Publications by authors named "M W Mariet Elting"

46 Publications

Usefulness of NGS for Diagnosis of Dominant Beta-Thalassemia and Unstable Hemoglobinopathies in Five Clinical Cases.

Front Physiol 2021 5;12:628236. Epub 2021 Feb 5.

Translational Research in Child and Adolescent Cancer - Rare Anemia Disorders Research Laboratory, Vall d'Hebron Research Institute, ERN-EuroBloodNet Member, Barcelona, Spain.

Unstable hemoglobinopathies (UHs) are rare anemia disorders (RADs) characterized by abnormal hemoglobin (Hb) variants with decreased stability. UHs are therefore easily precipitating, causing hemolysis and, in some cases, leading to dominant beta-thalassemia (dBTHAL). The clinical picture of UHs is highly heterogeneous, inheritance pattern is dominant, instead of recessive as in more prevalent major Hb syndromes, and may occur . Most cases of UHs are not detected by conventional testing, therefore diagnosis requires a high index of suspicion of the treating physician. Here, we highlight the importance of next generation sequencing (NGS) methodologies for the diagnosis of patients with dBTHAL and other less severe UH variants. We present five unrelated clinical cases referred with chronic hemolytic anemia, three of them with severe blood transfusion dependent anemia. Targeted NGS analysis was performed in three cases while whole exome sequencing (WES) analysis was performed in two cases. Five different UH variants were identified correlating with patients' clinical manifestations. Four variants were related to the beta-globin gene (Hb Bristol-Alesha, Hb Debrousse, Hb Zunyi, and the novel Hb Mokum) meanwhile one case was caused by a mutation in the alpha-globin gene leading to Hb Evans. Inclusion of alpha and beta-globin genes in routine NGS approaches for RADs has to be considered to improve diagnosis' efficiency of RAD due to UHs. Reducing misdiagnoses and underdiagnoses of UH variants, especially of the severe forms leading to dBTHAL would also facilitate the early start of intensive or curative treatments for these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2021.628236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893112PMC
February 2021

Knitting Ripples.

Patterns (N Y) 2020 May 8;1(2):100034. Epub 2020 May 8.

Department of Physics, North Carolina State University, Raleigh, NC, USA.

Ripples are common in both biological systems and human clothes. Knitters have long exploited the ability of fabric to curl out of plane, by either removing or adding stitches to the material as it is created. Here, we present two knitting patterns for scarves to illustrate how ripples can arise through such additive processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.patter.2020.100034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660358PMC
May 2020

Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum.

Am J Hum Genet 2020 09 27;107(3):499-513. Epub 2020 Jul 27.

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

Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2020.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477014PMC
September 2020

Rapid whole exome sequencing in pregnancies to identify the underlying genetic cause in fetuses with congenital anomalies detected by ultrasound imaging.

Prenat Diagn 2020 07 5;40(8):972-983. Epub 2020 May 5.

Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.

Objective: The purpose of this study was to explore the diagnostic yield and clinical utility of trio-based rapid whole exome sequencing (rWES) in pregnancies of fetuses with a wide range of congenital anomalies detected by ultrasound imaging.

Methods: In this observational study, we analyzed the first 54 cases referred to our laboratory for prenatal rWES to support clinical decision making, after the sonographic detection of fetal congenital anomalies. The most common identified congenital anomalies were skeletal dysplasia (n = 20), multiple major fetal congenital anomalies (n = 17) and intracerebral structural anomalies (n = 7).

Results: A conclusive diagnosis was identified in 18 of the 54 cases (33%). Pathogenic variants were detected most often in fetuses with skeletal dysplasia (n = 11) followed by fetuses with multiple major fetal congenital anomalies (n = 4) and intracerebral structural anomalies (n = 3). A survey, completed by the physicians for 37 of 54 cases, indicated that the rWES results impacted clinical decision making in 68% of cases.

Conclusions: These results suggest that rWES improves prenatal diagnosis of fetuses with congenital anomalies, and has an important impact on prenatal and peripartum parental and clinical decision making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.5717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497059PMC
July 2020

De novo variants in PAK1 lead to intellectual disability with macrocephaly and seizures.

