Publications by authors named "Yvonne Hilhorst-Hofstee"

41 Publications

The Connective Tissue Disorder Associated with Recessive Variants in the Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases.

Genes (Basel) 2020 04 14;11(4). Epub 2020 Apr 14.

Division of Genetic Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland.

Recessive loss-of-function variants in a putative zinc transporter gene, were first associated with a connective tissue disorder that is now called "Ehlers-Danlos syndrome, spondylodysplastic form type 3" (SCD-EDS, OMIM 612350) in 2008. Nine individuals have been described. We describe here four additional affected individuals from three consanguineous families and the follow up of two of the original cases. In our series, cardinal findings included thin and finely wrinkled skin of the hands and feet, characteristic facial features with downslanting palpebral fissures, mild hypertelorism, prominent eyes with a paucity of periorbital fat, blueish sclerae, microdontia, or oligodontia, and-in contrast to most types of Ehlers-Danlos syndrome-significant short stature of childhood onset. Mild radiographic changes were observed, among which platyspondyly is a useful diagnostic feature. Two of our patients developed severe keratoconus, and two suffered from cerebrovascular accidents in their twenties, suggesting that there may be a vascular component to this condition. All patients tested had a significantly reduced ratio of the two collagen-derived crosslink derivates, pyridinoline-to-deoxypyridinoline, in urine, suggesting that this simple test is diagnostically useful. Additionally, analysis of the facial features of affected individuals by DeepGestalt technology confirmed their specificity and may be sufficient to suggest the diagnosis directly. Given that the clinical presentation in childhood consists mainly of short stature and characteristic facial features, the differential diagnosis is not necessarily that of a connective tissue disorder and therefore, we propose that is included in gene panels designed to address dysmorphism and short stature. This approach may result in more efficient diagnosis.
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http://dx.doi.org/10.3390/genes11040420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231014PMC
April 2020

Phenotypic spectrum of TGFB3 disease-causing variants in a Dutch-French cohort and first report of a homozygous patient.

Clin Genet 2020 05 16;97(5):723-730. Epub 2020 Jan 16.

Département de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France.

Disease-causing variants in TGFB3 cause an autosomal dominant connective tissue disorder which is hard to phenotypically delineate because of the small number of identified cases. The purpose of this retrospective cross-sectional multicenter study is to elucidate the genotype and phenotype in an international cohort of TGFB3 patients. Eleven (eight novel) TGFB3 disease-causing variants were identified in 32 patients (17 families). Aortic root dilatation and mitral valve disease represented the most common cardiovascular findings, reported in 29% and 32% of patients, respectively. Dissection involving distal aortic segments occurred in two patients at age 50 and 52 years. A high frequency of systemic features (65% high-arched palate, 63% arachnodactyly, 57% pectus deformity, 52% joint hypermobility) was observed. In familial cases, incomplete penetrance and variable clinical expressivity were noted. Our cohort included the first described homozygous patient, who presented with a more severe phenotype compared to her heterozygous relatives. In conclusion, TGFB3 variants were associated with a high percentage of systemic features and aortic disease (dilatation/dissection) in 35% of patients. No deaths occurred from cardiovascular events or pregnancy-related complications. Nevertheless, homozygosity may be driving a more severe phenotype.
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http://dx.doi.org/10.1111/cge.13700DOI Listing
May 2020

The CHD8 overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients.

Am J Med Genet C Semin Med Genet 2019 12 13;181(4):557-564. Epub 2019 Nov 13.

South West Thames Regional Genetics Service, St George's University NHS Foundation Trust, London, UK.

CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference ≥2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (≤15% each). These results suggest that, in addition to its established link with autism and intellectual disability, CHD8 causes an overgrowth phenotype, and should be considered in the differential diagnosis of patients presenting with increased height and/or head circumference in association with intellectual disability.
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http://dx.doi.org/10.1002/ajmg.c.31749DOI Listing
December 2019

Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency.

Genet Med 2020 03 3;22(3):524-537. Epub 2019 Oct 3.

INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.

Purpose: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved.

Methods: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated.

Results: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated.

Conclusions: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.
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http://dx.doi.org/10.1038/s41436-019-0657-0DOI Listing
March 2020

Insight Into Molecular Determinants of T3 vs T4 Recognition From Mutations in Thyroid Hormone Receptor α and β.

J Clin Endocrinol Metab 2019 08;104(8):3491-3500

Department of Internal Medicine, Erasmus Medical Center, Academic Center for Thyroid Diseases, Rotterdam, Netherlands.

Context: The two major forms of circulating thyroid hormones (THs) are T3 and T4. T3 is regarded as the biologically active hormone because it binds to TH receptors (TRs) with greater affinity than T4. However, it is currently unclear what structural mechanisms underlie this difference in affinity.

