Publications by authors named "Inge B Mathijssen"

25 Publications

  • Page 1 of 1

TMEM218 dysfunction causes ciliopathies, including Joubert and Meckel syndromes.

HGG Adv 2021 Jan 21;2(1). Epub 2020 Nov 21.

Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.

The Joubert-Meckel syndrome spectrum is a continuum of recessive ciliopathy conditions caused by primary cilium dysfunction. The primary cilium is a microtubule-based, antenna-like organelle that projects from the surface of most human cell types, allowing them to respond to extracellular signals. The cilium is partitioned from the cell body by the transition zone, a known hotspot for ciliopathy-related proteins. Despite years of Joubert syndrome (JBTS) gene discovery, the genetic cause cannot be identified in up to 30% of individuals with JBTS, depending on the cohort, sequencing method, and criteria for pathogenic variants. Using exome and targeted sequencing of 655 families with JBTS, we identified three individuals from two families harboring biallelic, rare, predicted-deleterious missense variants. Via MatchMaker Exchange, we identified biallelic variants in four additional families with ciliopathy phenotypes. Of note, four of the six families carry missense variants affecting the same highly conserved amino acid position 115. Clinical features included the molar tooth sign (N = 2), occipital encephalocele (N = 5, all fetuses), retinal dystrophy (N = 4, all living individuals), polycystic kidneys (N = 2), and polydactyly (N = 2), without liver involvement. Combined with existing functional data linking TMEM218 to ciliary transition zone function, our human genetic data make a strong case for TMEM218 dysfunction as a cause of ciliopathy phenotypes including JBTS with retinal dystrophy and Meckel syndrome. Identifying all genetic causes of the Joubert-Meckel spectrum enables diagnostic testing, prognostic and recurrence risk counseling, and medical monitoring, as well as work to delineate the underlying biological mechanisms and identify targets for future therapies.
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http://dx.doi.org/10.1016/j.xhgg.2020.100016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009330PMC
January 2021

Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms.

Genet Med 2021 Jan 21;23(1):103-110. Epub 2020 Aug 21.

Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Purpose: In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728.

Methods: Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts: one with 2685 CHD cases versus 4370 . These controls were also ancestry-matched (same as FTAA controls), and the other with 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls. Functional consequences of identified variants were evaluated using expression studies.

Results: We identified a loss-of-function variant in the Notch target transcription factor-encoding gene HEY2. The homozygous state (n = 3) causes life-threatening congenital heart defects, while 80% of heterozygous carriers (n = 20) had cardiovascular defects, mainly CHD and FTAA of the ascending aorta. We confirm enrichment of rare risk variants in HEY2 functional domains after meta-analysis (MetaSKAT p = 0.018). Furthermore, we show that several identified variants lead to dysregulation of repression by HEY2.

Conclusion: A homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects.
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http://dx.doi.org/10.1038/s41436-020-00939-4DOI Listing
January 2021

How will new genetic technologies, such as gene editing, change reproductive decision-making? Views of high-risk couples.

Eur J Hum Genet 2021 Jan 9;29(1):39-50. Epub 2020 Aug 9.

Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Clinical Genetics, section Community Genetics and Amsterdam Reproduction & Development research institute, PO Box 7057, 1007, MB, Amsterdam, The Netherlands.

Couples at increased risk of having offspring with a specific genetic disorder who want to avoid having an affected child have several reproductive options including prenatal diagnosis (PND) and preimplantation genetic testing (PGT). In the future, non-invasive prenatal diagnosis (NIPD), germline gene editing (GGE) and somatic gene editing (SGE) might become available. This study explores if, and how, availability of new genetic technologies, including NIPD, GGE, SGE, would change reproductive decision-making of high-risk couples. In 2018, semi-structured interviews were conducted with 25 genetically at-risk couples. Couples previously had received genetic counselling for PND and PGT, and in most cases opted for (one of) these techniques, at one Dutch Clinical Genetics Center between 2013 and 2017. Considerations participants mentioned regarding the hypothetical use of NIPD, GGE and SGE, seem similar to considerations regarding PND and PGT and are reflected in underlying concepts. These include safety and burden for mother and child, and moral considerations. Couples generally favoured NIPD over PND as this would be safe and enables earlier diagnosis. Increased opportunities of having a 'healthy' embryo and less embryo disposal were considerations in favour of GGE. Some regarded GGE as unsafe and feared slippery slope scenarios. Couples were least favourable towards SGE compared to choosing for a genetic reproductive technology, because of the perceived burden for the affected offspring. With the possibly growing number of technological options, understanding high risk couples' perspectives can assist in navigating the reproductive decision-making process. Counsellors should be prepared to counsel on more and complex reproductive options.
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http://dx.doi.org/10.1038/s41431-020-00706-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852899PMC
January 2021