Brain 2019 11;142(11):3351-3359

Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany.

Using trio exome sequencing, we identified de novo heterozygous missense variants in PAK1 in four unrelated individuals with intellectual disability, macrocephaly and seizures. PAK1 encodes the p21-activated kinase, a major driver of neuronal development in humans and other organisms. In normal neurons, PAK1 dimers reside in a trans-inhibited conformation, where each autoinhibitory domain covers the kinase domain of the other monomer. Upon GTPase binding via CDC42 or RAC1, the PAK1 dimers dissociate and become activated. All identified variants are located within or close to the autoinhibitory switch domain that is necessary for trans-inhibition of resting PAK1 dimers. Protein modelling supports a model of reduced ability of regular autoinhibition, suggesting a gain of function mechanism for the identified missense variants. Alleviated dissociation into monomers, autophosphorylation and activation of PAK1 influences the actin dynamics of neurite outgrowth. Based on our clinical and genetic data, as well as the role of PAK1 in brain development, we suggest that gain of function pathogenic de novo missense variants in PAK1 lead to moderate-to-severe intellectual disability, macrocephaly caused by the presence of megalencephaly and ventriculomegaly, (febrile) seizures and autism-like behaviour.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awz264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821231PMC
November 2019

KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.

Eur J Hum Genet 2020 01 5;28(1):40-49. Epub 2019 Sep 5.

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

Variants in the KIF1A gene can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal (de novo) dominant mental retardation type 9. More recently, variants in KIF1A have also been described in a few cases with autosomal dominant spastic paraplegia. Here, we describe 20 KIF1A variants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly 'pure' spastic paraplegia. In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0-57 years). Segregation analyses showed a de novo occurrence in seven cases, and a dominant inheritance pattern in 11 families. The motor domain of KIF1A is a hotspot for disease causing variants in autosomal dominant spastic paraplegia, similar to mental retardation type 9 and recessive spastic paraplegia type 30. However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families. Finally, three missense variants were outside the motor domain and need further characterization. In conclusion, KIF1A variants are a frequent cause of autosomal dominant spastic paraplegia in our cohort (6-7%). The identification of KIF1A loss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic paraplegia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-019-0497-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906463PMC
January 2020

Prenatal ultrasound findings of rasopathies in a cohort of 424 fetuses: update on genetic testing in the NGS era.

J Med Genet 2019 10 30;56(10):654-661. Epub 2019 Apr 30.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands

Background: This study evaluates 6 years of prenatal rasopathy testing in the Netherlands, updates on previous data and gives recommendations for prenatal rasopathy testing.

Methods: 424 fetal samples, sent in for prenatal rasopathy testing in 2011-2016, were collected. Cohort 1 included 231 samples that were sequenced for 1-5 rasopathy genes. Cohort 2 included 193 samples that were analysed with a 14-gene next generation sequencing (NGS) panel. For all mutation-positive samples in both cohorts, the referring physician provided detailed ultrasound findings and postnatal follow-up. For 168 mutation-negative samples in cohort 2, solely clinical information on the requisition form was collected.

Results: In total, 40 (likely) pathogenic variants were detected (9.4%). All fetuses showed a variable degree of involvement of prenatal findings: increased nuchal translucency (NT)/cystic hygroma, distended jugular lymph sacs (JLS), hydrops fetalis, polyhydramnios, pleural effusion, ascites, cardiac defects and renal anomalies. An increased NT was the most common finding. Eight fetuses showed solely an increased NT/cystic hygroma, which were all larger than 5.5 mm. Ascites and renal anomalies appeared to be poor predictors of pathogenic outcome.

Conclusion: Fetuses with a rasopathy show in general multiple ultrasound findings. The larger the NT and the longer it persists, the more likely it is to find a pathogenic variant. Rasopathy testing is recommended when the fetus shows an isolated increased NT ≥5.0 mm or when NT of ≥3.5 mm and at least one of the following ultrasound anomalies is present: distended JLS, hydrops fetalis, polyhydramnios, pleural effusion, ascites, cardiac defects and renal anomalies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2018-105746DOI Listing
October 2019

Fatal neonatal hypertrophic cardiomyopathy caused by compound heterozygous truncating MYBPC3 mutation.

