Publications by authors named "Guillaume Smits"

38 Publications

Performance and Diagnostic Value of Genome-Wide Noninvasive Prenatal Testing in Multiple Gestations.

Obstet Gynecol 2021 May 6. Epub 2021 May 6.

Department of Human Genetics, Katholieke Universiteit Leuven, Leuven, the Center for Human Genetics and the Department of Obstetrics and Gynecology, Universitair Ziekenhuis Leuven, Leuven, the Center for Medical Genetics, Universitair Ziekenhuis Gent, Ghent, the Center for Medical Genetics, Universitair Ziekenhuis Antwerpen, Antwerp, the Center for Medical Genetics, Universiteit Antwerpen, Antwerp, the Center for Medical Genetics, Centre Hospitalier Universitaire de Liège, Liège, the Center for Human Genetics, Université Libre de Bruxelles, Brussels, the Center for Human Genetics, Université Catholique de Louvain, Brussels, the Center for Medical Genetics, Institut de Pathologie et de Génétique Gosselies, Charleroi, the Center for Medical Genetics, Vrije Universiteit Brussel, Brussels, and the Department of Obstetrics, Women's Clinic, Universitair Ziekenhuis Gent, Ghent, Belgium.

Objective: To evaluate the accuracy and diagnostic value of genome-wide noninvasive prenatal testing (NIPT) for the detection of fetal aneuploidies in multiple gestations, with a focus on dichorionic-diamniotic twin pregnancies.

Methods: We performed a retrospective cohort study including data from pregnant women with a twin or higher-order gestation who underwent genome-wide NIPT at one of the eight Belgian genetic centers between November 1, 2013, and March 1, 2020. Chorionicity and amnionicity were determined by ultrasonography. Follow-up invasive testing was carried out in the event of positive NIPT results. Sensitivity and specificity were calculated for the detection of trisomy 21, 18, and 13 in the dichorionic-diamniotic twin cohort.

Results: Unique NIPT analyses were performed for 4,150 pregnant women with a multiple gestation and an additional 767 with vanishing gestations. The failure rate in multiple gestations excluding vanishing gestations ranged from 0% to 11.7% among the different genetic centers. Overall, the failure rate was 4.8%, which could be reduced to 1.2% after single resampling. There were no common fetal trisomies detected among the 86 monochorionic-monoamniotic and 25 triplet cases. Two monochorionic-diamniotic twins had an NIPT result indicative of a trisomy 21, which was confirmed in both fetuses. Among 2,716 dichorionic-diamniotic twin gestations, a sensitivity of 100% (95% CI 74.12-100%) and a specificity of 100% (95% CI 99.86-100%) was reached for trisomy 21 (n=12). For trisomy 18 (n=3), the respective values were 75% (95% CI 30.06-95.44%) sensitivity and 100% (95% CI 99.86-100%) specificity, and for trisomy 13 (n=2), 100% (95% CI 20.65-100%) sensitivity and 99.96% (95% CI 99.79-99.99%) specificity. In the vanishing gestation group, 28 NIPT results were positive for trisomy 21, 18, or 13, with only five confirmed trisomies.

Conclusion: Genome-wide NIPT performed accurately for detection of aneuploidy in dichorionic-diamniotic twin gestations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/AOG.0000000000004385DOI Listing
May 2021

Outcome of publicly funded nationwide first-tier noninvasive prenatal screening.

Genet Med 2021 Feb 9. Epub 2021 Feb 9.

Center for Medical Genetics, Vrije Universiteit Brussel, Brussels, Belgium.

Purpose: Noninvasive prenatal screening (NIPS) using cell-free DNA has transformed prenatal care. Belgium was the first country to implement and fully reimburse NIPS as a first-tier screening test offered to all pregnant women. A consortium consisting of all Belgian genetic centers report the outcome of two years genome-wide NIPS implementation.

Methods: The performance for the common trisomies and for secondary findings was evaluated based on 153,575 genome-wide NIP tests. Furthermore, the evolution of the number of invasive tests and the incidence of Down syndrome live births was registered.

Results: Trisomies 21, 18, and 13 were detected in respectively 0.32%, 0.07%, and 0.06% of cases, with overall positive predictive values (PPVs) of 92.4%, 84.6%, and 43.9%. Rare autosomal trisomies and fetal segmental imbalances were detected in respectively 0.23% and 0.07% of cases with PPVs of 4.1% and 47%. The number of invasive obstetric procedures decreased by 52%. The number of trisomy 21 live births dropped to 0.04%.