Biallelic loss of function variants in COASY cause prenatal onset pontocerebellar hypoplasia, microcephaly, and arthrogryposis.

Eur J Hum Genet 2018 12 8;26(12):1752-1758. Epub 2018 Aug 8.

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

Pontocerebellar hypoplasia (PCH) is a heterogeneous neurodegenerative disorder with a prenatal onset. Using whole-exome sequencing, we identified variants in the gene Coenzyme A (CoA) synthase (COASY) gene, an enzyme essential in CoA synthesis, in four individuals from two families with PCH, prenatal onset microcephaly, and arthrogryposis. In family 1, compound heterozygous variants were identified in COASY: c.[1549_1550delAG]; [1486-3 C>G]. In family 2, all three affected siblings were homozygous for the c.1486-3 C>G variant. In both families, the variants segregated with the phenotype. RNA analysis showed that the c.1486-3 C>G variant leads to skipping of exon 7 with partial retention of intron 7, disturbing the reading frame and resulting in a premature stop codon (p.(Ala496Ilefs*20)). No CoA synthase protein was detected in patient cells by immunoblot analysis and CoA synthase activity was virtually absent. Partial CoA synthase defects were previously described as a cause of COASY Protein-Associated Neurodegeneration (CoPAN), a type of Neurodegeneration and Brain Iron Accumulation (NBIA). Here we demonstrate that near complete loss of function variants in COASY are associated with lethal PCH and arthrogryposis.
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http://dx.doi.org/10.1038/s41431-018-0233-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244412PMC
December 2018

Further delineation of Malan syndrome.

Hum Mutat 2018 09 25;39(9):1226-1237. Epub 2018 Jun 25.

Belfast HSC Trust, Northern Ireland Regional Genetics Service, Belfast, Northern Ireland.

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.
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http://dx.doi.org/10.1002/humu.23563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175110PMC
September 2018

Homozygous DMRT2 variant associates with severe rib malformations in a newborn.

Am J Med Genet A 2018 05;176(5):1216-1221

Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.

Spondylocostal dysostosis (SCD) is a rare disorder characterized by vertebral segmentation defects and malformations of the ribs. SCD patients have some degree of (kypho)scoliosis, short stature and suffer from respiratory impairment due to the reduced size of their thoracic cage. Mutations in DLL3, MESP2, LFNG, HES7, TBX6, and RIPPLY2 are known to cause different subtypes of SCD. Here, we report on a male neonate with an apparent distinct SCD-like phenotype only partly overlapping the previously described SCD subtypes. The proband presented with severe rib malformations (missing, fused, bifid, and hypoplastic ribs), vertebral malformations (intervertebral fusions of the laminae and irregular ossification of the vertebral bodies), and a mild scoliosis. Clear segmentation defects of the vertebral bodies were lacking. Other dysmorphic features were present as well. Severe respiratory insufficiency was present from birth. Whole exome sequencing identified a homozygous start-loss variant in DMRT2 (NM_006557.6: c.1A > T p.[Met1?]) being a likely cause of the SCD-like phenotype in the proband. Mutations in DMRT2 (OMIM#604935) have not been described in relation to SCD-related phenotypes in humans before. However, Dmrt2 knock-out mice exhibit severe rib and vertebral defects that strikingly overlap with the radiological phenotype of the proband reported here. Therefore, it seems plausible that mutations in DMRT2 are associated with a different (novel) subtype of SCD mainly characterized by severe rib anomalies but lacking clear segmentation defects of the vertebral bodies.
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http://dx.doi.org/10.1002/ajmg.a.38668DOI Listing
May 2018

Preconception carrier screening for multiple disorders: evaluation of a screening offer in a Dutch founder population.