Neth Heart J 2019 May;27(5):282-283

Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12471-019-1245-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470222PMC
May 2019

A common pathomechanism in GMAP-210- and LBR-related diseases.

JCI Insight 2018 12 6;3(23). Epub 2018 Dec 6.

Department of Pediatrics, Medical Centre-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Biallelic loss-of-function mutations in TRIP11, encoding the golgin GMAP-210, cause the lethal human chondrodysplasia achondrogenesis 1A (ACG1A). We now find that a homozygous splice-site mutation of the lamin B receptor (LBR) gene results in the same phenotype. Intrigued by the genetic heterogeneity, we compared GMAP-210- and LBR-deficient primary cells to unravel how particular mutations in LBR cause a phenocopy of ACG1A. We could exclude a regulatory interaction between LBR and GMAP-210 in patients' cells. However, we discovered a common disruption of Golgi apparatus architecture that was accompanied by decreased secretory trafficking in both cases. Deficiency of Golgi-dependent glycan processing indicated a similar downstream effect of the disease-causing mutations upon Golgi function. Unexpectedly, our results thus point to a common pathogenic mechanism in GMAP-210- and LBR-related diseases attributable to defective secretory trafficking at the Golgi apparatus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.121150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328090PMC
December 2018

Abnormal eyeblink conditioning is an early marker of cerebellar dysfunction in preclinical SCA3 mutation carriers.

Exp Brain Res 2019 Feb 14;237(2):427-433. Epub 2018 Nov 14.

Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.

Background: Spinocerebellar ataxias (SCAs) are a group of autosomal dominantly inherited degenerative diseases. As the pathological process probably commences years before the first appearance of clinical symptoms, preclinical carriers of a SCA mutation offer the opportunity to study the earliest stages of cerebellar dysfunction and degeneration. Eyeblink classical conditioning (EBCC) is a motor learning paradigm, crucially dependent on the integrity of the olivocerebellar circuit, and has been shown to be able to detect subtle alterations of cerebellar function, which might already be present in preclinical carriers.

Methods: In order to acquire conditioned responses, we performed EBCC, delay paradigm, in 18 preclinical carriers of a SCA3 mutation and 16 healthy, age-matched controls by presenting repeated pairings of an auditory tone with a supraorbital nerve stimulus with a delay interval of 400 ms.

Results: Preclinical carriers acquired significantly less conditioned eyeblink responses than controls and learning rates were significantly reduced. This motor learning defect was, however, not associated with the predicted time to onset.

Conclusions: EBCC is impaired in preclinical carriers of a SCA3 mutation, as a result of impaired motor learning capacities of the cerebellum and is thus suggestive of cerebellar dysfunction. EBCC can be used to detect but probably not monitor preclinical cerebellar dysfunction in genetic ataxias, such as SCA3.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00221-018-5424-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373441PMC
February 2019

KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.

Genet Med 2019 04 24;21(4):850-860. Epub 2018 Sep 24.

Clinical Genetics, University Hospitals Bristol, Southwell St, Bristol, UK.

Purpose: Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported.

Methods: We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review.

Results: We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late-truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction.

Conclusion: Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-018-0259-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634310PMC
April 2019

The Spindle: Integrating Architecture and Mechanics across Scales.

Trends Cell Biol 2018 11 6;28(11):896-910. Epub 2018 Aug 6.