Conclusion: Expanding the scope of NIPS beyond trisomy 21 fetal screening allows the implementation of personalized genomic medicine for the obstetric population. This genome-wide NIPS approach has been embedded successfully in prenatal genetic care in Belgium and might serve as a framework for other countries offering NIPS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-021-01101-4DOI Listing
February 2021

Distinct antibody repertoires against endemic human coronaviruses in children and adults.

JCI Insight 2021 02 22;6(4). Epub 2021 Feb 22.

Research Branch, Sidra Medicine, Doha, Qatar.

Four endemic human coronaviruses (HCoVs) are commonly associated with acute respiratory infection in humans. B cell responses to these "common cold" viruses remain incompletely understood. Here we report a comprehensive analysis of CoV-specific antibody repertoires in 231 children and 1168 adults using phage immunoprecipitation sequencing. Seroprevalence of antibodies against endemic HCoVs ranged between approximately 4% and 27% depending on the species and cohort. We identified at least 136 novel linear B cell epitopes. Antibody repertoires against endemic HCoVs were qualitatively different between children and adults in that anti-HCoV IgG specificities more frequently found among children targeted functionally important and structurally conserved regions of the spike, nucleocapsid, and matrix proteins. Moreover, antibody specificities targeting the highly conserved fusion peptide region and S2' cleavage site of the spike protein were broadly cross-reactive with peptides of epidemic human and nonhuman coronaviruses. In contrast, an acidic tandem repeat in the N-terminal region of the Nsp3 subdomain of the HCoV-HKU1 polyprotein was the predominant target of antibody responses in adult donors. Our findings shed light on the dominant species-specific and pan-CoV target sites of human antibody responses to coronavirus infection, thereby providing important insights for the development of prophylactic or therapeutic monoclonal antibodies and vaccine design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.144499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934927PMC
February 2021

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.

Science 2020 10 24;370(6515). Epub 2020 Sep 24.

Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.abd4570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857407PMC
October 2020

Novel homozygous variant of carbonic anhydrase 8 gene expanding the phenotype of cerebellar ataxia, mental retardation, and disequilibrium syndrome subtype 3.

Am J Med Genet A 2020 11 18;182(11):2685-2693. Epub 2020 Aug 18.

Department of Pediatric Neurology, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles (ULB), Brussels, Belgium.

We report the case of an 11-year-old Syrian girl born to consanguineous parents, who presents an ataxic gait from early childhood. On clinical examination, she presented a severe static - kinetic cerebellar syndrome, walking without support is possible for short distances only. Strikingly, three consecutive MRIs did not show any sign of cerebellar abnormalities, but a brain positron emission tomography (PET) using [18F]-fluorodeoxyglucose (FDG) demonstrated a clear decrease in glucose metabolism in the cerebellum as well as the anterior and medial temporal lobe bilaterally. A clinical exome analysis identified a novel homozygous c.251A > G (p.Asn84Ser) likely pathogenic variant in the carbonic anhydrase 8 (CA8) gene. CA8 mutations cause cerebellar ataxia, mental retardation, and disequilibrium syndrome subtype 3 (CAMRQ3), a rare genetically autosomal recessive disorder, only described in four families, so far with the frequent observation of quadrupedal gait. The proband differed with other reported CA8 mutations by the absence of clear cerebellar signs on brain MRI and the presence of focal seizures. This report expands the clinical spectrum associated with mutations in CA8 and illustrates the possible discrepancy between (mild) neuro-radiological images (MRI) and (severe) clinical phenotype in young individuals. In contrast, the observation of clear cerebellar abnormal metabolic findings suggests that the FDG-PET scan may be used as an early marker for hereditary ataxia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61805DOI Listing
November 2020

Three cases of molecularly confirmed Knobloch syndrome.

Ophthalmic Genet 2020 02 17;41(1):83-87. Epub 2020 Mar 17.

Department of Ophthalmology, University Hospital Erasme, Brussels, Belgium.

Knobloch syndrome (OMIM 267750) is a rare autosomal recessive disorder due to genetic defects in the gene. The triad of high myopia, occipital defect, vitreoretinal degeneration has been described as pathognomonic for this condition. Patients with Knobloch syndrome have also extraocular problems as brain and kidney malformations. High genetic and phenotypic variation has been reported in the affected patients. Here we provide detailed clinical description of 3 individuals with Knobloch syndrome. Ocular examination and fundus imaging have been performed. Detailed information about systemic conditions has been provided. Mutations in were identified in all three patients. Patient 1 had congenital hip dislocation and patient 2 had renal atrophy, cardiac insufficiency and difficult skin healing. With this report we add to the clinical and genetic knowledge of this rare condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13816810.2020.1737948DOI Listing
February 2020

Unraveling heteroplasmy patterns with NOVOPlasty.