Eur J Hum Genet 2018 02 10;26(2):166-175. Epub 2018 Jan 10.

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

Technological developments have enabled carrier screening for multiple disorders. This study evaluated experiences with a preconception carrier screening offer for four recessive disorders in a Dutch founder population. Questionnaires were completed by 182 attendees pretesting and posttesting and by 137 non-attendees. Semistructured interviews were conducted with seven of the eight carrier couples. Attendees were mainly informed about the existence of screening by friends/colleagues (49%) and family members (44%). Familiarity with the genetic disorders was high. Knowledge after counseling increased (p < 0.001); however, still 9%, compared to 29% before counseling, wrongly mentioned an increased risk of having an affected child if both parents are carriers of different disorders. Most attendees (97%) recalled their test results correctly, but two couples reported being carrier of another disorder than reported. Overall, 63% felt worried while waiting for results but anxiety levels returned to normal afterwards. In all, 2/39 (5%) carriers felt less healthy. Screened individuals were very satisfied; they did not regret testing (97%) and would recommend testing to others (97%). The majority (94%) stated that couples should always have a pretest consultation, preferably by a genetic counselor rather than their general practitioner (83%). All carrier couples made reproductive decisions based on their results. Main reason for non-attendance was unawareness of the screening offer. With expanded carrier screening, adequately informing couples pretest and posttesting is of foremost importance. Close influencers (family/friends) can be used to raise awareness of a screening offer. Our findings provide lessons for the implementation of expanded carrier screening panels in other communities and other settings.
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http://dx.doi.org/10.1038/s41431-017-0056-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838981PMC
February 2018

With expanded carrier screening, founder populations run the risk of being overlooked.

J Community Genet 2017 Oct 29;8(4):327-333. Epub 2017 May 29.

Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.

Genetically isolated populations exist worldwide. Specific genetic disorders, including rare autosomal recessive disorders may have high prevalences in these populations. We searched for Dutch genetically isolated populations and their autosomal recessive founder mutations. We investigated whether these founder mutations are covered in the (preconception) expanded carrier screening tests of five carrier screening providers. Our results show that the great majority of founder mutations are not covered in these screening panels, and these panels may thus not be appropriate for use in founder populations. It is therefore important to be aware of founder mutations in a population when offering carrier tests.
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http://dx.doi.org/10.1007/s12687-017-0309-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614881PMC
October 2017

Factors for successful implementation of population-based expanded carrier screening: learning from existing initiatives.

Eur J Public Health 2017 04;27(2):372-377

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

Background: Carrier screening for autosomal recessive disorders aims to facilitate reproductive decision-making by identifying couples with a 1-in-4 risk in every pregnancy of having an affected child. Except for a few countries or regions, carrier screening is not widely offered and is mostly ancestry-based. Technological advances enable carrier screening for multiple diseases simultaneously allowing universal screening regardless of ancestry (population-based expanded carrier screening). It is important to study how this can be successfully implemented. This study therefore aims to identify critical factors involved in successful implementation, from a user perspective, by learning from already implemented initiatives.

Methods: Factors associated with successful implementation were identified by: (i) a literature review and (ii) two case studies; studying experiences with carrier screening in two high-risk communities (a Dutch founder population and the Ashkenazi Jewish population), including a survey among community members.

Results: Factors identified were familiarity with (specific) genetic diseases and its availability, high perceived benefits of screening (e.g. screening avoids much suffering), acceptance of reproductive options, perceived risk of being a carrier and low perceived social barriers (e.g. stigmatization). In contrast to the Jewish community, the initial demand for screening in the Dutch founder population did not entirely come from the community itself. However, the large social cohesion of the community facilitated the implementation process.

Conclusion: To ensure successful implementation of population-based expanded carrier screening, efforts should be made to increase knowledge about genetic diseases, create awareness and address personal benefits of screening in a non-directive way.
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http://dx.doi.org/10.1093/eurpub/ckw110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421354PMC
April 2017

LONG-TERM FOLLOW-UP OF PATIENTS WITH RETINITIS PIGMENTOSA TYPE 12 CAUSED BY CRB1 MUTATIONS: A Severe Phenotype With Considerable Interindividual Variability.

