifiable cardiovascular risk factors, specifically blood pressure and cholesterol levels. Despite the moderate quality, small trial sample sizes, and study heterogeneity, these findings support the prescription of SET programs not only to increase walking distances but also for risk factor modification. Future studies should address the potential effectiveness of SET to promote a healthier lifestyle and to improve cardiovascular outcomes in patients with claudication.
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http://dx.doi.org/10.1016/j.jvs.2018.10.069DOI Listing
April 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

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

Authors:
Pleuntje J van der Sluijs Sandra Jansen Samantha A Vergano Miho Adachi-Fukuda Yasemin Alanay Adila AlKindy Anwar Baban Allan Bayat Stefanie Beck-Wödl Katherine Berry Emilia K Bijlsma Levinus A Bok Alwin F J Brouwer Ineke van der Burgt Philippe M Campeau Natalie Canham Krystyna Chrzanowska Yoyo W Y Chu Brain H Y Chung Karin Dahan Marjan De Rademaeker Anne Destree Tracy Dudding-Byth Rachel Earl Nursel Elcioglu Ellen R Elias Christina Fagerberg Alice Gardham Blanca Gener Erica H Gerkes Ute Grasshoff Arie van Haeringen Karin R Heitink Johanna C Herkert Nicolette S den Hollander Denise Horn David Hunt Sarina G Kant Mitsuhiro Kato Hülya Kayserili Rogier Kersseboom Esra Kilic Malgorzata Krajewska-Walasek Kylin Lammers Lone W Laulund Damien Lederer Melissa Lees Vanesa López-González Saskia Maas Grazia M S Mancini Carlo Marcelis Francisco Martinez Isabelle Maystadt Marianne McGuire Shane McKee Sarju Mehta Kay Metcalfe Jeff Milunsky Seiji Mizuno John B Moeschler Christian Netzer Charlotte W Ockeloen Barbara Oehl-Jaschkowitz Nobuhiko Okamoto Sharon N M Olminkhof Carmen Orellana Laurent Pasquier Caroline Pottinger Vera Riehmer Stephen P Robertson Maian Roifman Caroline Rooryck Fabienne G Ropers Monica Rosello Claudia A L Ruivenkamp Mahmut S Sagiroglu Suzanne C E H Sallevelt Amparo Sanchis Calvo Pelin O Simsek-Kiper Gabriela Soares Lucia Solaeche Fatma Mujgan Sonmez Miranda Splitt Duco Steenbeek Alexander P A Stegmann Constance T R M Stumpel Saori Tanabe Eyyup Uctepe G Eda Utine Hermine E Veenstra-Knol Sunita Venkateswaran Catheline Vilain Catherine Vincent-Delorme Anneke T Vulto-van Silfhout Patricia Wheeler Golder N Wilson Louise C Wilson Bernd Wollnik Tomoki Kosho Dagmar Wieczorek Evan Eichler Rolph Pfundt Bert B A de Vries Jill Clayton-Smith Gijs W E Santen

Genet Med 2019 Sep;21(9):2160-2161

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

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-018-0368-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752317PMC
September 2019

De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms.

Eur J Hum Genet 2019 05 24;27(5):738-746. Epub 2019 Jan 24.

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

Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.
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http://dx.doi.org/10.1038/s41431-018-0292-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462006PMC
May 2019

De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders.

Am J Hum Genet 2019 01 27;104(1):139-156. Epub 2018 Dec 27.

Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboudumc, PO Box 9101, 6500 HB Nijmegen, the Netherlands. Electronic address:

Type 2A protein phosphatases (PP2As) are highly expressed in the brain and regulate neuronal signaling by catalyzing phospho-Ser/Thr dephosphorylations in diverse substrates. PP2A holoenzymes comprise catalytic C-, scaffolding A-, and regulatory B-type subunits, which determine substrate specificity and physiological function. Interestingly, de novo mutations in genes encoding A- and B-type subunits have recently been implicated in intellectual disability (ID) and developmental delay (DD). We now report 16 individuals with mild to profound ID and DD and a de novo mutation in PPP2CA, encoding the catalytic Cα subunit. Other frequently observed features were severe language delay (71%), hypotonia (69%), epilepsy (63%), and brain abnormalities such as ventriculomegaly and a small corpus callosum (67%). Behavioral problems, including autism spectrum disorders, were reported in 47% of individuals, and three individuals had a congenital heart defect. PPP2CA de novo mutations included a partial gene deletion, a frameshift, three nonsense mutations, a single amino acid duplication, a recurrent mutation, and eight non-recurrent missense mutations. Functional studies showed complete PP2A dysfunction in four individuals with seemingly milder ID, hinting at haploinsufficiency. Ten other individuals showed mutation-specific biochemical distortions, including poor expression, altered binding to the A subunit and specific B-type subunits, and impaired phosphatase activity and C-terminal methylation. Four were suspected to have a dominant-negative mechanism, which correlated with severe ID. Two missense variants affecting the same residue largely behaved as wild-type in our functional assays. Overall, we found that pathogenic PPP2CA variants impair PP2A-B56(δ) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes.
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http://dx.doi.org/10.1016/j.ajhg.2018.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323609PMC
January 2019

Next-generation phenotyping using computer vision algorithms in rare genomic neurodevelopmental disorders.

Genet Med 2019 08 20;21(8):1719-1725. Epub 2018 Dec 20.

Princess Máxima Center for Pediatric Oncology, Bilthoven, The Netherlands.

Purpose: The interpretation of genetic variants after genome-wide analysis is complex in heterogeneous disorders such as intellectual disability (ID). We investigate whether algorithms can be used to detect if a facial gestalt is present for three novel ID syndromes and if these techniques can help interpret variants of uncertain significance.

Methods: Facial features were extracted from photos of ID patients harboring a pathogenic variant in three novel ID genes (PACS1, PPM1D, and PHIP) using algorithms that model human facial dysmorphism, and facial recognition. The resulting features were combined into a hybrid model to compare the three cohorts against a background ID population.

Results: We validated our model using images from 71 individuals with Koolen-de Vries syndrome, and then show that facial gestalts are present for individuals with a pathogenic variant in PACS1 (p = 8 × 10), PPM1D (p = 4.65 × 10), and PHIP (p = 6.3 × 10). Moreover, two individuals with a de novo missense variant of uncertain significance in PHIP have significant similarity to the expected facial phenotype of PHIP patients (p < 1.52 × 10).

Conclusion: Our results show that analysis of facial photos can be used to detect previously unknown facial gestalts for novel ID syndromes, which will facilitate both clinical and molecular diagnosis of rare and novel syndromes.
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http://dx.doi.org/10.1038/s41436-018-0404-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752476PMC
August 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

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

Authors:
Pleuntje J van der Sluijs Sandra Jansen Samantha A Vergano Miho Adachi-Fukuda Yasemin Alanay Adila AlKindy Anwar Baban Allan Bayat Stefanie Beck-Wödl Katherine Berry Emilia K Bijlsma Levinus A Bok Alwin F J Brouwer Ineke van der Burgt Philippe M Campeau Natalie Canham Krystyna Chrzanowska Yoyo W Y Chu Brain H Y Chung Karin Dahan Marjan De Rademaeker Anne Destree Tracy Dudding-Byth Rachel Earl Nursel Elcioglu Ellen R Elias Christina Fagerberg Alice Gardham Blanca Gener Erica H Gerkes Ute Grasshoff Arie van Haeringen Karin R Heitink Johanna C Herkert Nicolette S den Hollander Denise Horn David Hunt Sarina G Kant Mitsuhiro Kato Hülya Kayserili Rogier Kersseboom Esra Kilic Malgorzata Krajewska-Walasek Kylin Lammers Lone W Laulund Damien Lederer Melissa Lees Vanesa López-González Saskia Maas Grazia M S Mancini Carlo Marcelis Francisco Martinez Isabelle Maystadt Marianne McGuire Shane McKee Sarju Mehta Kay Metcalfe Jeff Milunsky Seiji Mizuno John B Moeschler Christian Netzer Charlotte W Ockeloen Barbara Oehl-Jaschkowitz Nobuhiko Okamoto Sharon N M Olminkhof Carmen Orellana Laurent Pasquier Caroline Pottinger Vera Riehmer Stephen P Robertson Maian Roifman Caroline Rooryck Fabienne G Ropers Monica Rosello Claudia A L Ruivenkamp Mahmut S Sagiroglu Suzanne C E H Sallevelt Amparo Sanchis Calvo Pelin O Simsek-Kiper Gabriela Soares Lucia Solaeche Fatma Mujgan Sonmez Miranda Splitt Duco Steenbeek Alexander P A Stegmann Constance T R M Stumpel Saori Tanabe Eyyup Uctepe G Eda Utine Hermine E Veenstra-Knol Sunita Venkateswaran Catheline Vilain Catherine Vincent-Delorme Anneke T Vulto-van Silfhout Patricia Wheeler Golder N Wilson Louise C Wilson Bernd Wollnik Tomoki Kosho Dagmar Wieczorek Evan Eichler Rolph Pfundt Bert B A de Vries Jill Clayton-Smith Gijs W E Santen