NAR Genom Bioinform 2020 Mar 24;2(1):lqz011. Epub 2019 Oct 24.

Interuniversity Institute of Bioinformatics in Brussels (IB2), Université Libre de Bruxelles and Vrije Universiteit Brussel, Triomflaan CP 263, 1050 Brussels, Belgium.

Heteroplasmy, the existence of multiple mitochondrial haplotypes within an individual, has been studied across different scientific fields. Mitochondrial genome polymorphisms have been linked to multiple severe disorders and are of interest to evolutionary studies and forensic science. Before the development of massive parallel sequencing (MPS), most studies of mitochondrial genome variation were limited to short fragments and to heteroplasmic variants associated with a relatively high frequency (>10%). By utilizing ultra-deep sequencing, it has now become possible to uncover previously undiscovered patterns of intra-individual polymorphisms. Despite these technological advances, it is still challenging to determine the origin of the observed intra-individual polymorphisms. We therefore developed a new method that not only detects intra-individual polymorphisms within mitochondrial and chloroplast genomes more accurately, but also looks for linkage among polymorphic sites by assembling the sequence around each detected polymorphic site. Our benchmark study shows that this method is capable of detecting heteroplasmy more accurately than any method previously available and is the first tool that is able to completely or partially reconstruct the sequence for each mitochondrial haplotype (allele). The method is implemented in our open source software NOVOPlasty that can be downloaded at https://github.com/ndierckx/NOVOPlasty.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nargab/lqz011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671380PMC
March 2020

Using game theory and decision decomposition to effectively discern and characterise bi-locus diseases.

Artif Intell Med 2019 08 23;99:101690. Epub 2019 Jul 23.

Interuniversity Institute for Bioinformatics in Brussels, ULB-VUB, 1050 Brussels, Belgium; Machine Learning Group, Université Libre de Bruxelles, 1050 Brussels, Belgium; Artificial Intelligence Lab, Vrije Universiteit Brussel, 1050 Brussels, Belgium. Electronic address:

In order to gain insight into oligogenic disorders, understanding those involving bi-locus variant combinations appears to be key. In prior work, we showed that features at multiple biological scales can already be used to discriminate among two types, i.e. disorders involving true digenic and modifier combinations. The current study expands this machine learning work towards dual molecular diagnosis cases, providing a classifier able to effectively distinguish between these three types. To reach this goal and gain an in-depth understanding of the decision process, game theory and tree decomposition techniques are applied to random forest predictors to investigate the relevance of feature combinations in the prediction. A machine learning model with high discrimination capabilities was developed, effectively differentiating the three classes in a biologically meaningful manner. Combining prediction interpretation and statistical analysis, we propose a biologically meaningful characterization of each class relying on specific feature strengths. Figuring out how biological characteristics shift samples towards one of three classes provides clinically relevant insight into the underlying biological processes as well as the disease itself.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.artmed.2019.06.006DOI Listing
August 2019

ORVAL: a novel platform for the prediction and exploration of disease-causing oligogenic variant combinations.

Nucleic Acids Res 2019 07;47(W1):W93-W98

Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium.

A tremendous amount of DNA sequencing data is being produced around the world with the ambition to capture in more detail the mechanisms underlying human diseases. While numerous bioinformatics tools exist that allow the discovery of causal variants in Mendelian diseases, little to no support is provided to do the same for variant combinations, an essential task for the discovery of the causes of oligogenic diseases. ORVAL (the Oligogenic Resource for Variant AnaLysis), which is presented here, provides an answer to this problem by focusing on generating networks of candidate pathogenic variant combinations in gene pairs, as opposed to isolated variants in unique genes. This online platform integrates innovative machine learning methods for combinatorial variant pathogenicity prediction with visualization techniques, offering several interactive and exploratory tools, such as pathogenic gene and protein interaction networks, a ranking of pathogenic gene pairs, as well as visual mappings of the cellular location and pathway information. ORVAL is the first web-based exploration platform dedicated to identifying networks of candidate pathogenic variant combinations with the sole ambition to help in uncovering oligogenic causes for patients that cannot rely on the classical disease analysis tools. ORVAL is available at https://orval.ibsquare.be.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkz437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602484PMC
July 2019

Predicting disease-causing variant combinations.