Retina 2017 Jan;37(1):161-172

*Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands; †The Rotterdam Eye Hospital, Rotterdam, the Netherlands; ‡Rivas Zorggroep, Vianen, the Netherlands; §Department of Genome Analysis, Academic Medical Center, Amsterdam, the Netherlands; ¶The Netherlands Institute for Neurosciences (NIN-KNAW), Amsterdam, the Netherlands; and **Department of Ophthalmology, Academic Medical Center, Amsterdam, the Netherlands.

Purpose: To examine the long-term clinical course and variability in a large pedigree segregating CRB1 type autosomal recessive retinitis pigmentosa.

Methods: An observational case study of 30 patients with CRB1 type autosomal recessive retinitis pigmentosa, homozygous for the CRB1 c.3122T > C; p.(Met1041Thr) mutation from a Dutch genetically isolated population in which the CRB1 gene was originally identified. The authors evaluated medical records, analyzed a questionnaire, and performed a comprehensive ophthalmic examination, including optical coherence tomography.

Results: Mean follow-up was 19 years (range 0-45 years, SD 15 years). With aging, patients showed progressive visual decline, deterioration of visual fields, increasing narrowing of the anterior chamber, increased prevalence of cataract, and an increase in the amount of intraretinal pigmentations. Fifty percent of patients had a visual acuity of ≤0.3 at Age 18 and of ≤0.1 at Age 35. Electroretinogram responses were severely reduced or absent already at a young age and optical coherence tomography showed increased retinal thickness with often cystoid maculopathy at young age, and thinning of the retina and disorientation of the photoreceptor layer in the late stages. The clinical course showed considerable interindividual variability, but intraindividual similarity between both eyes was the rule.

Conclusion: The wide and variable clinical spectrum in patients with the same CRB1 mutation supports the hypothesis that the CRB1 type autosomal recessive retinitis pigmentosa-phenotype is modulated by other factors. The clinical variability will make it harder to evaluate the effect of (upcoming) therapies for retinitis pigmentosa, although because of the intraindividual similarity between both eyes, the contralateral eye can be used as an excellent internal control.
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http://dx.doi.org/10.1097/IAE.0000000000001127DOI Listing
January 2017

The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families.

Genet Med 2017 01 19;19(1):45-52. Epub 2016 May 19.

Department of Molecular Neuroscience, University College London Institute of Neurology, London, UK.

Purpose: Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11-13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients' phenotypes was questioned, as MAGEL2 whole-gene deletions seem to cause little or no clinical phenotype.

Methods: Here we report a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families, including 1 family with 3 individuals found to be affected with a truncating variant of MAGEL2, 11 individuals who are clinically affected but were not tested molecularly, and a presymptomatic fetal sibling carrying the pathogenic MAGEL2 variant.

Results: All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990-1996 arise as a mutational hotspot, with 10 individuals and 1 fetus harboring a c.1996dupC (p.Q666fs) mutation and 2 fetuses harboring a c.1996delC (p.Q666fs) mutation. The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to neurobehavioral disease and contractures of the small finger joints.

Conclusion: This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling for affected families.Genet Med 19 1, 45-52.
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http://dx.doi.org/10.1038/gim.2016.53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116288PMC
January 2017

Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome.

Eur J Med Genet 2015 May 16;58(5):279-92. Epub 2015 Mar 16.

Genetic Health Service NZ, Wellington, New Zealand.