Department of Cell & Tissue Biology, 513 Parnassus Ave, University of California, San Francisco, CA 94143, USA; Biophysics Graduate Program, 513 Parnassus Ave, University of California, San Francisco, CA 94143, USA; Department of Cellular & Molecular Pharmacology, 513 Parnassus Ave, University of California, San Francisco, CA 94143, USA. Electronic address:

The spindle segregates chromosomes at cell division, and its task is a mechanical one. While we have a nearly complete list of spindle components, how their molecular-scale mechanics give rise to cellular-scale spindle architecture, mechanics, and function is not yet clear. Recent in vitro and in vivo measurements bring new levels of molecular and physical control and shed light on this question. Highlighting recent findings and open questions, we introduce the molecular force generators of the spindle, and discuss how they organize microtubules into diverse architectural modules and give rise to the emergent mechanics of the mammalian spindle. Throughout, we emphasize the breadth of space and time scales at play, and the feedback between spindle architecture, dynamics, and mechanics that drives robust function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tcb.2018.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197898PMC
November 2018

Further audiovestibular characterization of DFNB77, caused by deleterious variants in LOXHD1, and investigation into the involvement of Fuchs corneal dystrophy.

Clin Genet 2018 08 8;94(2):221-231. Epub 2018 Jun 8.

Department of Otorhinolaryngology, Hearing & Genes, Radboud University Medical Center, Nijmegen, the Netherlands.

This study focuses on further characterization of the audiovestibular phenotype and on genotype-phenotype correlations of DFNB77, an autosomal recessive type of hearing impairment (HI). DFNB77 is associated with disease-causing variants in LOXHD1, and is genetically and phenotypically highly heterogeneous. Heterozygous deleterious missense variants in LOXHD1 have been associated with late-onset Fuchs corneal dystrophy (FCD). However, up to now screening for FCD of heterozygous carriers in DFNB77 families has not been reported. This study describes the genotype and audiovestibular phenotype of 9 families with DFNB77. In addition, carriers within the families were screened for FCD. Fifteen pathogenic missense and truncating variants were identified, of which 12 were novel. The hearing phenotype showed high inter- and intrafamilial variation in severity and progression. There was no evidence for involvement of the vestibular system. None of the carriers showed (pre-clinical) symptoms of FCD. Our findings expand the genotypic and phenotypic spectrum of DFNB77, but a clear correlation between the type or location of the variant and the severity or progression of HI could not be established. We hypothesize that environmental factors or genetic modifiers are responsible for phenotypic differences. No association was found between heterozygous LOXHD1 variants and the occurrence of FCD in carriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13368DOI Listing
August 2018

Toward clinical and molecular understanding of pathogenic variants in the ZBTB18 gene.

Mol Genet Genomic Med 2018 05 24;6(3):393-400. Epub 2018 Mar 24.

Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.

Background: Patients with pathogenic variants in ZBTB18 present with Intellectual Disability (ID) with frequent co-occurrence of corpus callosum (CC) anomalies, hypotonia, microcephaly, growth problems and variable facial dysmorphologies. These features illustrate a key role for ZBTB18 in brain development.

Methods: Patients with a pathogenic variant in ZBTB18 were detected by diagnostic whole exome sequencing (WES) performed in our center. We reviewed the literature and used GeneMatcher to include other cases. YASARA and WHAT IF were used to provide insight into the structural effect of missense variants located in the C2H2 zinc finger domains of the ZBTB18 protein.

Results: We give a complete overview of pathogenic variants in ZBTB18 detected to date, showing inconsistent presence of clinical features, including CC anomalies. We present four new cases with a de novo pathogenic variant in the ZBTB18 gene, including the fourth case in which a de novo p.Arg464His variant was found.

Conclusion: Homology modeling of protein structure points to a variable degree of impaired DNA binding caused by missense variants in these domains probably leading to Loss of Function (LoF). Putative partial LoF may present with a less distinctive phenotype than complete LoF, as seen in truncating variants, which presents with an extensive variability in the phenotypic spectrum. Our data do not support a clear genotype to phenotype correlation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014478PMC
May 2018

Mapping Load-Bearing in the Mammalian Spindle Reveals Local Kinetochore Fiber Anchorage that Provides Mechanical Isolation and Redundancy.

Curr Biol 2017 Jul 6;27(14):2112-2122.e5. Epub 2017 Jul 6.

Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address:

Active forces generated at kinetochores move chromosomes, and the dynamic spindle must robustly anchor kinetochore fibers (k-fibers) to bear this load. The mammalian spindle bears the load of chromosome movement far from poles, but we do not know where and how-physically and molecularly-this load distributes across the spindle. In part, this is because probing spindle mechanics in live cells is difficult. Yet answering this question is key to understanding how the spindle generates and responds to force and performs its diverse mechanical functions. Here, we map load-bearing across the mammalian spindle in space-time and dissect local anchorage mechanics and mechanism. To do so, we laser-ablate single k-fibers at different spindle locations and in different molecular backgrounds and quantify the immediate relaxation of chromosomes, k-fibers, and microtubule speckles. We find that load redistribution is locally confined in all directions: along the first 3-4 μm from kinetochores, scaling with k-fiber length, and laterally within ∼2 μm of k-fiber sides, without detectable load sharing between neighboring k-fibers. A phenomenological model suggests that dense, transient crosslinks to the spindle along k-fibers bear the load of chromosome movement but that these connections do not limit the timescale of spindle reorganization. The microtubule crosslinker NuMA is needed for the local load-bearing observed, whereas Eg5 and PRC1 are not detectably required, suggesting specialization in mechanical function. Together, the data and model suggest that NuMA-mediated crosslinks locally bear load, providing mechanical isolation and redundancy while allowing spindle fluidity. These features are well suited to support robust chromosome segregation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cub.2017.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579025PMC
July 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.38279DOI Listing
August 2017

The chromokinesin Klp3a and microtubules facilitate acentric chromosome segregation.

J Cell Biol 2017 06 12;216(6):1597-1608. Epub 2017 May 12.

Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064

Although poleward segregation of acentric chromosomes is well documented, the underlying mechanisms remain poorly understood. Here, we demonstrate that microtubules play a key role in poleward movement of acentric chromosome fragments generated in neuroblasts. Acentrics segregate with either telomeres leading or lagging in equal frequency and are preferentially associated with peripheral bundled microtubules. In addition, laser ablation studies demonstrate that segregating acentrics are mechanically associated with microtubules. Finally, we show that successful acentric segregation requires the chromokinesin Klp3a. Reduced Klp3a function results in disorganized interpolar microtubules and shortened spindles. Normally, acentric poleward segregation occurs at the periphery of the spindle in association with interpolar microtubules. In mutants, acentrics fail to localize and segregate along the peripheral interpolar microtubules and are abnormally positioned in the spindle interior. These studies demonstrate an unsuspected role for interpolar microtubules in driving acentric segregation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1083/jcb.201604079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461011PMC
June 2017

Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy.

Am J Hum Genet 2016 06 26;98(6):1249-1255. Epub 2016 May 26.

Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA; Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ 85004, USA; Neurogenetics Research Program, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA; Program in Neuroscience, Arizona State University, Tempe, AZ 85287, USA; Pediatric Movement Disorders Center, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA. Electronic address:

Glutamatergic neurotransmission governs excitatory signaling in the mammalian brain, and abnormalities of glutamate signaling have been shown to contribute to both epilepsy and hyperkinetic movement disorders. The etiology of many severe childhood movement disorders and epilepsies remains uncharacterized. We describe a neurological disorder with epilepsy and prominent choreoathetosis caused by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer-core protein. Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities of glutamatergic neurotransmission in this monogenic neurological disease of childhood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2016.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908178PMC
June 2016

Two cases of RIT1 associated Noonan syndrome: Further delineation of the clinical phenotype and review of the literature.

Am J Med Genet A 2016 07 25;170(7):1874-80. Epub 2016 Apr 25.

Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.

Mutations in RIT1, involved in the RAS-MAPK pathway, have recently been identified as a cause for Noonan syndrome. We present two patients with Noonan syndrome caused by a RIT1 mutation with novel phenotypic manifestations, severe bilateral lower limb lymphedema starting during puberty, and fetal hydrops resulting in intrauterine fetal death, respectively. Including our patients, a total of 52 patients have been reported with Noonan syndrome caused by a RIT1 mutation. Our report contributes to the delineation of the phenotype associated with RIT1 mutations and underlines that lymphatic involvement is part of this spectrum. In addition, we provide an overview of the currently described Noonan syndrome patients with RIT1 mutations in literature. © 2016 Wiley Periodicals, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.37657DOI Listing
July 2016

[Maternal uniparental disomy 14; differential diagnosis with Prader-Willi syndrome].