Proc Natl Acad Sci U S A 2019 06 24;116(24):11878-11887. Epub 2019 May 24.

Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium;

Notwithstanding important advances in the context of single-variant pathogenicity identification, novel breakthroughs in discerning the origins of many rare diseases require methods able to identify more complex genetic models. We present here the Variant Combinations Pathogenicity Predictor (VarCoPP), a machine-learning approach that identifies pathogenic variant combinations in gene pairs (called digenic or bilocus variant combinations). We show that the results produced by this method are highly accurate and precise, an efficacy that is endorsed when validating the method on recently published independent disease-causing data. Confidence labels of 95% and 99% are identified, representing the probability of a bilocus combination being a true pathogenic result, providing geneticists with rational markers to evaluate the most relevant pathogenic combinations and limit the search space and time. Finally, the VarCoPP has been designed to act as an interpretable method that can provide explanations on why a bilocus combination is predicted as pathogenic and which biological information is important for that prediction. This work provides an important step toward the genetic understanding of rare diseases, paving the way to clinical knowledge and improved patient care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1815601116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6575632PMC
June 2019

Truncating RAX Mutations: Anophthalmia, Hypopituitarism, Diabetes Insipidus, and Cleft Palate in Mice and Men.

J Clin Endocrinol Metab 2019 07;104(7):2925-2930

Department of Biochemistry, West Virginia University School of Medicine, Morgantown, West Virginia.

Context: The transcription factor RAX is a paired-type homeoprotein that plays a critical role in eye and forebrain development of vertebrate species. RAX knockout mice have anophthalmia, cleft palate, and an abnormal hypothalamus and display perinatal lethality. In humans, homozygous or compound heterozygous RAX mutations have been reported to cause bilateral microphthalmia or anophthalmia without consistent associated features. Congenital hypopituitarism can be associated with various eye or craniofacial anomalies; however, the co-occurrence of congenital hypopituitarism, anophthalmia, cleft palate, and diabetes insipidus has been very rare.

Results: We report the case of a child with anophthalmia, congenital hypopituitarism, diabetes insipidus, and bilateral cleft lip and palate who had a homozygous frameshift truncating mutation c.266delC (p.Pro89Argfs*114) in exon 1 of the RAX gene. Rax knockout mice show loss of ventral forebrain structures, pituitary, and basosphenoid bone and palate and a misplaced anterior pituitary gland along the roof of the oral cavity.

Conclusions: Our patient's phenotype was more severe than that reported in other patients. Although most of the previously reported patients with RAX mutations showed either a missense or some less severe mutation in at least one of their RAX alleles, our patient was homozygous for truncating mutations that would yield a severe, null protein phenotype. The severity of the genetic defect, the precise match between the knockout mouse and the patient's endocrine phenotypes, and the prominent roles of RAX in eye and pituitary development and diencephalic patterning suggest that the RAX null mutations could fully account for the observed phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2018-02316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543774PMC
July 2019

HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond.

Brain 2018 11;141(11):3160-3178

Neuropediatric Department, Centro Hospitalar do Porto, Porto, Portugal.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awy263DOI Listing
November 2018

Correction: IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients.

Genet Med 2019 Aug;21(8):1897-1898

APHP, Service de genetique medicale, Necker- Enfants Malades Hospital, Imagine Institute, Paris Descartes University, Paris, France.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-018-0327-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608434PMC
August 2019

IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients.

Genet Med 2019 04 12;21(4):837-849. Epub 2018 Sep 12.

APHP, Service de genetique medicale, Necker-Enfants Malades Hospital, Imagine Institute, Paris Descartes University, Paris, France.

Purpose: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences.

Methods: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms.

Results: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments.

Conclusion: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-018-0268-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752297PMC
April 2019

BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems.

Am J Med Genet A 2018 01 27;176(1):201-208. Epub 2017 Sep 27.

Department of Pediatric Neurology, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium.

We report the case of a 7-year-old male of Western European origin presenting with moderate intellectual disability, severe childhood apraxia of speech in the presence of oral and manual dyspraxia, and hypotonia across motor systems including the oral and speech motor systems. Exome sequencing revealed a de novo frameshift protein truncating mutation in the fourth exon of BCL11A, a gene recently demonstrated as being involved in cognition and language development. Making parallels with a previously described patient with a 200 kb 2p15p16.1 deletion encompassing the entire BCL11A gene and displaying a similar phenotype, we characterize in depth how BCL11A is involved in clinical aspects of language development and oral praxis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.38479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765401PMC
January 2018

Understanding mutational effects in digenic diseases.