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities, and subdivided in TRPS I, caused by mutations in TRPS1, and TRPS II, caused by a contiguous gene deletion affecting (amongst others) TRPS1 and EXT1. We performed a collaborative international study to delineate phenotype, natural history, variability, and genotype-phenotype correlations in more detail. We gathered information on 103 cytogenetically or molecularly confirmed affected individuals. TRPS I was present in 85 individuals (22 missense mutations, 62 other mutations), TRPS II in 14, and in 5 it remained uncertain whether TRPS1 was partially or completely deleted. Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella. The facial manifestations in patients with TRPS I and TRPS II do not show a significant difference. In the limbs the main findings are short hands and feet, hypermobility, and a tendency for isolated metacarpals and metatarsals to be shortened. Nails of fingers and toes are typically thin and dystrophic. The radiological hallmark are the cone-shaped epiphyses and in TRPS II multiple exostoses. Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally. Variability for all findings, also within a single family, can be marked. Morbidity mostly concerns joint problems, manifesting in increased or decreased mobility, pain and in a minority an increased fracture rate. The hips can be markedly affected at a (very) young age. Intellectual disability is uncommon in TRPS I and, if present, usually mild. In TRPS II intellectual disability is present in most but not all, and again typically mild to moderate in severity. Missense mutations are located exclusively in exon 6 and 7 of TRPS1. Other mutations are located anywhere in exons 4-7. Whole gene deletions are common but have variable breakpoints. Most of the phenotype in patients with TRPS II is explained by the deletion of TRPS1 and EXT1, but haploinsufficiency of RAD21 is also likely to contribute. Genotype-phenotype studies showed that mutations located in exon 6 may have somewhat more pronounced facial characteristics and more marked shortening of hands and feet compared to mutations located elsewhere in TRPS1, but numbers are too small to allow firm conclusions.
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http://dx.doi.org/10.1016/j.ejmg.2015.03.002DOI Listing
May 2015

Noninvasive prenatal diagnosis of Huntington disease: detection of the paternally inherited expanded CAG repeat in maternal plasma.

Prenat Diagn 2015 Oct 5;35(10):945-9. Epub 2015 Apr 5.

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

Objective: With a shift towards noninvasive testing, we have explored and validated the use of noninvasive prenatal diagnosis (NIPD) for Huntington disease (HD).

Methods: Fifteen couples have been included, assessing a total of n = 20 pregnancies. Fetal paternally inherited CAG repeat length was determined in total cell-free DNA from maternal plasma using a direct approach by PCR and subsequent fragment analysis.

Results: All fetal HD (n = 7) and intermediate (n = 3) CAG repeats could be detected in maternal plasma. Detection of repeats in the normal range (n = 10) was successful in n = 5 cases where the paternal repeat size could be distinguished from maternal repeat patterns after fragment analysis. In all other cases (n = 5), the paternal peaks coincided with the maternal peak pattern. All NIPD results were concordant with results from routine diagnostics on fetal genomic DNA from chorionic villi.

Conclusion: In this validation study, we demonstrated that all fetuses at risk for HD could be identified noninvasively in maternal plasma. Additionally, we have confirmed results from previously described case reports that NIPD for HD can be performed using a direct approach by PCR. For future diagnostics, parental CAG profiles can be used to predict the success rate for NIPD prior to testing.
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http://dx.doi.org/10.1002/pd.4593DOI Listing
October 2015

Targeted carrier screening for four recessive disorders: high detection rate within a founder population.

Eur J Med Genet 2015 Mar 30;58(3):123-8. Epub 2015 Jan 30.

Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.

In a genetically isolated community in the Netherlands four severe recessive genetic disorders occur at relatively high frequency (pontocerebellar hypoplasia type 2 (PCH2), fetal akinesia deformation sequence (FADS), rhizomelic chondrodysplasia punctata type 1 (RCDP1), and osteogenesis imperfecta (OI) type IIB/III. Over the past decades multiple patients with these disorders have been identified. This warranted the start of a preconception outpatient clinic, in 2012, aimed at couples planning a pregnancy. The aim of our study was to evaluate the offer of targeted genetic carrier screening as a method to identify high-risk couples for having affected offspring in this high-risk subpopulation. In one year, 203 individuals (92 couples and 19 individuals) were counseled. In total, 65 of 196 (33.2%) tested individuals were carriers of at least one disease, five (7.7%) of them being carriers of two diseases. Carrier frequencies of PCH2, FADS, RCDP1, and OI were 14.3%, 11.2%, 6.1%, and 4.1% respectively. In individuals with a positive family history for one of the diseases, the carrier frequency was 57.8%; for those with a negative family history this was 25.8%. Four PCH2 carrier-couples were identified. Thus, targeted (preconception) carrier screening in this genetically isolated population in which a high prevalence of specific disorders occurs detects a high number of carriers, and is likely to be more effective compared to cascade genetic testing. Our findings and set-up can be seen as a model for carrier screening in other high-risk subpopulations and contributes to the discussion about the way carrier screening can be offered and organized in the general population.
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http://dx.doi.org/10.1016/j.ejmg.2015.01.004DOI Listing
March 2015

Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence.