Objective: Prompted by the identification of a novel M256T mutation in a resistance to TH (RTH)α patient, we investigated Met256 in TRα1 and the corresponding residue (Met310) in TRβ1, residues previously predicted by crystallographic studies in discrimination of T3 vs T4.

Methods: Clinical characterization of the RTHα patient and molecular studies (in silico protein modeling, radioligand binding, transactivation, and receptor-cofactor studies) were performed.

Results: Structural modeling of the TRα1-M256T mutant showed that distortion of the hydrophobic niche to accommodate the outer ring of ligand was more pronounced for T3 than T4, suggesting that this substitution has little impact on the affinity for T4. In agreement with the model, TRα1-M256T selectively reduced the affinity for T3. Also, unlike other naturally occurring TRα mutations, TRα1-M256T had a differential impact on T3- vs T4-dependent transcriptional activation. TRα1-M256A and TRβ1-M310T mutants exhibited similar discordance for T3 vs T4.

Conclusions: Met256-TRα1/Met310-TRβ1 strongly potentiates the affinity of TRs for T3, thereby largely determining that T3 is the bioactive hormone rather than T4. These observations provide insight into the molecular basis for underlying the different affinity of TRs for T3 vs T4, delineating a fundamental principle of TH signaling.
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http://dx.doi.org/10.1210/jc.2018-02794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599431PMC
August 2019

Whole Exome Sequencing Is the Preferred Strategy to Identify the Genetic Defect in Patients With a Probable or Possible Mitochondrial Cause.

Front Genet 2018 12;9:400. Epub 2018 Oct 12.

Department of Genetics and Cell Biology, Maastricht University Medical Centre, Maastricht, Netherlands.

Mitochondrial disorders, characterized by clinical symptoms and/or OXPHOS deficiencies, are caused by pathogenic variants in mitochondrial genes. However, pathogenic variants in some of these genes can lead to clinical manifestations which overlap with other neuromuscular diseases, which can be caused by pathogenic variants in non-mitochondrial genes as well. Mitochondrial pathogenic variants can be found in the mitochondrial DNA (mtDNA) or in any of the 1,500 nuclear genes with a mitochondrial function. We have performed a two-step next-generation sequencing approach in a cohort of 117 patients, mostly children, in whom a mitochondrial disease-cause could likely or possibly explain the phenotype. A total of 86 patients had a mitochondrial disorder, according to established clinical and biochemical criteria. The other 31 patients had neuromuscular symptoms, where in a minority a mitochondrial genetic cause is present, but a non-mitochondrial genetic cause is more likely. All patients were screened for pathogenic variants in the mtDNA and, if excluded, analyzed by whole exome sequencing (WES). Variants were filtered for being pathogenic and compatible with an autosomal or X-linked recessive mode of inheritance in families with multiple affected siblings and/or consanguineous parents. Non-consanguineous families with a single patient were additionally screened for autosomal and X-linked dominant mutations in a predefined gene-set. We identified causative pathogenic variants in the mtDNA in 20% of the patient-cohort, and in nuclear genes in 49%, implying an overall yield of 68%. We identified pathogenic variants in mitochondrial and non-mitochondrial genes in both groups with, obviously, a higher number of mitochondrial genes affected in mitochondrial disease patients. Furthermore, we show that 31% of the disease-causing genes in the mitochondrial patient group were not included in the MitoCarta database, and therefore would have been missed with MitoCarta based gene-panels. We conclude that WES is preferable to panel-based approaches for both groups of patients, as the mitochondrial gene-list is not complete and mitochondrial symptoms can be secondary. Also, clinically and genetically heterogeneous disorders would require sequential use of multiple different gene panels. We conclude that WES is a comprehensive and unbiased approach to establish a genetic diagnosis in these patients, able to resolve multi-genic disease-causes.
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http://dx.doi.org/10.3389/fgene.2018.00400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194163PMC
October 2018

A potential gain-of-function variant of SLC9A6 leads to endosomal alkalinization and neuronal atrophy associated with Christianson Syndrome.

Neurobiol Dis 2019 01 5;121:187-204. Epub 2018 Oct 5.

Department of Physiology, McGill University, Montreal, Canada. Electronic address:

Loss-of-function mutations in the recycling endosomal (Na,K)/H exchanger gene SLC9A6/NHE6 result in overacidification and dysfunction of endosomal-lysosomal compartments, and cause a neurodevelopmental and degenerative form of X-linked intellectual disability called Christianson Syndrome (CS). However, knowledge of the disease heterogeneity of CS is limited. Here, we describe the clinical features and underlying molecular and cellular mechanisms associated with a CS patient carrying a de novo missense variant (p.Gly218Arg; G218R) of a conserved residue in its ion translocation domain that results in a potential gain-of-function. The patient manifested several core symptoms typical of CS, including pronounced cognitive impairment, mutism, epilepsy, ataxia and microcephaly; however, deterioration of motor function often observed after the first decade of life in CS children with total loss of SLC9A6/NHE6 function was not evident. In transfected non-neuronal cells, complex glycosylation and half-life of the G218R were significantly decreased compared to the wild-type transporter. This correlated with elevated ubiquitination and partial proteasomal-mediated proteolysis of G218R. However, a major fraction was delivered to the plasma membrane and endocytic pathways. Compared to wild-type, G218R-containing endosomes were atypically alkaline and showed impaired uptake of recycling endosomal cargo. Moreover, instead of accumulating in recycling endosomes, G218R was redirected to multivesicular bodies/late endosomes and ejected extracellularly in exosomes rather than progressing to lysosomes for degradation. Attenuated acidification and trafficking of G218R-containing endosomes were also observed in transfected hippocampal neurons, and correlated with diminished dendritic branching and density of mature mushroom-shaped spines and increased appearance of filopodia-like protrusions. Collectively, these findings expand our understanding of the genetic diversity of CS and further elucidate a critical role for SLC9A6/NHE6 in fine-tuning recycling endosomal pH and cargo trafficking, processes crucial for the maintenance of neuronal polarity and mature synaptic structures.
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http://dx.doi.org/10.1016/j.nbd.2018.10.002DOI Listing
January 2019

Putting genome-wide sequencing in neonates into perspective.

Genet Med 2019 05 5;21(5):1074-1082. Epub 2018 Oct 5.

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

Purpose: Several studies have reported diagnostic yields up to 57% for rapid exome or genome sequencing (rES/GS) as a single test in neonatal intensive care unit (NICU) patients, but the additional yield of rES/GS compared with other available diagnostic options still remains unquantified in this population.

Methods: We retrospectively evaluated all genetic NICU consultations in a 2-year period.

Results: In 132 retrospectively evaluated NICU consultations 27 of 32 diagnoses (84.4%) were made using standard genetic workup. Most diagnoses (65.6%) were made within 16 days. Diagnostic ES yield was 5/29 (17.2%). Genetic diagnoses had a direct effect on clinical management in 90.6% (29/32) of patients.

Conclusions: Our study shows that exome sequencing has a place in NICU diagnostics, but given the associated costs and the high yield of alternative diagnostic strategies, we recommend to first perform clinical genetic consultation.
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http://dx.doi.org/10.1038/s41436-018-0293-0DOI Listing
May 2019

Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders.

Hum Mutat 2018 09 12;39(9):1173-1192. Epub 2018 Jul 12.

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

Simultaneous analysis of multiple genes using next-generation sequencing (NGS) technology has become widely available. Copy-number variations (CNVs) in disease-associated genes have emerged as a cause for several hereditary disorders. CNVs are, however, not routinely detected using NGS analysis. The aim of this study was to assess the diagnostic yield and the prevalence of CNVs using our panel of Hereditary Thoracic Aortic Disease (H-TAD)-associated genes. Eight hundred ten patients suspected of H-TAD were analyzed by targeted NGS analysis of 21 H-TAD associated genes. In addition, the eXome hidden Markov model (XHMM; an algorithm to identify CNVs in targeted NGS data) was used to detect CNVs in these genes. A pathogenic or likely pathogenic variant was found in 66 of 810 patients (8.1%). Of these 66 pathogenic or likely pathogenic variants, six (9.1%) were CNVs not detectable by routine NGS analysis. These CNVs were four intragenic (multi-)exon deletions in MYLK, TGFB2, SMAD3, and PRKG1, respectively. In addition, a large duplication including NOTCH1 and a large deletion encompassing SCARF2 were detected. As confirmed by additional analyses, both CNVs indicated larger chromosomal abnormalities, which could explain the phenotype in both patients. Given the clinical relevance of the identification of a genetic cause, CNV analysis using a method such as XHMM should be incorporated into the clinical diagnostic care for H-TAD patients.
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http://dx.doi.org/10.1002/humu.23565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175145PMC
September 2018

Expert consensus recommendations on the cardiogenetic care for patients with thoracic aortic disease and their first-degree relatives.

Int J Cardiol 2018 05 7;258:243-248. Epub 2018 Feb 7.

Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address:

Background: Thoracic aortic aneurysm (TAA) is a potentially life-threatening disorder with a strong genetic component. The number of genes implicated in TAA has increased exponentially over the last decade. Approximately 20% of patients with TAA have a positive family history. As most TAA remain asymptomatic for a long time, screening of at risk relatives is warranted to prevent complications. Existing international guidelines lack detailed instructions regarding genetic evaluation and family screening of TAA patients. We aimed to develop a consensus document to provide medical guidance for all health care professionals involved in the recognition, diagnosis and treatment of patients with thoracic aortic disease and their relatives.

