Papers by KOENRAAD DEVRIENDT
Journal of Inherited Metabolic Disease, 2006
European journal of human genetics : EJHG, Jan 23, 2014
Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been... more Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode β- and γ-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree o...
Seminars in Fetal and Neonatal Medicine, 2010
An increasing number of fetal anomalies are being diagnosed prior to birth, some of them amenable... more An increasing number of fetal anomalies are being diagnosed prior to birth, some of them amenable to fetal surgical intervention. We discuss the current clinical status and recent advances in endoscopic and open surgical interventions. In Europe, fetoscopic interventions are widely embraced, whereas the uptake of open fetal surgery is much less. The indications for each access modality are different, hence they cannot substitute each other. Although the stage of technical experimentation is over, most interventions remain investigational. Today there is level I evidence that fetoscopic laser surgery for twin-to-twin transfusion syndrome is the preferred therapy, but this operation actually takes place on the placenta. In terms of surgery on the fetus, an increasingly frequent indication is severe congenital diaphragmatic hernia as well as myelomeningocele. Overall maternal safety is high, but rupture of the membranes and preterm delivery remain a problem. The increasing application of fetal surgery and its mediagenicity has triggered the interest to embark on fetal surgical therapy, although the complexity as well as the overall rare indications are a limitation to sufficient experience on an individual basis. We plead for increased exchange between high volume units and collaborative studies; there may also be a case for self-regulation. Inclusion of patients into trials whenever possible should be encouraged rather than building up casuistic experience.
Journal of Medical Genetics, 2008
Recent molecular studies of breakpoints of recurrent chromosome rearrangements revealed the role ... more Recent molecular studies of breakpoints of recurrent chromosome rearrangements revealed the role of genomic architecture in their formation. In particular, segmental duplications representing blocks of >1 kb with >90% sequence homology were shown to mediate non-allelic homologous recombination (NAHR). However, the occurrence of the majority of newly detected submicroscopic imbalances cannot be explained by the presence of segmental duplications. Therefore, further studies are needed to investigate whether architectural features other than segmental duplications mediate these rearrangements. We analysed a series of patients with breakpoints clustering within chromosome band 5q35. Using high density arrays and subsequent quantitative polymerase chain reaction (qPCR), we characterised the breakpoints of four interstitial deletions (including one associated with an unbalanced paracentric inversion), a duplication and a familial reciprocal t(5;18)(q35;q22) translocation. Five of the breakpoints were located within an interval of approximately 265 kb encompassing the RANBP17 and TLX3 genes. This region is also targeted by the recurrent cryptic t(5;14)(q35;q32) translocation, which occurs in approximately 20% of childhood T cell acute lymphoblastic leukaemia (T-ALL). In silico analysis indicated the architectural features most likely to contribute to the genomic instability of this region, which was supported by our molecular data. Of further interest, in two patients and the familial translocation, the delineated breakpoint regions encompassed highly homologous LINEs (long interspersed nuclear elements), suggesting that NAHR between these LINEs may have mediated these rearrangements.
Human Mutation, 2007
Subtelomeric imbalances are identified in $5% of patients with idiopathic mental retardation (MR)... more Subtelomeric imbalances are identified in $5% of patients with idiopathic mental retardation (MR) and multiple congenital anomalies (MCA). Because of this high incidence, screening for subtelomeric anomalies became part of the routine genetic evaluation of MCA/MR patients. In contrast to the general view that subtelomeric imbalances cause MCA/MR, we report here 15 subtelomeric copy-number changes in 12 families in which the imbalance is inherited from a phenotypically normal parent. We detected inherited deletions at subtelomeres 2q, 3p, 4p, 4q, 6q, 10q, 17p, 17q, Xp, and Yq and duplications at 1q, 4q, 10q, and 11q. Interestingly, in addition to small deletions (o1 Mb) also unexpected large deletions and duplications up to 7.8 Mb were detected. Taken together with previous reports, a total of 16 subtelomeric duplications and 18 deletions inherited from a phenotypically normal parent have now been reported. Clearly, more extensive genotype-phenotype correlations are needed to better understand the phenotypic consequences of these subtelomeric copy number variations and to resolve the current uncertainty for genetic counseling in postnatal and prenatal diagnosis. Hum Mutat 28(10), 958-967, 2007.