Eur J Hum Genet 2015 Sep 24;23(9):1151-7. Epub 2014 Dec 24.

1] Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands [2] Department of Functional Genomics, Center for Neurogenomics and Cognition Research, VU University, Amsterdam, The Netherlands.

Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing.
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http://dx.doi.org/10.1038/ejhg.2014.273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538208PMC
September 2015

Variants in CUL4B are associated with cerebral malformations.

Hum Mutat 2015 Jan;36(1):106-17

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

Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating variants. Neuroimaging data, available for 15 patients, showed the presence of cerebral malformations in ten patients. The cerebral anomalies comprised malformations of cortical development (MCD), ventriculomegaly, and diminished white matter volume. The phenotypic heterogeneity of the cerebral malformations might result from the involvement of CUL-4B in various cellular pathways essential for normal brain development. Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD. This interaction might contribute to the development of cerebral malformations in patients with variants in CUL4B.
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http://dx.doi.org/10.1002/humu.22718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608231PMC
January 2015

Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings.

Eur J Hum Genet 2013 Sep 16;21(9):936-42. Epub 2013 Jan 16.

Department of Paediatrics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

In recent studies on prenatal testing for Noonan syndrome (NS) in fetuses with an increased nuchal translucency (NT) and a normal karyotype, mutations have been reported in 9-16% of cases. In this study, DNA of 75 fetuses with a normal karyotype and abnormal ultrasound findings was tested in a diagnostic setting for mutations in (a subset of) the four most commonly mutated NS genes. A de novo mutation in either PTPN11, KRAS or RAF1 was detected in 13 fetuses (17.3%). Ultrasound findings were increased NT, distended jugular lymphatic sacs (JLS), hydrothorax, renal anomalies, polyhydramnios, cystic hygroma, cardiac anomalies, hydrops fetalis and ascites. A second group, consisting of anonymized DNA of 60 other fetuses with sonographic abnormalities, was tested for mutations in 10 NS genes. In this group, five possible pathogenic mutations have been identified (in PTPN11 (n=2), RAF1, BRAF and MAP2K1 (each n=1)). We recommend prenatal testing of PTPN11, KRAS and RAF1 in pregnancies with an increased NT and at least one of the following additional features: polyhydramnios, hydrops fetalis, renal anomalies, distended JLS, hydrothorax, cardiac anomalies, cystic hygroma and ascites. If possible, mutation analysis of BRAF and MAP2K1 should be considered.
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http://dx.doi.org/10.1038/ejhg.2012.285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746261PMC
September 2013

Prenatal diagnosis of a trisomy 7/trisomy 13 mosaicism.

Mol Cytogenet 2012 Jan 27;5(1). Epub 2012 Jan 27.

Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.

Double aneuploidy mosaicism of two different aneuploidy cell lines is rare. We describe for the first time a double trisomy mosaicism, involving chromosomes 7 and 13 in a fetus presenting with multiple congenital anomalies. No evidence for chimerism was found by DNA genotyping. The origin of both trisomies are consistent with isodisomy of maternal origin. Therefore, it is most likely that the double trisomy mosaicism arose from two independent events very early in embryonic development. The trisomy 7 and 13 cells were shown to be of maternal origin.
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http://dx.doi.org/10.1186/1755-8166-5-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3293093PMC
January 2012

A novel autosomal dominant condition consisting of congenital heart defects and low atrial rhythm maps to chromosome 9q.

Eur J Hum Genet 2011 Jul 9;19(7):820-6. Epub 2011 Mar 9.

Heart Failure Research Centre, Department of Anatomy and Embryology, Academic Medical Centre, Amsterdam, The Netherlands.