Methods: A multidisciplinary panel of experts including cardiologists, cardiothoracic surgeons, clinical geneticists and general practitioners, convened to review and discuss the current literature, guidelines and clinical practice on genetic testing and family screening in TAA.

Results: There is a lack of high-quality evidence in the literature. This consensus statement, based on the available literature and expert opinions, summarizes our recommendations in order to standardize and optimize the cardiogenetic care for patients and families with thoracic aortic disease. In particular, we provide criteria to identify those patients most likely to have a genetic predisposition, and discuss the preferred modality and frequency of screening in their relatives.

Conclusions: Age, family history, aortic size and syndromic features determine who is advised to have genetic testing as well as screening of first-degree relatives. There is a need for more prospective multicenter studies to optimize current recommendations.
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http://dx.doi.org/10.1016/j.ijcard.2018.01.145DOI Listing
May 2018

A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3.

Hum Mutat 2018 05 6;39(5):621-634. Epub 2018 Mar 6.

Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.

The Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-β (TGF-β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-β signaling. More recently, TGF-β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF-β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.
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http://dx.doi.org/10.1002/humu.23407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947146PMC
May 2018

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

Polyhydramnios and cerebellar atrophy: a prenatal presentation of mitochondrial encephalomyopathy caused by mutations in the FBXL4 gene.

Clin Case Rep 2016 Apr 16;4(4):425-8. Epub 2016 Mar 16.

Department of Clinical Genetics Leiden University Medical Centre Leiden Netherlands.

Severe recessive mitochondrial myopathy caused by FBXL4 gene mutations may present prenatally with polyhydramnios and cerebellar hypoplasia. Characteristic dysmorphic features are: high and arched eyebrows, triangular face, a slight upslant of palpebral fissures, and a prominent pointed chin. Metabolic investigations invariably show increased serum lactate and pyruvate levels.
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http://dx.doi.org/10.1002/ccr3.511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831400PMC
April 2016

Higher Incidence of Hypospadias in Monochorionic Twins.

Twin Res Hum Genet 2015 Oct 14;18(5):591-4. Epub 2015 Aug 14.

Division of Neonatology,Department of Pediatrics,Leiden University Medical Center,Leiden,The Netherlands.

Background: Hypospadias is associated with twinning. The incidence of hypospadias in monochorionic and dichorionic male twins is, however, yet to be determined.

Methods: All medical records of monochorionic and dichorionic twins admitted to our neonatal nursery between January 2004 and August 2013 were reviewed for the presence of hypospadias.

Results: A total of 350 monochorionic and 303 dichorionic male twins were included in the study. The incidence of hypospadias in monochorionic and dichorionic groups was 4% (14/350) and 1% (3/303) (p = .016) respectively. In 11 of the 15 twin couples, hypospadias occurred in the twin with the lowest birth weight. The rate of hypospadias in twin infants small-for-gestational-age group was 10% (6/60) compared with 2% (11/593) in the appropriate-for-gestational-age group (p = .002). In a multivariate analysis, both monochorionicity and small-for-gestational-age were independently associated with hypospadias, odds ratio 4.1 (95% confidence interval (CI): 1.1-14.7) and 6.1 (95% CI: 2.2-17.2) respectively.

Conclusions: The incidence of hypospadias is four-fold higher in monochorionic twins compared with dichorionic twins. Hypospadias is also independently associated with small-for-gestational-age.
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http://dx.doi.org/10.1017/thg.2015.55DOI Listing
October 2015

SMAD2 Mutations Are Associated with Arterial Aneurysms and Dissections.

Hum Mutat 2015 Dec 10;36(12):1145-9. Epub 2015 Sep 10.

Department of Clinical Genetics, Center for Connective Tissue Research, VU University Medical Center, Amsterdam, 1007, MB, The Netherlands.

We report three families with arterial aneurysms and dissections in which variants predicted to be pathogenic were identified in SMAD2. Moreover, one variant occurred de novo in a proband with unaffected parents. SMAD2 is a strong candidate gene for arterial aneurysms and dissections given its role in the TGF-β signaling pathway. Furthermore, although SMAD2 and SMAD3 probably have functionally distinct roles in cell signaling, they are structurally very similar. Our findings indicate that SMAD2 mutations are associated with arterial aneurysms and dissections and are in accordance with the observation that patients with pathogenic variants in genes encoding proteins involved in the TGF-β signaling pathway exhibit arterial aneurysms and dissections as key features.
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http://dx.doi.org/10.1002/humu.22854DOI Listing
December 2015

Clinical and molecular characterization of an infant with a tandem duplication and deletion of 19p13.

Am J Med Genet A 2015 Aug 21;167A(8):1884-9. Epub 2015 Apr 21.