Human Genetics, 1997
The mechanism(s) for the origin of jumping translocations (JTs) are unknown. To assess the possib... more The mechanism(s) for the origin of jumping translocations (JTs) are unknown. To assess the possible involvement of telomeric sequences in the jumping process, metaphases of a patient with hydrops fetalis having a JT were analyzed for the presence of interstitial telomeres. Telomere DNA sequences were detected at the junction sites of the donor and the recipient chromosomes. Interstitial telomeric sequences have so far only been detected in JTs involving chromosome 15q in patients with Prader-Willi syndrome. Our finding of interstitial telomeric sequences in a JT with a chromosome different from chromosome arm 15q in a patient without Prader-Willi syndrome implies that telomere sequences may be common to all telomeric JTs. The possible role of telomeric sequences as a cause of the observed chromosomal mosaicism is discussed.
Genome Medicine, 2012
The increasing size and complexity of exome/genome sequencing data requires new tools for clinica... more The increasing size and complexity of exome/genome sequencing data requires new tools for clinical geneticists to discover disease-causing variants. Bottlenecks in identifying the causative variation include poor cross-sample querying, constantly changing functional annotation and not considering existing knowledge concerning the phenotype. We describe a methodology that facilitates exploration of patient sequencing data towards identification of causal variants under different genetic hypotheses. Annotate-it facilitates handling, analysis and interpretation of high-throughput single nucleotide variant data. We demonstrate our strategy using three case studies. Annotate-it is freely available and test data are accessible to all users at .
European Journal of Medical Genetics, 2009
Refining the locus of branchio-otic syndrome 2 (BOS2) to a 5.25 Mb locus on chromosome 1q31.3q32.1
European Journal of Medical Genetics, 2005
Mowat-Wilson Syndrome is a recently delineated mental retardation syndrome usually associated wit... more Mowat-Wilson Syndrome is a recently delineated mental retardation syndrome usually associated with multiple malformations and a recognizable facial phenotype caused by defects of the transcriptional repressor ZFHX1B. To address the question of clinical and mutational variability, we analysed a large number of patients with suspected Mowat-Wilson Syndrome (MWS). Without prior knowledge of their mutational status, 70 patients were classified into "typical MWS", "ambiguous" and "atypical" groups according to their facial phenotype. Using FISH, qPCR and sequencing, ZFHX1B deletions, splice site or truncating mutations were detected in all 28 patients classified as typical MWS. No ZFHX1B defect was apparent in the remaining 15 cases with ambiguous facial features or in the 27 atypical patients. Genotype-phenotype analysis confirmed that ZFHX1B deletions and stop mutations result in a recognizable facial dysmorphism with associated severe mental retardation and variable malformations such as Hirschsprung disease and congenital heart defects. Our findings indicate that structural eye anomalies such as microphthalmia should be considered as part of the MWS spectrum. We also show that agenesis of the corpus callosum and urogenital anomalies (especially hypospadias) are significant positive predictors of a ZFHX1B defect. Based on our observation of affected siblings and the number of MWS cases previously reported, we suggest a recurrence risk of around 1%. The lack of missense mutations in MWS and MWS-like patients suggests there may be other, as yet unrecognized phenotypes, associated with missense mutations of this transcription factor.