Ned Tijdschr Geneeskd 2015 ;159:A8240

VUmc, afd. Klinische genetica, Amsterdam.

Background: Maternal uniparental disomy 14 is a rare genetic disorder in which both chromosomes 14 are maternally inherited. The disorder is characterised by neonatal hypotonia and feeding difficulties, intrauterine or later growth retardation, truncal obesity and precocious puberty. During the neonatal period its clinical phenotype shows great similarities with that of Prader-Willi syndrome.

Case Description: We describe two patients with dysmaturity, neonatal hypotonia and feeding difficulties who initially showed clinical signs of Prader-Willi syndrome. However, molecular testing for this disorder was normal. Some years later, additional molecular testing confirmed the diagnosis of maternal uniparental disomy 14.

Conclusion: Maternal uniparental disomy 14 shows many phenotypic similarities with Prader-Willi syndrome. In a hypotonic neonate, molecular testing for maternal uniparental disomy 14 should therefore be considered if Prader-Willi syndrome has been excluded.
View Article and Find Full Text PDF

Download full-text PDF

Source
December 2015

A study of the clinical and radiological features in a cohort of 93 patients with a COL2A1 mutation causing spondyloepiphyseal dysplasia congenita or a related phenotype.

Am J Med Genet A 2015 Mar 21;167A(3):461-75. Epub 2015 Jan 21.

Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.

Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n = 64), others having SEMD (n = 5), Kniest dysplasia (n = 7), spondyloperipheral dysplasia (n = 2), or Torrance-like dysplasia (n = 2). The remaining 13 patients had normal stature with mild SED, Stickler-like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype-phenotype correlations in this cohort, we propose guidelines for the management and follow-up in this group of disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.36922DOI Listing
March 2015

Force on spindle microtubule minus ends moves chromosomes.

J Cell Biol 2014 Jul 14;206(2):245-56. Epub 2014 Jul 14.

Department of Cell and Tissue Biology, Biomedical Sciences Graduate Program, and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143Department of Cell and Tissue Biology, Biomedical Sciences Graduate Program, and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143Department of Cell and Tissue Biology, Biomedical Sciences Graduate Program, and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143

The spindle is a dynamic self-assembling machine that coordinates mitosis. The spindle's function depends on its ability to organize microtubules into poles and maintain pole structure despite mechanical challenges and component turnover. Although we know that dynein and NuMA mediate pole formation, our understanding of the forces dynamically maintaining poles is limited: we do not know where and how quickly they act or their strength and structural impact. Using laser ablation to cut spindle microtubules, we identify a force that rapidly and robustly pulls severed microtubules and chromosomes poleward, overpowering opposing forces and repairing spindle architecture. Molecular imaging and biophysical analysis suggest that transport is powered by dynein pulling on minus ends of severed microtubules. NuMA and dynein/dynactin are specifically enriched at new minus ends within seconds, reanchoring minus ends to the spindle and delivering them to poles. This force on minus ends represents a newly uncovered chromosome transport mechanism that is independent of plus end forces at kinetochores and is well suited to robustly maintain spindle mechanical integrity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1083/jcb.201401091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107791PMC
July 2014

Informed consent for exome sequencing in diagnostics: exploring first experiences and views of professionals and patients.

Clin Genet 2014 May 4;85(5):417-22. Epub 2013 Nov 4.

Department of Clinical Genetics, Section of Community Genetics, EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands.

