Marja W Wessels

Erasmus MC | Erasmus MC · Department of Clinical Genetics

Introduction The diagnosis of Ehlers-Danlos syndrome is usually based on well-defined diagnostic criteria and the result of DNA investigation. Classical (cEDS) and vascular type (vEDS) are the most prevalent subtypes and are caused by heterozygous pathogenic variants in COL5A1, COL5A2, COL1A1 or, respectively, in COL3A1. We describe 3 cases with co...

Recently, ADAMTS19 was identified as a novel causative gene for heart valve disease (HVD), affecting mainly the aortic and pulmonary valves. Exome sequencing and data repository (CentoMD) analyses were performed to identify patients with ADAMTS19 variants (two families). A third family was recognized based on cardiac phenotypic similarities and SNP...

Background Patients with a bicuspid aortic valve (BAV) are at risk of developing valve deterioration and aortic dilatation. We aimed to investigate whether blood biomarkers are associated with disease stage in patients with BAV. Methods Serum levels of high sensitivity C-reactive protein (hsCRP), high sensitivity troponin T (hsTnT), N-terminal pro...

Background Idiopathic dilated cardiomyopathy (DCM) is recognised to be a heritable disorder, yet clinical genetic testing does not produce a diagnosis in >50% of paediatric patients. Identifying a genetic cause is crucial because this knowledge can affect management options, cardiac surveillance in relatives and reproductive decision-making. In thi...

Background: Pediatric cardiomyopathies are a clinically and genetically heterogeneous group of heart muscle disorders associated with high morbidity and mortality. Although knowledge of the genetic basis of pediatric cardiomyopathy has improved considerably, the underlying cause remains elusive in a substantial proportion of cases. Methods: Exom...

Background Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy, found in ≤25% of familial cases. Moreover, TTNtv associated with dilated cardiomyopathy are estimated to be present in 0.5% of the general population. The prognosis of asymptomatic carriers of TTNtv is poorly understood because TTNtv are ass...

Background: There is overlap in genetic causes and cardiac features in noncompaction cardiomyopathy (NCCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM). Objectives: The goal of this study was to predict phenotype and outcome in relatives according to the clinical features and genotype of NCCM index cases. Methods: Retro...

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1–2%)1–3 that frequently presents with ascending aortic aneurysm (AscAA)⁴. BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for ≤1% of nonsyndromic BAV...

The pathogenicity of previously published disease-associated genes and variants is sometimes questionable. Large-scale, population-based sequencing studies have uncovered numerous false assignments of pathogenicity. Misinterpretation of sequence variants may have serious implications for the patients and families involved, as genetic test results a...

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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) w...

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 r...

[This corrects the article on p. 400 in vol. 8, PMID: 28659821.].

Bicuspid aortic valve (BAV) is the most common congenital heart defect. Although many BAV patients remain asymptomatic, at least 20% develop thoracic aortic aneurysm (TAA). Historically, BAV-related TAA was considered as a hemodynamic consequence of the valve defect. Multiple lines of evidence currently suggest that genetic determinants contribute...

For adult patients with congenital heart disease (CHD), knowledge about the origin and inheritance of their disease and the recurrence risk in (future) offspring is important. Therefore, clinical genetic counseling should be part of the multidisciplinary preconception counseling of all men and women with a CHD who are in the reproductive age. In th...

Acrofacial dysostosis syndrome of Rodriguez is characterized by severe mandibular underdevelopment, upper limb phocomelia with absent fingers, absent fibulae, cleft palate, microtia, and abnormal pulmonary function. First reported in three siblings it was assumed to be an autosomal recessive condition. However, subsequent publication reported a fur...

Cardiomyopathies are usually inherited and predominantly affect adults, but they can also present in childhood. Although our understanding of the molecular basis of pediatric cardiomyopathy has improved, the underlying mechanism remains elusive in a substantial proportion of cases.

Purpose: We aimed to determine the prevalence and phenotypic spectrum of NOTCH1 mutations in left-sided congenital heart disease (LS-CHD). LS-CHD includes aortic valve stenosis, a bicuspid aortic valve, coarctation of the aorta, and hypoplastic left heart syndrome. Methods: NOTCH1 was screened for mutations in 428 nonsyndromic probands with LS-C...