European Journal of Human Genetics, 2007
Array-based whole genome investigation or molecular karyotyping enables the genome-wide detection... more Array-based whole genome investigation or molecular karyotyping enables the genome-wide detection of submicroscopic imbalances. Proof-of-principle experiments have demonstrated that molecular karyotyping outperforms conventional karyotyping with regard to detection of chromosomal imbalances. This article identifies areas for which the technology seems matured and areas that require more investigations. Molecular karyotyping should be part of the genetic diagnostic work-up of patients with developmental disorders. For the implementation of the technique for other constitutional indications and in prenatal diagnosis, more research is appropriate. Also, the article aims to provide best practice guidelines for the application of array comparative genomic hybridisation to ensure both technical and clinical quality criteria that will optimise and standardise results and reports in diagnostic laboratories. In short, both the specificity and the sensitivity of the arrays should be evaluated in every laboratory offering the diagnostic test. Internal and external quality control programmes are urgently needed to evaluate and standardise the test results between laboratories.
European Journal of Human Genetics, 2010
DISEASE CHARACTERISTICS 1.1 Name of the disease (synonyms) DiGeorge syndrome (DGS), velocardiofac... more DISEASE CHARACTERISTICS 1.1 Name of the disease (synonyms) DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), Shprintzen syndrome, Takao syndrome, Sedlackova syndrome, chromosome 22q11.2 deletion syndrome. 1.2 OMIM# of the disease 188400 (DGS), 192430 (VCFS). 1.3 Name of the analysed genes or DNA/chromosome segments 22q11.2, TBX1. 1.4 OMIM# of the gene(s) 602054 (TBX1). 1.5 Mutational spectrum Deletions in 22q11.2: 1,2 3 Mb (90% of cases) 1.5 Mb (7-8% of cases) Atypical smaller deletions. Point mutations in TBX1. 3 1.6 Analytical methods FISH, MLPA, quantitative PCR, array CGH, sequencing. Conventional cytogenetics usually normal except for rare cases resulting from unbalanced translocations. Parallel analysis of positive and negative controls, depending on the method. 1.8 Estimated frequency of the disease (incidence at birth ('birth prevalence') or population prevalence) Prevalence at birth: 1:5000 (ranges from 1:4000 to 1:10 000 in the literature). 4-8 1.9 If applicable, prevalence in the ethnic group of investigated person None. Depends on analytical method: Typical 3 and 1.5 Mb deletions: almost 100% for all methods. Atypical deletions: FISH: 495%. MLPA, array CGH: virtually 100%. Point mutations in TBX1: 0%, requires sequencing (research). 9,10 2.2 Analytical specificity (proportion of negative tests if the genotype is not present) Nearly 100%. Yes No A. (Differential) diagnostics 2 & B. Predictive testing & 2 C. Risk assessment in relatives 2 & D. Prenatal
European Journal of Human Genetics, 2011
Wolf-Hirschhorn syndrome is caused by anomalies of the short arm of chromosome 4. About 55% of ca... more Wolf-Hirschhorn syndrome is caused by anomalies of the short arm of chromosome 4. About 55% of cases are due to de novo terminal deletions, 40% from unbalanced translocations and 5% from other abnormalities. The facial phenotype is characterized by hypertelorism, protruding eyes, prominent glabella, broad nasal bridge and short philtrum. We used dense surface modelling and pattern recognition techniques to delineate the milder facial phenotype of individuals with a small terminal deletion (breakpoint within 4p16.3) compared to those with a large deletion (breakpoint more proximal than 4p16.3). Further, fine-grained facial analysis of several individuals with an atypical genotype and/or phenotype suggests that multiple genes contiguously contribute to the characteristic Wolf-Hirschhorn syndrome facial phenotype.