Genet Med 2019 06 8;21(6):1295-1307. Epub 2018 Nov 8.

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

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting.

Methods: Clinicians entered clinical data in an extensive web-based survey.

Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified.

Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.
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http://dx.doi.org/10.1038/s41436-018-0330-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752273PMC
June 2019

Do patients' demographic characteristics affect their perceptions of self-care actions to find safe and decent care?

Appl Nurs Res 2018 10 28;43:24-29. Epub 2018 Jun 28.

Whitson-Hester School of Nursing, Tennessee Technological University, Cookeville, TN 38506, USA. Electronic address:

Aim(s): This exploratory study examined the relationship of five patient demographic characteristics (residence in an urban or rural site, gender, age group, marital status, and education level) with the patients' (1) perceived importance of, (2) desire to, (3) ability to perform four patient engagement self-care actions that result in finding safe and decent care.

Background: Equitable access to health care is essential in a humanized health care system. Healthcare providers must engage patients in discussions about their desires for their care to create person-centered care plans reflecting patient values and wishes.

Methods: This secondary data analysis from a cross-sectional survey project surveyed community-dwelling adults living in the southern United States, 2015-2016. This paper only includes responses of participants aged 65 years and older (N = 123). Data collected in The Patient Action Inventory for Self-Care and demographic questions were used. Chi-square tests and multiple logistic regression analyses were used.

Results: As revealed in the Chi-square and logistic regression findings, self-care actions of "finding a doctor or practitioner who meets your needs," "using available information to choose a doctor or practitioner," and "using data to choose a hospital or clinic" showed some associations with whether seniors resided in an urban or rural community, age group, and marital status (P < 0.05). No significant associations between these four self-care actions with gender or education were found.

Conclusions: A community-based solution is warranted to leverage between patient demographic characteristics and their perceived self-care actions by harnessing local factors in collaboration with identified patient needs.
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http://dx.doi.org/10.1016/j.apnr.2018.06.020DOI Listing
October 2018

Should the Extended Lateral Approach Remain Part of Standard Treatment in Displaced Intra-articular Calcaneal Fractures?

J Foot Ankle Surg 2018 Nov - Dec;57(6):1120-1124. Epub 2018 Sep 8.

Trauma Surgeon, Department of Surgery and Traumatology, Catharina Hospital, Eindhoven, the Netherlands.

The aim of this study was to evaluate the results of open reduction and internal fixation through the extended lateral approach (ELA) in displaced intra-articular calcaneal fractures and to determine whether this approach should remain part of standard therapy. This retrospective cohort study included 60 patients with 64 displaced intra-articular calcaneal fractures who underwent surgical treatment through the ELA. Outcome measures were the visual analog scale foot and ankle (VAS FA), the American Orthopedic Foot and Ankle Society (AOFAS) score, surgical site infections (SSIs), and reoperations. We determined the AOFAS score for 40 patients with 42 fractures, and 42 patients with 44 fractures completed the VAS FA questionnaire. The mean VAS FA score was 61.0 ± 23.4 and the median AOFAS score was 83 (range 33 to 100), with 55% good to excellent scores. We found 10.9% superficial SSIs successfully treated with antibiotics. In 4.7% of patients a deep SSI was diagnosed, wherefore premature implant removal was necessary. Patients with an SSI did not have significantly lower VAS FA or AOFAS scores than did patients without an SSI (p = .318 and p = .766, respectively). Implant removal in absence of SSIs was necessary in 17 patients because of pain, and 3 patients needed secondary arthrodesis because of persistent pain. We concluded that the ELA proved to be a safe procedure, and moreover the most common complications did not influence the long-term outcomes of patients. However, recent literature demonstrates that less invasive techniques seem to exceed the ELA with respect to wound complications.
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http://dx.doi.org/10.1053/j.jfas.2018.05.015DOI Listing
February 2019