Congenital heart defects (CHDs) occur mostly sporadic, but familial CHD cases have been reported. Mutations in several genes, including NKX2.5, GATA4 and NOTCH1, were identified in families and patients with CHD, but the mechanisms underlying CHD are largely unknown. We performed genome-wide linkage analysis in a large four-generation family with autosomal dominant CHD (including atrial septal defect type I and II, tetralogy of Fallot and persistent left superior vena cava) and low atrial rhythm, a unique phenotype that has not been described before. We obtained phenotypic information including electrocardiography, echocardiography and DNA of 23 family members. Genome-wide linkage analysis on 12 affected, 5 unaffected individuals and 1 obligate carrier demonstrated significant linkage only to chromosome 9q21-33 with a multipoint maximum LOD score of 4.1 at marker D9S1690, between markers D9S167 and D9S1682. This 48-cM critical interval corresponds to 39 Mb and contains 402 genes. Sequence analysis of nine candidate genes in this region (INVS, TMOD1, TGFBR1, KLF4, IPPK, BARX1, PTCH1, MEGF9 and S1PR3) revealed no mutations, nor were genomic imbalances detected using array comparative genomic hybridization. In conclusion, we describe a large family with CHD and low atrial rhythm with a significant LOD score to chromosome 9q. The phenotype is representative of a mild form of left atrial isomerism or a developmental defect of the sinus node and surrounding tissue. Because the mechanisms underlying CHD are largely unknown, this study represents an important step towards the discovery of genes implied in cardiogenesis.
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http://dx.doi.org/10.1038/ejhg.2011.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137501PMC
July 2011

Functional analysis of novel TBX5 T-box mutations associated with Holt-Oram syndrome.

Cardiovasc Res 2010 Oct 2;88(1):130-9. Epub 2010 Jun 2.

Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Aims: Holt-Oram syndrome (HOS) is a heart/hand syndrome clinically characterized by upper limb and cardiac malformations. Mutations in T-box transcription factor 5 (TBX5) underlie this syndrome, the majority of which lead to premature stops. In this study, we present our functional analyses of five (novel) missense TBX5 mutations identified in HOS patients, most of whom presented with severe cardiac malformations.

Methods And Results: Functional characterization of mutant proteins shows a dramatic loss of DNA-binding capacity, as well as diminished binding to known cardiac interaction partners NKX2-5 and GATA4. The disturbance of these interactions leads to a loss of function, as measured by the reduced activation of Nppa and FGF10 in rat heart derived cells, although with variable severity. Two out of the five mutations are peculiar: one, p.H220del, is associated with additional extra-cardiac defects, perhaps by interfering with other T-box dependant pathways, and another, p.I106V, leads to limb defects only, which is supported by its normal interaction with cardiac-specific interaction partners.

Conclusion: Overall, our data are consistent with the hypothesis that these novel missense mutations in TBX5 lead to functional haploinsufficiency and result in a reduced transcriptional activation of target genes, which is likely central to the pathogenesis of HOS.
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http://dx.doi.org/10.1093/cvr/cvq178DOI Listing
October 2010

A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation.

Circ Res 2008 Jun 1;102(11):1433-42. Epub 2008 May 1.

Heart Failure Research Center, L2-108-1, Academic Medical Center, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands.

Holt-Oram syndrome (HOS) is a heart/hand syndrome clinically characterized by upper limb and cardiac malformations. Mutations in T-box transcription factor 5 (TBX5) underlie this syndrome. Here, we describe a large atypical HOS family in which affected patients have mild skeletal deformations and paroxysmal atrial fibrillation, but few have congenital heart disease. Sequencing of TBX5 revealed a novel mutation, c.373G>A, resulting in the missense mutation p.Gly125Arg, in all investigated affected family members, cosegregating with the disease. We demonstrate that the mutation results in normal Nkx2-5 interaction, is correctly targeted to the nucleus, has significantly enhanced DNA binding and activation of both the Nppa(Anf) and Cx40 promoter, and significantly augments expression of Nppa, Cx40, Kcnj2, and Tbx3 in comparison with wild-type TBX5. Thus, contrary to previously published HOS mutations, the p.G125R TBX5 mutation results in a gain-of-function. We speculate that the gain-of-function mechanism underlies the mild skeletal phenotype and paroxysmal atrial fibrillation and suggest a possible role of TBX5 in the development of (paroxysmal) atrial fibrillation based on a gain-of-function either through a direct stimulation of target genes via TBX5 or indirectly via TBX5 stimulated TBX3. These findings may warrant a renewed look at the phenotypes of families and individuals hitherto not classified as HOS or as atypical but presenting with paroxysmal atrial fibrillation, because these may possibly be the result of additional TBX5 gain-of-function mutations.
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http://dx.doi.org/10.1161/CIRCRESAHA.107.168294DOI Listing
June 2008