European Heart Journal, 2007
Aims Congenital heart defects (CHDs) are frequently caused by chromosomal imbalances, especially ... more Aims Congenital heart defects (CHDs) are frequently caused by chromosomal imbalances, especially when associated with additional malformations, dysmorphism, or developmental delay. Only in a subset of such patients, a chromosomal aberration can be identified with current cytogenetic tests. Array Comparative Genomic Hybridization (Array-CGH) now enables the detection of submicroscopic chromosomal imbalances at high resolution. In this report, we evaluate for the first time the use of array-CGH as a diagnostic tool in a selected group of patients with a CHD. Methods and results Sixty patients with a CHD of unknown cause but with features suggestive of a chromosomal aberration were selected. Array-CGH was performed using an in-house made 1 Mb micro-array. Chromosomal imbalances not previously described as polymorphisms were detected in 18/60 patients (30%). Ten of these (17%) are considered to be causal. In three deletions, genes known to cause CHDs were implicated (NKX2.5, NOTCH1, NSD1, EHMT). One patient carried a duplication of chromosome 22q11.2, previously associated with CHD. In the other six patients, both the de novo occurrence as well as the size of the imbalance indicated causality. In addition, seven inherited aberrations unreported thus far were detected. Their causal relationship with CHDs remains to be established. Finally, a mosaic monosomy 7 was not considered as causal but did enable to make a diagnosis of Fanconi anaemia. Conclusion This study shows that array-CGH is able to provide an etiological diagnosis in a large proportion of patients with a CHD, selected for a 'chromosomal phenotype'. Besides their usefulness in genetic counselling, identified chromosomal aberrations may aid in the medical follow-up of these individuals.
Human genetics, 2003
Opitz G/BBB syndrome is a malformation syn-drome of the ventral midline mainly characterized by h... more Opitz G/BBB syndrome is a malformation syn-drome of the ventral midline mainly characterized by hy-pertelorism, swallowing difficulties, hypospadias and de-velopmental delay. SSCP analysis and genomic sequenc-ing of the MID1 open reading frame have identified muta-tions in ...
American Journal of Medical Genetics Part A, 2004
American Journal of Medical Genetics Part A, 2005
Opitz syndrome (OS; MIM 145410 and MIM 300000) is a congenital midline malformation syndrome char... more Opitz syndrome (OS; MIM 145410 and MIM 300000) is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal (LTE) abnormalities, imperforate anus, developmental delay, and cardiac defects. The X‐linked form (XLOS) is caused by mutations in the MID1 gene, which encodes a microtubule‐associated RBCC protein. In this study, phenotypic manifestations of patients with and without MID1 mutations were compared to determine genotype‐phenotype correlations. We detected 10 novel mutations, 5 in familial cases, 2 in sporadic cases, and 3 in families for whom it was not clear if they were familial or sporadic. The genotype and phenotype was compared for these 10 families, clinically diagnosed OS patients found not to have MID1 mutations, and 4 families in whom we have previously reported MID1 mutations. This combined data set includes clinical and mutation data on 70 patients. The XLOS patients with MID1 mutations were les...
American Journal of Medical Genetics Part A, 2010
Mutations in the FGD1 gene have been shown to cause Aarskog–Scott syndrome (AAS), or facio‐digito... more Mutations in the FGD1 gene have been shown to cause Aarskog–Scott syndrome (AAS), or facio‐digito‐genital dysplasia (OMIM#305400), an X‐linked disorder characterized by distinctive genital and skeletal developmental abnormalities with a broad spectrum of clinical phenotypes. To date, 20 distinct mutations have been reported, but little phenotypic data are available on patients with molecularly confirmed AAS. In the present study, we report on our experience of screening for mutations in the FGD1 gene in a cohort of 60 European patients with a clinically suspected diagnosis of AAS. We identified nine novel mutations in 11 patients (detection rate of 18.33%), including three missense mutations (p.R402Q; p.S558W; p.K748E), four truncating mutations (p.Y530X; p.R656X; c.806delC; c.1620delC), one in‐frame deletion (c.2020_2022delGAG) and the first reported splice site mutation (c.1935+3A>C). A recurrent mutation (p.R656X) was detected in three independent families. We did not find any...