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

Recurrent De Novo Mutations Disturbing the GTP/GDP Binding Pocket of RAB11B Cause Intellectual Disability and a Distinctive Brain Phenotype.

Am J Hum Genet 2017 Nov 26;101(5):824-832. Epub 2017 Oct 26.

Department of Human Genetics, and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6500 HB, the Netherlands. Electronic address:

The Rab GTPase family comprises ∼70 GTP-binding proteins, functioning in vesicle formation, transport and fusion. They are activated by a conformational change induced by GTP-binding, allowing interactions with downstream effectors. Here, we report five individuals with two recurrent de novo missense mutations in RAB11B; c.64G>A; p.Val22Met in three individuals and c.202G>A; p.Ala68Thr in two individuals. An overlapping neurodevelopmental phenotype, including severe intellectual disability with absent speech, epilepsy, and hypotonia was observed in all affected individuals. Additionally, visual problems, musculoskeletal abnormalities, and microcephaly were present in the majority of cases. Re-evaluation of brain MRI images of four individuals showed a shared distinct brain phenotype, consisting of abnormal white matter (severely decreased volume and abnormal signal), thin corpus callosum, cerebellar vermis hypoplasia, optic nerve hypoplasia and mild ventriculomegaly. To compare the effects of both variants with known inactive GDP- and active GTP-bound RAB11B mutants, we modeled the variants on the three-dimensional protein structure and performed subcellular localization studies. We predicted that both variants alter the GTP/GDP binding pocket and show that they both have localization patterns similar to inactive RAB11B. Evaluation of their influence on the affinity of RAB11B to a series of binary interactors, both effectors and guanine nucleotide exchange factors (GEFs), showed induction of RAB11B binding to the GEF SH3BP5, again similar to inactive RAB11B. In conclusion, we report two recurrent dominant mutations in RAB11B leading to a neurodevelopmental syndrome, likely caused by altered GDP/GTP binding that inactivate the protein and induce GEF binding and protein mislocalization.
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http://dx.doi.org/10.1016/j.ajhg.2017.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673605PMC
November 2017

Biallelicframeshift mutation in RIN2 in a patient with intellectual disability and cataract, without RIN2 syndrome.

Am J Med Genet A 2017 12 19;173(12):3238-3240. Epub 2017 Oct 19.

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

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http://dx.doi.org/10.1002/ajmg.a.38396DOI Listing
December 2017

Phenotypes and genotypes in individuals with SMC1A variants.

Am J Med Genet A 2017 Aug 26;173(8):2108-2125. Epub 2017 May 26.

Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.
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http://dx.doi.org/10.1002/ajmg.a.38279DOI Listing
August 2017

Oral administration of methysticin improves cognitive deficits in a mouse model of Alzheimer's disease.

Redox Biol 2017 08 19;12:843-853. Epub 2017 Apr 19.

Department of Anatomy and Cell Biology, Uniklinik RWTH Aachen University, Aachen, Germany. Electronic address:

Introduction: There is increasing evidence for the involvement of chronic inflammation and oxidative stress in the pathogenesis of Alzheimer's disease (AD). Nuclear factor erythroid 2-related factor 2 (Nrf2) is an anti-inflammatory transcription factor that regulates the oxidative stress defense. Our previous experiments demonstrated that kavalactones protect neuronal cells against Amyloid β (Aβ)-induced oxidative stress in vitro by Nrf2 pathway activation. Here, we tested an in vivo kavalactone treatment in a mouse model of AD.