Recurrent copy number variants of the q21.1 region of chromosome 1 have been associated with variable clinical features, including developmental delay, mild to moderate intellectual disability, psychiatric and behavioral problems, congenital heart malformations, and craniofacial abnormalities. A subset of individuals is clinically unaffected. We de...

Primary familial brain calcification (PFBC) is a neurological disease characterized by calcium phosphate deposits in the basal ganglia and other brain regions and has thus far been associated with SLC20A2, PDGFB or PDGFRB mutations. We identified in multiple families with PFBC mutations in XPR1, a gene encoding a retroviral receptor with phosphate...

Background: Aneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture. Investigations of the pathogenic mechanisms involved in syndromic types of thoracic aortic aneurysms, such as Marfan and Loeys-Dietz syndromes, have revealed an important contribution of disturbed transformin...

A 35-year-old female patient was admitted to the hospital after an accidental car crash. Medical history noted anal surgery for rectovaginal fistula at young age. She complained of dyspnea on exertion for several years. On physical examination, a diastolic murmur at the left second intercostal space was noted. No relevant abnormalities were seen in...

Familial hypertrophic cardiomyopathy (HCM) is usually caused by autosomal dominant pathogenic mutations in genes encoding sarcomeric or sarcomere-associated cardiac muscle proteins. The disease mainly affects adults, although young children with severe HCM have also been reported. We describe four unrelated neonates with lethal cardiomyopathy, and...

What's already known about this topic? Single nucleotide polymorphism (SNP) array detects submicroscopic chromosome aberrations that can be missed by karyotyping.Isochromosome i(X)(p10) is supposed to be lethal if it does not contain the X‐inactivation center and has never been detected.

Reduced generation of multiple motile cilia (RGMC) is a rare mucociliary clearance disorder. Affected persons suffer from recurrent infections of upper and lower airways because of highly reduced numbers of multiple motile respiratory cilia. Here we report recessive loss-of-function and missense mutations in MCIDAS-encoding Multicilin, which was sh...

Acrocallosal syndrome is characterized by postaxial polydactyly, macrocephaly, agenesis of the corpus callosum, and severe developmental delay. In a few patients with this disorder, a mutation in the KIF7 gene has been reported, which was associated with impaired GLI3 processing and dysregulaton of GLI3 transcription factors. A single patient with...

We describe three cases where Marfan syndrome was suspected, but genetic tests were negative. Two patients, a 38-year-old male and a 45-year-old female, were asymptomatic, but were referred to a clinical geneticist because multiple family members had died of aortic dissections at a young age. The third patient, a 55-year-old female, has been monito...

Glycosylated α-dystroglycan (α-DG) serves as cellular entry receptor for multiple pathogens, and defects in its glycosylation cause hereditary Walker-Warburg syndrome (WWS). At least eight proteins are critical to glycosylate α-DG, but many genes mutated in WWS remain unknown. To identify modifiers of α-DG, we performed a haploid screen for Lassa v...

OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X-linked condition with lethality in males. Mutations in OFD1 also cause X-linked Joubert syndrome (JBTS10) and Simpson-Golabi-Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of sus...

Interstitial deletions of the chromosome 22q11.2 region are the most common microdeletions in humans. The TBX1 gene is considered to be the major candidate gene for the main features in 22q11.2 deletion syndrome, including congenital heart malformations, (para)thyroid hypoplasia, and craniofacial abnormalities. We report on eight patients with atyp...

Thoracic aortic aneurysms and dissections (TAAD) is a serious condition with high morbidity and mortality. It is estimated that 20% of non-syndromic TAAD cases are inherited in an autosomal-dominant pattern with variable expression and reduced penetrance. Mutations in myosin heavy chain 11 (MYH11), one of several identified TAAD genes, were shown t...