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

Copy number variations (CNVs) on the short arm of chromosome 19 are relatively rare. We present a patient with a tandem de novo 3.9 Mb duplication of 19p13.12p13.2 and an adjacent 288 kb deletion of 19p13.12. The CNVs were detected by genome wide SNP-array and confirmed by fluorescence in situ hybridization. Mate-pair sequencing revealed two breakpoint junctions leading to a germline tandem inverted duplication and an adjacent deletion. The patient had a major congenital heart defect and refractory edema leading to metabolic and endocrinological disturbances. Further complications occurred due to refractory chylothorax, severe inflammatory response syndrome, and repeating sepsis. After 2 months, the child died due to intractable respiratory failure. The phenotype of this patient was compared with reported patients with overlapping deletions or duplications. We conclude that the congenital heart defect, respiratory insufficiency, and abnormal neurologic examination are most likely due the contiguous gene deletion/duplication.
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http://dx.doi.org/10.1002/ajmg.a.37076DOI Listing
August 2015

[Multidisciplinary practice guideline 'Marfan syndrome'].

Ned Tijdschr Geneeskd 2013 ;157(50):A6658

*Namens de werkgroep 'Landelijke multidisciplinaire richtlijn Marfan syndroom' waarvan de leden aan het eind van dit artikel worden genoemd.

Marfan syndrome is a multi-system disorder of dominant inheritance in which the cardiovasculature, in particular the aorta, the eyes and the skeleton are affected. Diagnostic assessment and treatment of patients who are suspected of or have Marfan syndrome should preferably be done by multidisciplinary teams such as those found in specialised Marfan syndrome centres. The practice guideline is intended for all care givers involved with the recognition, diagnosis, consultations and the medicinal and surgical treatment of Marfan patients; it includes referral criteria and information on the referral process. A diagnosis of Marfan syndrome is based on international criteria in which aortic root dilatation and dissection, ectopia lentis, an affected first-degree family member and a pathogenic FBN1 mutation are the cardinal features. Alternative diagnoses are also included in the practice guideline. Recommendations are given for the monitoring and treatment of Marfan patients during pregnancy and delivery. Advice on lifestyle is mainly focussed on sports activities.
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August 2014

GPSM2 and Chudley-McCullough syndrome: a Dutch founder variant brought to North America.

Am J Med Genet A 2013 May 13;161A(5):973-6. Epub 2013 Mar 13.

Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Chudley-McCullough syndrome (CMS) is characterized by profound sensorineural hearing loss and brain anomalies. Variants in GPSM2 have recently been reported as a cause of CMS by Doherty et al. In this study we have performed exome sequencing of three CMS patients from two unrelated families from the same Dutch village. We identified one homozygous frameshift GPSM2 variants c.1473delG in all patients. We show that this variant arises from a shared, rare haplotype. Since the c.1473delG variant was found in Mennonite settlers, it likely originated in Europe. To support DNA diagnostics, we established an LOVD database for GPSM2 containing all variants thus far described.
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http://dx.doi.org/10.1002/ajmg.a.35808DOI Listing
May 2013

Rapid aortic aneurysm formation in Marfan patient with dissection of the entire aorta.

Eur Heart J Cardiovasc Imaging 2013 May 5;14(5):507. Epub 2012 Dec 5.

Department of Cardiology, Leiden University Medical Center, PO Box 9600, Albinusdreef 2, Leiden, The Netherlands.

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http://dx.doi.org/10.1093/ehjci/jes289DOI Listing
May 2013

MRI-assessed regional pulse wave velocity for predicting absence of regional aorta luminal growth in marfan syndrome.

Int J Cardiol 2013 Sep 20;167(6):2977-82. Epub 2012 Sep 20.

Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.

Background: In patients with Marfan syndrome (MFS), increased aortic wall stiffening may lead to progressive aortic dilatation. Aortic Pulse Wave Velocity (PWV), a marker of wall stiffness can be assessed regionally, using in-plane multi-directional velocity-encoded MRI. This study examined the diagnostic accuracy of regional PWV for prediction of regional aortic luminal growth during 2-year follow-up in MFS patients.

Methods: In twenty-one MFS patients (mean age 36 ± 15 years, 11 male) regional PWV and aortic luminal areas were assessed by 1.5 T MRI. At 2-year follow-up, the incidence of luminal growth, defined as mean luminal diameter increase >2mm was determined for five aortic segments (S1, ascending aorta; S2, aortic arch; S3, thoracic descending aorta, S4, supra-renal and S5, infra-renal abdominal aorta). Regional PWV at baseline was considered increased when exceeding age-related normal PWV (healthy volunteers (n=26; mean age 30 ± 10 years, 15 male)) by two standard-errors. Sensitivity and specificity of regional PWV-testing for prediction of regional luminal growth were determined.

Results: Regional PWV at baseline was increased in 17 out of 102 segments (17%). Significant luminal growth at follow-up was reported in 14 segments (14%). The specificity of regional PWV-testing was ≥ 78% for all aortic segments, sensitivity was ≤ 33%.