Testicular cancer in a patient with Primrose syndrome.

Eur J Med Genet 2006 Mar-Apr;49(2):127-33. Epub 2005 Jun 23.

Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, The Netherlands.

A mentally retarded, adult man was found to have joint contractures, sparse body hair, hearing loss, dysmorphic facial features, large calcified pinnae and a huge torus palatinus. All features are similar to those earlier described in patients with Primrose syndrome. In addition he developed a germ cell tumour of his right testicle at age 27 years. A comparison is provided between the main findings in the four previously reported cases with Primrose syndrome and the current patient. Calcification of the pinnae is an infrequent symptom in the general population, and a torus palatinus of limited size is commonly found but a torus of the size reported here is extremely unusual. Both symptoms are excellent handles for diagnosing this entity. It remains as yet uncertain whether an increased risk to malignancies forms part of this syndrome or is only a consequence of cryptorchidism in this patient.
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http://dx.doi.org/10.1016/j.ejmg.2005.06.001DOI Listing
April 2009

Array comparative genomic hybridization analysis of a familial duplication of chromosome 13q: a recognizable syndrome.

Am J Med Genet A 2005 Jul;136(1):76-80

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

We report on a family with six persons in three generations who have mild mental retardation, behavioral problems, seizures, hearing loss, strabismus, dental anomalies, hypermobility, juvenile hallux valgus, and mild dysmorphic features. Classical cytogenetic analysis showed a partial duplication of chromosome 13q, array comparative genomic hybridization showed the duplication to span approximately 21 Mb, ranging from chromosome band 13q21.31 to 13q31.1. The relatively mild presentation of this large duplication may be explained by the relative paucity of genes in the chromosome region involved. Genotype-phenotype correlations in patients with similar partial 13q duplications are inconsistent. Emerging cytogenetic techniques will allow more reliable genotype-phenotype correlations.
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http://dx.doi.org/10.1002/ajmg.a.30758DOI Listing
July 2005

Genotype-phenotype correlation in patients suspected of having Sotos syndrome.

Horm Res 2004 24;62(4):197-207. Epub 2004 Sep 24.

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

Background: Deletions and mutations in the NSD1 gene are the major cause of Sotos syndrome. We wanted to evaluate the genotype-phenotype correlation in patients suspected of having Sotos syndrome and determine the best discriminating parameters for the presence of a NSD1 gene alteration.

Methods: Mutation and fluorescence in situ hybridization analysis was performed on blood samples of 59 patients who were clinically scored into 3 groups. Clinical data were compared between patients with and without NSD1 alterations. With logistic regression analysis the best combination of predictive variables was obtained.

Results: In the groups of typical, dubious and atypical Sotos syndrome, 81, 36 and 0% of the patients, respectively, showed NSD1 gene alterations. Four deletions were detected. In 23 patients (2 families) 19 mutations were detected (1 splicing defect, 3 non-sense, 7 frameshift and 8 missense mutations). The best predictive parameters for a NSD1 gene alteration were frontal bossing, down-slanted palpebral fissures, pointed chin and overgrowth. Higher incidences of feeding problems and cardiac anomalies were found. The parameters, delayed development and advanced bone age, did not differ between the 2 subgroups.

Conclusions: In our patients suspected of having Sotos syndrome, facial features and overgrowth were highly predictive of a NSD1 gene aberration, whereas developmental delay and advanced bone age were not.
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http://dx.doi.org/10.1159/000081063DOI Listing
February 2005