Background: Aneurysms-osteoarthritis syndrome (AOS), caused by SMAD3 mutations, is a recently described autosomal dominant condition characterized by aneurysms throughout the arterial tree in combination with osteoarthritis. The objective of the present study was to evaluate progression rate of aortic dilation and surgical outcome in AOS patients....

The purpose of this study was describe the cardiovascular phenotype of the aneurysms-osteoarthritis syndrome (AOS) and to provide clinical recommendations. AOS, caused by pathogenic SMAD3 variants, is a recently described autosomal dominant syndrome characterized by aneurysms and arterial tortuosity in combination with osteoarthritis. AOS patients...

Congenital heart malformations are a major cause of morbidity and mortality, especially in young children. Failure to establish normal left-right (L-R) asymmetry often results in cardiovascular malformations and other laterality defects of visceral organs. To identify genetic mutations causing cardiac laterality defects. We performed a genome-wide...

GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGFβ signaling. Willaert A et al (2012). Hum Mol Genet. 2011: Nov 24 [Epub ahead of print].

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...

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. A cohort of 393 patient...

We recently identified Rbm24 as a novel gene expressed during mouse cardiac development. Due to its tightly restricted and persistent expression from formation of the cardiac crescent onwards and later in forming vasculature we posited it to be a key player in cardiogenesis with additional roles in vasculogenesis and angiogenesis. To determine the...

rbm24a MO injected zebrafish heart 48 hpf. Digital video (time-lapse) captured of an rbm24a MO injected embryo (lateral) at 48 hpf. Movie highlights the unlooped (linear) structure of the rbm24a morphant heart displaying edema at this stage in development. Atrial and ventricular chambers are still evident despite structural anomaly; however contrac...

rbm24b MO injected zebrafish heart 48 hpf. Digital video (time-lapse) captured of an rbm24b MO injected embryo (lateral) at 48 hpf. Movie highlights the unlooped (linear) structure of the rbm24b morphant heart displaying edema at this stage in development. Atrial and ventricular chambers are still evident despite structural anomaly.

Translation Blocking MO titrations. Quantitative representation of percentage of embryos displaying cardiac phenotypes achieved from MO titrations. rbm24a MO 1, 2, 5 and 10 ng injected (A). rbm24b MO 1, 2.5, 5, 7 and 9 ng (B). Normal, looped beating heart with no cardiac edema; Class I, looped beating heart with cardiac edema; Class II, unlooped be...

Uninjected zebrafish heart 48 hpf. Digital video (time-lapse) captured of an uninjected control embryo (lateral) at 48 hpf. Movie demonstrates the looped structure and regular rhythm of the normal heart.

rbm24b MO injected zebrafish heart 72 hpf. Digital video (time-lapse) captured of an rbm24b MO injected embryo (lateral) at 72 hpf. Movie highlights the unlooped (linear) structure of the rbm24b morphant heart at this stage in development with additional cardiac edema. Atrial and ventricular chambers are still evident but highly distended, with no...

rbm24a MO injected zebrafish heart 72 hpf. Digital video (time-lapse) captured of an rbm24a MO injected embryo (lateral) at 72 hpf. Movie highlights the unlooped (linear) structure of the rbm24a morphant heart at this stage in development with cardiac edema. Heart atrial and ventricular chambers are difficult to distinguish and contracting with mar...

Uninjected zebrafish heart 96 hpf. Digital video (time-lapse) captured of an uninjected control embryo (lateral) at 96 hpf. Movie demonstrates the looped structure and regular rhythm of the normal heart, with circulation at this stage in development.

rbm24a and rbm24b splice blocked morphants display cardiac defects. Injection of 7.5 ng of rbm24a splice blocking morpholino results in a substantial reduction of full-length transcript (A). Injection of 9 ng of rbm24b splice blocking morpholino results in aberrant splicing of the transcript. There is a reduction of full-length transcript 250 bp fr...

rbm24a MO injected zebrafish heart 96 hpf. Digital video (time-lapse) captured of an rbm24a MO injected embryo (lateral) at 96 hpf. Movie highlights the unlooped (linear) structure of the rbm24a morphant heart at this stage in development with extreme cardiac edema. Heart atrial and ventricular chambers are difficult to distinguish and contracting...