Conclusions: Regional PWV was significantly increased in MFS patients as compared to healthy volunteers within similar age range, in all aortic segments except the ascending aorta. Furthermore, regional PWV-assessment has moderate to high specificity for predicting absence of regional aortic luminal growth for all aortic segments in MFS patients.
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http://dx.doi.org/10.1016/j.ijcard.2012.08.057DOI Listing
September 2013

Subtelomeric deletion of chromosome 10p15.3: clinical findings and molecular cytogenetic characterization.

Am J Med Genet A 2012 Sep 27;158A(9):2152-61. Epub 2012 Jul 27.

Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.

We describe 19 unrelated individuals with submicroscopic deletions involving 10p15.3 characterized by chromosomal microarray (CMA). Interestingly, to our knowledge, only two individuals with isolated, submicroscopic 10p15.3 deletion have been reported to date; however, only limited clinical information is available for these probands and the deleted region has not been molecularly mapped. Comprehensive clinical history was obtained for 12 of the 19 individuals described in this study. Common features among these 12 individuals include: cognitive/behavioral/developmental differences (11/11), speech delay/language disorder (10/10), motor delay (10/10), craniofacial dysmorphism (9/12), hypotonia (7/11), brain anomalies (4/6) and seizures (3/7). Parental studies were performed for nine of the 19 individuals; the 10p15.3 deletion was de novo in seven of the probands, not maternally inherited in one proband and inherited from an apparently affected mother in one proband. Molecular mapping of the 19 individuals reported in this study has identified two genes, ZMYND11 (OMIM 608668) and DIP2C (OMIM 611380; UCSC Genome Browser), mapping within 10p15.3 which are most commonly deleted. Although no single gene has been identified which is deleted in all 19 individuals studied, the deleted region in all but one individual includes ZMYND11 and the deleted region in all but one other individual includes DIP2C. There is not a clearly identifiable phenotypic difference between these two individuals and the size of the deleted region does not generally predict clinical features. Little is currently known about these genes complicating a direct genotype/phenotype correlation at this time. These data however, suggest that ZMYND11 and/or DIP2C haploinsufficiency contributes to the clinical features associated with 10p15 deletions in probands described in this study.
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http://dx.doi.org/10.1002/ajmg.a.35574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429713PMC
September 2012

Evaluation of sampling density on the accuracy of aortic pulse wave velocity from velocity-encoded MRI in patients with Marfan syndrome.

J Magn Reson Imaging 2012 Dec 22;36(6):1470-6. Epub 2012 Jun 22.

Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: To evaluate the effect of spatial (ie, number of sampling locations along the aorta) and temporal sampling density on aortic pulse wave velocity (PWV) assessment from velocity-encoded MRI in patients with Marfan syndrome (MFS).

Materials And Methods: Twenty-three MFS patients (12 men, mean age 36 ± 14 years) were included. Three PWV-methods were evaluated: 1) reference PWV(i.p.) from in-plane velocity-encoded MRI with dense temporal and spatial sampling; 2) conventional PWV(t.p.) from through-plane velocity-encoded MRI with dense temporal but sparse spatial sampling at three aortic locations; 3) EPI-accelerated PWV(t.p.) with sparse temporal but improved spatial sampling at five aortic locations with acceleration by echo-planar imaging (EPI).

Results: Despite inferior temporal resolution, EPI-accelerated PWV(t.p.) showed stronger correlation (r = 0.92 vs. r = 0.65, P = 0.03) with reference PWV(i.p.) in the total aorta, with less error (8% vs. 16%) and variation (11% vs. 27%) as compared to conventional PWV(t.p.) . In the aortic arch, correlation was comparable for both EPI-accelerated and conventional PWV(t.p.) with reference PWV(i.p.) (r = 0.66 vs. r = 0.67, P = 0.46), albeit 92% scan-time reduction by EPI-acceleration.

Conclusion: Improving spatial sampling density by adding two acquisition planes along the aorta results in more accurate PWV assessment, even when temporal resolution decreases. For regional PWV assessment in the aortic arch, EPI-accelerated and conventional PWV assessment are comparably accurate. Scan-time reduction makes EPI-accelerated PWV assessment the preferred method of choice.
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http://dx.doi.org/10.1002/jmri.23729DOI Listing
December 2012

Aggressive cardiovascular phenotype of aneurysms-osteoarthritis syndrome caused by pathogenic SMAD3 variants.

J Am Coll Cardiol 2012 Jul 23;60(5):397-403. Epub 2012 May 23.

Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands.

Objectives: The purpose of this study was describe the cardiovascular phenotype of the aneurysms-osteoarthritis syndrome (AOS) and to provide clinical recommendations.

Background: AOS, caused by pathogenic SMAD3 variants, is a recently described autosomal dominant syndrome characterized by aneurysms and arterial tortuosity in combination with osteoarthritis.