The American Journal of Human Genetics, 2007
Pitt-Hopkins syndrome is a rarely reported syndrome of so-far-unknown etiology characterized by m... more Pitt-Hopkins syndrome is a rarely reported syndrome of so-far-unknown etiology characterized by mental retardation, wide mouth, and intermittent hyperventilation. By molecular karyotyping with GeneChip Human Mapping 100K SNP arrays, we detected a 1.2-Mb deletion on 18q21.2 in one patient. Sequencing of the TCF4 transcription factor gene, which is contained in the deletion region, in 30 patients with significant phenotypic overlap revealed heterozygous stop, splice, and missense mutations in five further patients with severe mental retardation and remarkable facial resemblance. Thus, we establish the Pitt-Hopkins syndrome as a distinct but probably heterogeneous entity caused by autosomal dominant de novo mutations in TCF4. Because of its phenotypic overlap, Pitt-Hopkins syndrome evolves as an important differential diagnosis to Angelman and Rett syndromes. Both null and missense mutations impaired the interaction of TCF4 with ASCL1 from the PHOX-RET pathway in transactivating an E box-containing reporter construct; therefore, hyperventilation and Hirschsprung disease in patients with Pitt-Hopkins syndrome might be explained by altered development of noradrenergic derivatives.
The American Journal of Human Genetics, 2010
Congenital heart defects (CHDs) are the most common major developmental anomalies and the most fr... more Congenital heart defects (CHDs) are the most common major developmental anomalies and the most frequent cause for perinatal mortality, but their etiology remains often obscure. We identified a locus for CHDs on 6q24-q25. Genotype-phenotype correlations in 12 patients carrying a chromosomal deletion on 6q delineated a critical 850 kb region on 6q25.1 harboring five genes. Bioinformatics prioritization of candidate genes in this locus for a role in CHDs identified the TGF-b-activated kinase 1/MAP3K7 binding protein 2 gene (TAB2) as the top-ranking candidate gene. A role for this candidate gene in cardiac development was further supported by its conserved expression in the developing human and zebrafish heart. Moreover, a critical, dosage-sensitive role during development was demonstrated by the cardiac defects observed upon titrated knockdown of tab2 expression in zebrafish embryos. To definitively confirm the role of this candidate gene in CHDs, we performed mutation analysis of TAB2 in 402 patients with a CHD, which revealed two evolutionarily conserved missense mutations. Finally, a balanced translocation was identified, cosegregating with familial CHD. Mapping of the breakpoints demonstrated that this translocation disrupts TAB2. Taken together, these data clearly demonstrate a role for TAB2 in human cardiac development.
The American Journal of Human Genetics, 2015
and the International Chromosome 22q11.2 Consortium The 22q11.2 deletion syndrome (22q11DS; veloc... more and the International Chromosome 22q11.2 Consortium The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS) is the most common microdeletion syndrome and the phenotypic presentation is highly variable. Approximately 65% of individuals with 22q11DS have a congenital heart defect (CHD), mostly of the conotruncal type, and/or an aortic arch defect. The etiology of this phenotypic variability is not currently known. We hypothesized that copy-number variants (CNVs) outside the 22q11.2 deleted region might increase the risk of being born with a CHD in this sensitized population. Genotyping with Affymetrix SNP Array 6.0 was performed on two groups of subjects with 22q11DS separated by time of ascertainment and processing. CNV analysis was completed on a total of 949 subjects (cohort 1, n ¼ 562; cohort 2, n ¼ 387), 603 with CHDs (cohort 1, n ¼ 363; cohort 2, n ¼ 240) and 346 with normal cardiac anatomy (cohort 1, n ¼ 199; cohort 2, n ¼ 147). Our analysis revealed that a duplication of SLC2A3 was the most frequent CNV identified in the first cohort. It was present in 18 subjects with CHDs and 1 subject without (p ¼ 3.12 3 10 À3 , two-tailed Fisher's exact test). In the second cohort, the SLC2A3 duplication was also significantly enriched in subjects with CHDs (p ¼ 3.30 3 10 À2 , two-tailed Fisher's exact test). The SLC2A3 duplication was the most frequent CNV detected and the only significant finding in our combined analysis (p ¼ 2.68 3 10 À4 , two-tailed Fisher's exact test), indicating that the SLC2A3 duplication might serve as a genetic modifier of CHDs and/or aortic arch anomalies in individuals with 22q11DS.
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Papers by KOENRAAD DEVRIENDT