rbm24b MO injected zebrafish heart 96 hpf. Digital video (time-lapse) captured of severe example of one rbm24b MO injected embryo (lateral) at 96 hpf. Movie highlights the phenotype of the unlooped (linear) highly distended heart of rbm24b morphants at this stage in development, with no detectable circulation. The heart with distinct atrial and ven...

p53 MO co-injection does not alter rbm24a and rbm24 morphant phenotypes. Phenotypes were evaluated for embryos post injection rbm24a MO (5 ng) or rbm24b MO (8 ng) alone or in conjunction with p53 MO (1 ng) phenotypes were compared at 48, 72 & 96 hpf. Lateral heart views are shown with a dotted outline around embryo heart chambers. No cardiac phenot...

Uninjected zebrafish heart 72 hpf. Digital video (time-lapse) captured of an uninjected control embryo (lateral) at 72 hpf. Movie demonstrates the looped structure and regular rhythm of the normal heart, with circulation at this stage in development.

Supplemental Table 1. Cardiac phenotypes displayed upon knockdown of rbm24a or rbm24b expression via splice blocking morpholino.

Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contras...

Kabuki Syndrome (KS) is a rare syndrome characterized by intellectual disability and multiple congenital abnormalities, in particular a distinct dysmorphic facial appearance. KS is caused by mutations in the MLL2 gene, encoding an H3K4 histone methyl transferase which acts as an epigenetic transcriptional activator during growth and development. Di...

Tracheal agenesis (TA) is a rare congenital anomaly of the respiratory tract. Many patients have associated anomalies, suggesting a syndromal phenotype. In a cohort of 12 patients, we aimed to detect copy number variations. In addition to routine cytogenetic analysis, we applied oligonucleotide array comparative genomic hybridization. Our patient c...

Partial monosomy 21 has been reported, but the phenotypes described are variable with location and size of the deletion. We present 2 patients with a partially overlapping microdeletion of 21q22 and a striking phenotypic resemblance. They both presented with severe psychomotor delay, behavioral problems, no speech, microcephaly, feeding problems wi...

Left ventricular (LV) noncompaction (LVNC) is a distinct cardiomyopathy featuring a thickened bilayered LV wall consisting of a thick endocardial layer with prominent intertrabecular recesses with a thin, compact epicardial layer. Similar to hypertrophic and dilated cardiomyopathy, LVNC is genetically heterogeneous and was recently associated with...

Mucopolysaccharidosis III D (Sanfilippo disease type D, MPS IIID) is a rare autosomal recessive lysosomal storage disorder previously described in only 20 patients. MPS IIID is caused by a deficiency of N-acetylglucosamine-6-sulphate sulphatase (GNS), one of the enzymes required for the degradation of heparan sulphate. So far only seven mutations i...

The VACTERL association is a non-random association of congenital defects with an unknown aetiology in the majority of patients. A male newborn is reported with features of the VACTERL association, including anal atresia, laryngeal and oesophageal atresia with tracheo-oesophageal fistula, dextroposition of the heart with persistent left superior ve...

Wessels MW, Willems PJ. Genetic factors in non-syndromic congenital heart malformations. The genetic defect in most patients with non-syndromic congenital heart malformations (CHM) is unknown, although more than 40 different genes have already been implicated. Only a minority of CHM seems to be due to monogenetic mutations, and the majority occurs...

We present a family segregating for an autosomal dominant syndrome of hypotelorism, cleft palate/uvula, high-arched palate and mild mental retardation. Although these findings may suggest a form of holoprosencephaly, no holoprosencephaly was found on MRI of the proposita. Results of genetic studies were normal including FISH for deletion of 22q11,...

CONTEXT AND OBJECTIVE: Mutations in EIF2AK3 cause Wolcott-Rallison syndrome (WRS), a rare recessive disorder characterized by early-onset diabetes, skeletal abnormalities, and liver dysfunction. Although early diagnosis is important for clinical management, genetic testing is generally performed after the full clinical picture develops. We aimed to...