Methods: AOS patients in participating centers underwent extensive cardiovascular evaluation, including imaging, arterial stiffness measurements, and biochemical studies.

Results: We included 44 AOS patients from 7 families with pathogenic SMAD3 variants (mean age: 42 ± 17 years). In 71%, an aortic root aneurysm was found. In 33%, aneurysms in other arteries in the thorax and abdomen were diagnosed, and in 48%, arterial tortuosity was diagnosed. In 16 patients, cerebrovascular imaging was performed, and cerebrovascular abnormalities were detected in 56% of them. Fifteen deaths occurred at a mean age of 54 ± 15 years. The main cause of death was aortic dissection (9 of 15; 60%), which occurred at mildly increased aortic diameters (range: 40 to 63 mm). Furthermore, cardiac abnormalities were diagnosed, such as congenital heart defects (6%), mitral valve abnormalities (51%), left ventricular hypertrophy (19%), and atrial fibrillation (22%). N-terminal brain natriuretic peptide (NT-proBNP) was significantly higher in AOS patients compared with matched controls (p < 0.001). Aortic pulse wave velocity was high-normal (9.2 ± 2.2 m/s), indicating increased aortic stiffness, which strongly correlated with NT-proBNP (r = 0.731, p = 0.005).

Conclusions: AOS predisposes patients to aggressive and widespread cardiovascular disease and is associated with high mortality. Dissections can occur at relatively mildly increased aortic diameters; therefore, early elective repair of the ascending aorta should be considered. Moreover, cerebrovascular abnormalities were encountered in most patients.
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http://dx.doi.org/10.1016/j.jacc.2011.12.052DOI Listing
July 2012

Inflammation aggravates disease severity in Marfan syndrome patients.

PLoS One 2012 30;7(3):e32963. Epub 2012 Mar 30.

Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, Amsterdam, The Netherlands.

Background: Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-β signaling. However, the contribution of tissue inflammation is not addressed so far.

Methodology/principal Findings: Here we showed that both TGF-β and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-β and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-β were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10(-6), 95% CI: 70-159 pg/ml). Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR) = 0%), ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC) = 1.8; 1.4; 1.5, FDR = 0%) and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%). Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF) in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients.

Conclusion/significance: In conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032963PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316543PMC
August 2012

Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome.

Nat Genet 2012 Mar 18;44(4):379-80. Epub 2012 Mar 18.

Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

We identified de novo truncating mutations in ARID1B in three individuals with Coffin-Siris syndrome (CSS) by exome sequencing. Array-based copy-number variation (CNV) analysis in 2,000 individuals with intellectual disability revealed deletions encompassing ARID1B in 3 subjects with phenotypes partially overlapping that of CSS. Taken together with published data, these results indicate that haploinsufficiency of the ARID1B gene, which encodes an epigenetic modifier of chromatin structure, is an important cause of CSS and is potentially a common cause of intellectual disability and speech impairment.
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http://dx.doi.org/10.1038/ng.2217DOI Listing
March 2012

Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome.

J Med Genet 2012 Jan;49(1):47-57

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

Background: Aneurysms-osteoarthritis syndrome (AOS) is a new autosomal dominant syndromic form of thoracic aortic aneurysms and dissections characterised by the presence of arterial aneurysms and tortuosity, mild craniofacial, skeletal and cutaneous anomalies, and early-onset osteoarthritis. AOS is caused by mutations in the SMAD3 gene.

Methods: A cohort of 393 patients with aneurysms without mutation in FBN1, TGFBR1 and TGFBR2 was screened for mutations in SMAD3. The patients originated from The Netherlands, Belgium, Switzerland and USA. The clinical phenotype in a total of 45 patients from eight different AOS families with eight different SMAD3 mutations is described. In all patients with a SMAD3 mutation, clinical records were reviewed and extensive genetic, cardiovascular and orthopaedic examinations were performed.

Results: Five novel SMAD3 mutations (one nonsense, two missense and two frame-shift mutations) were identified in five new AOS families. A follow-up description of the three families with a SMAD3 mutation previously described by the authors was included. In the majority of patients, early-onset joint abnormalities, including osteoarthritis and osteochondritis dissecans, were the initial symptom for which medical advice was sought. Cardiovascular abnormalities were present in almost 90% of patients, and involved mainly aortic aneurysms and dissections. Aneurysms and tortuosity were found in the aorta and other arteries throughout the body, including intracranial arteries. Of the patients who first presented with joint abnormalities, 20% died suddenly from aortic dissection. The presence of mild craniofacial abnormalities including hypertelorism and abnormal uvula may aid the recognition of this syndrome.