Next-generation sequencing is increasingly being chosen as a diagnostic tool for cases of expected genetic, but unresolved origin. The consequential increased need for decisions on disclosure of unsolicited findings poses a challenge for the informed consent procedure. This study explored the first experiences with, and needs for, the informed consent procedure in diagnostic exome sequencing, with the stakeholders involved. Semi-structured interviews were conducted with 11 professional experts and one professional gave a written response. Furthermore, the counseling process was observed in three cases where exome sequencing was offered, followed by interviews with the patient (representative) and the genetic counselor. The respondents not only preferred an opt-out for unsolicited findings but also identified many challenges and therefore more experiences with exome sequencing was considered needed. Context-dependent decision-making was observed and an Advisory Board for unsolicited findings was considered helpful while doubts were raised about the feasibility and the possibility of undermining patients' autonomy. Finally, respondents brought up the complexity of information provision, and division of responsibilities between clinicians and the lab. These challenges and needs, raised by stakeholders involved, provide more insight in the next steps needed for an optimal informed consent procedure for exome sequencing in diagnostics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.12299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231277PMC
May 2014

ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3.

Nat Genet 2013 Aug 23;45(8):951-6. Epub 2013 Jun 23.

Department of Medicine, Renal Division, University of Freiburg Medical Center, Freiburg, Germany.

Nephronophthisis is an autosomal recessive cystic kidney disease that leads to renal failure in childhood or adolescence. Most NPHP gene products form molecular networks. Here we identify ANKS6 as a new NPHP family member that connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3. We show that ANKS6 localizes to the proximal cilium and confirm its role in renal development through knockdown experiments in zebrafish and Xenopus laevis. We also identify six families with ANKS6 mutations affected by nephronophthisis, including severe cardiovascular abnormalities, liver fibrosis and situs inversus. The oxygen sensor HIF1AN hydroxylates ANKS6 and INVS and alters the composition of the ANKS6-INVS-NPHP3 module. Knockdown of Hif1an in Xenopus results in a phenotype that resembles loss of other NPHP proteins. Network analyses uncovered additional putative NPHP proteins and placed ANKS6 at the center of this NPHP module, explaining the overlapping disease manifestation caused by mutation in ANKS6, NEK8, INVS or NPHP3.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.2681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3786259PMC
August 2013

Reflecting on earlier experiences with unsolicited findings: points to consider for next-generation sequencing and informed consent in diagnostics.

Hum Mutat 2013 Oct 16;34(10):1322-8. Epub 2013 Jul 16.

Department of Clinical Genetics, Section of Community Genetics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.

High-throughput nucleotide sequencing (often referred to as next-generation sequencing; NGS) is increasingly being chosen as a diagnostic tool for cases of expected but unresolved genetic origin. When exploring a higher number of genetic variants, there is a higher chance of detecting unsolicited findings. The consequential increased need for decisions on disclosure of these unsolicited findings poses a challenge for the informed consent procedure. This article discusses the ethical and practical dilemmas encountered when contemplating informed consent for NGS in diagnostics from a multidisciplinary point of view. By exploring recent similar experiences with unsolicited findings in other settings, an attempt is made to describe what can be learned so far for implementing NGS in standard genetic diagnostics. The article concludes with a set of points to consider in order to guide decision-making on the extent of return of results in relation to the mode of informed consent. We hereby aim to provide a sound basis for developing guidelines for optimizing the informed consent procedure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.22370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4285964PMC
October 2013

Single-molecule fluorescence imaging of processive myosin with enhanced background suppression using linear zero-mode waveguides (ZMWs) and convex lens induced confinement (CLIC).

Opt Express 2013 Jan;21(1):1189-202

Department of Applied Physics, Stanford University, Stanford, California 94305, USA.

Resolving single fluorescent molecules in the presence of high fluorophore concentrations remains a challenge in single-molecule biophysics that limits our understanding of weak molecular interactions. Total internal reflection fluorescence (TIRF) imaging, the workhorse of single-molecule fluorescence microscopy, enables experiments at concentrations up to about 100 nM, but many biological interactions have considerably weaker affinities, and thus require at least one species to be at micromolar or higher concentration. Current alternatives to TIRF often require three-dimensional confinement, and thus can be problematic for extended substrates, such as cytoskeletal filaments. To address this challenge, we have demonstrated and applied two new single-molecule fluorescence microscopy techniques, linear zero-mode waveguides (ZMWs) and convex lens induced confinement (CLIC), for imaging the processive motion of molecular motors myosin V and VI along actin filaments. Both technologies will allow imaging in the presence of higher fluorophore concentrations than TIRF microscopy. They will enable new biophysical measurements of a wide range of processive molecular motors that move along filamentous tracks, such as other myosins, dynein, and kinesin. A particularly salient application of these technologies will be to examine chemomechanical coupling by directly imaging fluorescent nucleotide molecules interacting with processive motors as they traverse their actin or microtubule tracks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3632498PMC
http://dx.doi.org/10.1364/OE.21.001189DOI Listing
January 2013

Prenatal testing for Huntington's disease in the Netherlands from 1998 to 2008.