Methods: The kavalactone methysticin was administered once a week for a period of 6 months to 6 month old transgenic APP/Psen1 mice by oral gavage. Nrf2 pathway activation was measured by methysticin treatment of ARE-luciferase mice, by qPCR of Nrf2-target genes and immunohistochemical detection of Nrf2. Aβ burden was analyzed by CongoRed staining, immunofluorescent detection and ELISA. Neuroinflammation was assessed by immunohistochemical stainings for microglia and astrocytes. Pro-inflammatory cytokines in the hippocampus was determined by Luminex multi-plex assays. The hippocampal oxidative damage was detected by oxyblot technique and immunohistochemical staining against DT3 and 4-HNE. The cognitive ability of mice was evaluated using Morris water maze.

Results: Methysticin treatment activated the Nrf2 pathway in the hippocampus and cortex of mice. The Aβ deposition in brains of methysticin-treated APP/Psen1 mice was not altered compared to untreated mice. However, methysticin treatment significantly reduced microgliosis, astrogliosis and secretion of the pro-inflammatory cytokines TNF-α and IL-17A. In addition, the oxidative damage of hippocampi from APP/Psen1 mice was reduced by methysticin treatment. Most importantly, methysticin treatment significantly attenuated the long-term memory decline of APP/Psen1 mice.

Conclusion: In summary, these findings show that methysticin administration activates the Nrf2 pathway and reduces neuroinflammation, hippocampal oxidative damage and memory loss in a mouse model of AD. Therefore, kavalactones might be suitable candidates to serve as lead compounds for the development of a new class of neuroprotective drugs.
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http://dx.doi.org/10.1016/j.redox.2017.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5406548PMC
August 2017

De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome.

Am J Hum Genet 2017 Apr 23;100(4):650-658. Epub 2017 Mar 23.

Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands. Electronic address:

Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.
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http://dx.doi.org/10.1016/j.ajhg.2017.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384016PMC
April 2017

Psoriasin has divergent effects on the innate immune responses of murine glial cells.

J Neurochem 2017 04 27;141(1):86-99. Epub 2017 Feb 27.

Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany.

Antimicrobial peptides are an important part of the innate immune defense in the central nervous system (CNS). The expression of the antimicrobial peptides psoriasin (S100A7) is up-regulated during bacterial meningitis. However, the exact mechanisms induced by psoriasin to modulate glial cell activity are not yet fully understood. Our hypothesis is that psoriasin induced pro- and anti-inflammatory signaling pathways as well as regenerative factors to contribute in total to a balanced immune response. Therefore, we used psoriasin-stimulated glial cells and analyzed the translocation of the pro-inflammatory transcription factor nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFκB) in murine glial cells and the expression of pro- and anti-inflammatory mediators by real time RT-PCR, ELISA technique, and western blotting. Furthermore, the relationship between psoriasin and the antioxidative stress transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) was investigated. Stimulation with psoriasin not only enhanced NFκB translocation and increased the expression of the pro-inflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α) but also neurotrophin expression. Evidence for functional interactions between psoriasin and Nrf2 were detected in the form of increased antioxidant response element (ARE) activity and induction of Nrf2/ARE-dependent heme oxygenase 1 (HO-1) expression in psoriasin-treated microglia and astrocytes. The results illustrate the ability of psoriasin to induce immunological functions in glia cells where psoriasin exerts divergent effects on the innate immune response.
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http://dx.doi.org/10.1111/jnc.13959DOI Listing
April 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

Duplications of SLC1A3: Associated with ADHD and autism.

Eur J Med Genet 2016 Aug 11;59(8):373-6. Epub 2016 Jun 11.

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

We report four patients with a similar gain in 5p13.2 encompassing a single gene: SLC1A3. Behavioural problems resembling ADHD and/or autism-like features are observed which is in line with the glial glutamate transporter role of SLC1A3. We consider an association between SLC1A3 and the behavioural problems which can also be considered a contributing factor to behavioural problems in larger duplications overlapping the 5p13 microduplication syndrome region.
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http://dx.doi.org/10.1016/j.ejmg.2016.06.003DOI Listing
August 2016