Conclusion: The authors provide further insight into the phenotype of AOS with SMAD3 mutations, and present recommendations for a clinical work-up.
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http://dx.doi.org/10.1136/jmedgenet-2011-100382DOI Listing
January 2012

Biventricular performance in patients with marfan syndrome without significant valvular disease: comparison to normal subjects and longitudinal follow-up.

J Am Soc Echocardiogr 2011 Dec 14;24(12):1392-1399.e1. Epub 2011 Oct 14.

Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.

Background: The presence and progressive nature of primary myocardial involvement in Marfan syndrome are debated. The aim of this study was to evaluate the clinical relevance of left ventricular (LV) and right ventricular (RV) strain in adult patients with Marfan syndrome without significant valvular disease.

Methods: Adult patients with Marfan syndrome (n = 50; mean age, 35.2 ± 12.9 years) were followed prospectively. Echocardiography was performed annually and consisted of comprehensive assessment of ventricular and valvular function. Using speckle-tracking imaging, the baseline strain values of the Marfan population were calculated and compared with the values of normal controls. The follow-up evaluations were used to assess changes in ventricular strain. The association between the incidence of adverse events (heart failure, [supra]ventricular arrhythmias, and proximal aorta surgery) and baseline strain values was investigated.

Results: Compared with controls, patients with Marfan syndrome had significantly lower peak longitudinal LV strain (-18.9 ± 2.3% vs -20.1 ± 1.9%, P < .01) and RV strain (±26.9 ± 5.2% vs ±29.3 ± 4.25%, P < .01). The absolute changes in LV longitudinal, radial, and circumferential strain and RV longitudinal strain during a median 4 years of follow-up were 0.1 ± 2.8%, 1.12 ± 7.6%, 0.3 ± 3.7%, and 0.9 ± 5.5%, respectively, which was not statistically significant. Cox regression demonstrated that reduced LV or RV strain was not associated with adverse outcome (supraventricular arrhythmias, n = 3; proximal aorta surgery, n = 4).

Conclusions: This study suggests that patients with Marfan syndrome show lower ventricular strain and strain rate values compared with healthy controls. However, no relevant changes in LV and RV function occurred during midterm follow-up in patients with Marfan syndrome without valvular disease at baseline. Although ventricular strain and strain rate were mildly reduced in patients with Marfan syndrome, this did not affect outcomes negatively in the present study.
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http://dx.doi.org/10.1016/j.echo.2011.09.004DOI Listing
December 2011

Age-related and regional changes of aortic stiffness in the Marfan syndrome: assessment with velocity-encoded MRI.

J Magn Reson Imaging 2011 Sep 14;34(3):526-31. Epub 2011 Jul 14.

Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: To study age-related change in aortic stiffness in patients with Marfan syndrome (MFS) versus healthy volunteers using velocity-encoded (VE) MRI.

Materials And Methods: Twenty-five MFS patients (age range, 18-63 years; mean age 36 ± 14 years, 13 men) and 25 age-/gender-matched healthy volunteers were examined with VE-MRI. Aortic stiffness was expressed by pulse wave velocity (PWV), assessed in the proximal and distal part of the aorta and in the total aorta. PWV was compared between patients and volunteers and age-relation was determined by linear regression.

Results: PWV was significantly higher in all parts of the aorta in patients when compared with healthy volunteers (proximal aorta 5.7 ± 1.5 m/s versus 4.8 ± 0.9 m/s, distal aorta 6.4 ± 2.4 m/s versus 5.0 ± 1.2 m/s and total aorta 5.9 ± 1.7 m/s versus 4.9 ± 1.1 m/s, all P < 0.004). PWV correlated significantly with age (Pearson R between 0.45 and 0.94). Only in the proximal aorta, the increase in PWV with age was significantly higher in patients (7 ± 2 cm/s increase with age) than in volunteers (3 ± 1 cm/s increase, P = 0.03); in the distal or total aorta, the increase in PWV with age was not different between patients and volunteers.

Conclusion: Velocity-encoded MRI detects more pronounced age-related aortic stiffening in the proximal aorta in MFS patients versus healthy volunteers, suggesting more severe wall disease in MFS.
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http://dx.doi.org/10.1002/jmri.22646DOI Listing
September 2011

SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype.

Nat Genet 2011 Feb 16;43(2):138-41. Epub 2011 Jan 16.

Department of Clinical Genetics, Vrije Universiteit (VU) Medical Center, Amsterdam, The Netherlands.

DNA interstrand crosslink repair requires several classes of proteins, including structure-specific endonucleases and Fanconi anemia proteins. SLX4, which coordinates three separate endonucleases, was recently recognized as an important regulator of DNA repair. Here we report the first human individuals found to have biallelic mutations in SLX4. These individuals, who were previously diagnosed as having Fanconi anemia, add SLX4 as an essential component to the FA-BRCA genome maintenance pathway.
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http://dx.doi.org/10.1038/ng.751DOI Listing
February 2011