Clin Genet 2014 Jan 27;85(1):78-86. Epub 2013 Mar 27.

Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.

This study aims to give an overview of the number of prenatal tests for Huntington's disease (HD), test results, and pregnancy outcomes in the Netherlands between 1998 and 2008 and to compare them with available data from the period 1987 to 1997. A total of 126 couples underwent prenatal diagnosis (PND) on 216 foetuses: 185 (86%) direct tests and 31 (14%) exclusion tests. In 9% of direct tests the risk for the foetus was 25%. Four at-risk parents (4%) carried intermediate alleles. Ninety-one foetuses had CAG expansions ≥36% or 50% risk haplotypes: 75 (82%) were terminated for HD, 12 (13%) were carried to term; four pregnancies were miscarried, terminated for other reasons or lost to follow-up. Unaffected pregnancies (122 foetuses) resulted in the birth of 112 children. The estimated uptake of PND was 22% of CAG expansion carriers (≥36 repeats) at reproductive age. PND was used by two new subgroups: carriers of intermediate alleles and 50% at-risk persons opting for a direct prenatal test of the foetus. A significant number of HD expansion or 50% risk pregnancies were continued. Speculations were made on causative factors contributing to these continuations. Further research on these couples' motives is needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.12090DOI Listing
January 2014

Future challenges in single-molecule fluorescence and laser trap approaches to studies of molecular motors.

Dev Cell 2012 Dec;23(6):1084-91

Department of Biochemistry, Stanford University, Stanford, CA 94305, USA.

Single-molecule analysis is a powerful modern form of biochemistry, in which individual kinetic steps of a catalytic cycle of an enzyme can be explored in exquisite detail. Both single-molecule fluorescence and single-molecule force techniques have been widely used to characterize a number of protein systems. We focus here on molecular motors as a paradigm. We describe two areas where we expect to see exciting developments in the near future: first, characterizing the coupling of force production to chemical and mechanical changes in motors, and second, understanding how multiple motors work together in the environment of the cell.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.devcel.2012.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800137PMC
December 2012

Genetics of dementia: update and guidelines for the clinician.

Am J Med Genet B Neuropsychiatr Genet 2012 Sep 19;159B(6):628-43. Epub 2012 Jul 19.

Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.

With increased frequency, clinical geneticists are asked for genetic advice on the heredity of dementia in families. Alzheimer's disease is in most cases a complex disease, but may be autosomal dominant inherited. Mutations in the PSEN1 gene are the most common genetic cause of early onset Alzheimer's disease, whereas APP and PSEN2 gene mutations are less frequent. Familial frontotemporal dementia may be associated with a mutation in the MAPT or GRN gene, or with a repeat expansion in the C9orf72 gene. All these genes show autosomal dominant inheritance with a high penetrance. Although Alzheimer's disease and frontotemporal dementia are clinically distinguishable entities, phenotypical overlap may occur. Rarely, dementia is caused by mutations in other autosomal dominant genes or by genetic defects with autosomal recessive, X-linked dominant or mitochondrial inheritance. The inherited forms of frontotemporal dementia and Alzheimer's disease show a large phenotypic variability also within families, resulting in many remaining uncertainties for mutation carriers. Therefore, genetic counseling before performing genetic testing is essential in both symptomatic individuals and healthy at risk relatives. This review provides an overview of the genetic causes of dementia and discusses all aspects relevant for genetic counseling and testing. Furthermore, based on current knowledge, we provide algorithms for genetic testing in patients with early onset Alzheimer's disease or frontotemporal dementia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.b.32080DOI Listing
September 2012