Nucleic Acids Res 2017 Sep;45(15):e140

Interuniversity Institute for Bioinformatics in Brussels, ULB-VUB, Boulevard du Triomphe CP 263, 1050 Brussels, Belgium.

To further our understanding of the complexity and genetic heterogeneity of rare diseases, it has become essential to shed light on how combinations of variants in different genes are responsible for a disease phenotype. With the appearance of a resource on digenic diseases, it has become possible to evaluate how digenic combinations differ in terms of the phenotypes they produce. All instances in this resource were assigned to two classes of digenic effects, annotated as true digenic and composite classes. Whereas in the true digenic class variants in both genes are required for developing the disease, in the composite class, a variant in one gene is sufficient to produce the phenotype, but an additional variant in a second gene impacts the disease phenotype or alters the age of onset. We show that a combination of variant, gene and higher-level features can differentiate between these two classes with high accuracy. Moreover, we show via the analysis of three digenic disorders that a digenic effect decision profile, extracted from the predictive model, motivates why an instance was assigned to either of the two classes. Together, our results show that digenic disease data generates novel insights, providing a glimpse into the oligogenic realm.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkx557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587785PMC
September 2017

Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability.

Genome Med 2017 07 19;9(1):67. Epub 2017 Jul 19.

Interuniversity Institute of Bioinformatics in Brussels ULB-VUB, Brussels, 1050, Belgium.

Background: Tissue-specific integrative omics has the potential to reveal new genic elements important for developmental disorders.

Methods: Two pediatric patients with global developmental delay and intellectual disability phenotype underwent array-CGH genetic testing, both showing a partial deletion of the DLG2 gene. From independent human and murine omics datasets, we combined copy number variations, histone modifications, developmental tissue-specific regulation, and protein data to explore the molecular mechanism at play.

Results: Integrating genomics, transcriptomics, and epigenomics data, we describe two novel DLG2 promoters and coding first exons expressed in human fetal brain. Their murine conservation and protein-level evidence allowed us to produce new DLG2 gene models for human and mouse. These new genic elements are deleted in 90% of 29 patients (public and in-house) showing partial deletion of the DLG2 gene. The patients' clinical characteristics expand the neurodevelopmental phenotypic spectrum linked to DLG2 gene disruption to cognitive and behavioral categories.

Conclusions: While protein-coding genes are regarded as well known, our work shows that integration of multiple omics datasets can unveil novel coding elements. From a clinical perspective, our work demonstrates that two new DLG2 promoters and exons are crucial for the neurodevelopmental phenotypes associated with this gene. In addition, our work brings evidence for the lack of cross-annotation in human versus mouse reference genomes and nucleotide versus protein databases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-017-0452-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518101PMC
July 2017

NOVOPlasty: de novo assembly of organelle genomes from whole genome data.

Nucleic Acids Res 2017 02;45(4):e18

Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles and Vrije Universiteit Brussel, Triomflaan CP 263, 1050 Brussels, Belgium.

The evolution in next-generation sequencing (NGS) technology has led to the development of many different assembly algorithms, but few of them focus on assembling the organelle genomes. These genomes are used in phylogenetic studies, food identification and are the most deposited eukaryotic genomes in GenBank. Producing organelle genome assembly from whole genome sequencing (WGS) data would be the most accurate and least laborious approach, but a tool specifically designed for this task is lacking. We developed a seed-and-extend algorithm that assembles organelle genomes from whole genome sequencing (WGS) data, starting from a related or distant single seed sequence. The algorithm has been tested on several new (Gonioctena intermedia and Avicennia marina) and public (Arabidopsis thaliana and Oryza sativa) whole genome Illumina data sets where it outperforms known assemblers in assembly accuracy and coverage. In our benchmark, NOVOPlasty assembled all tested circular genomes in less than 30 min with a maximum memory requirement of 16 GB and an accuracy over 99.99%. In conclusion, NOVOPlasty is the sole de novo assembler that provides a fast and straightforward extraction of the extranuclear genomes from WGS data in one circular high quality contig. The software is open source and can be downloaded at https://github.com/ndierckx/NOVOPlasty.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkw955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389512PMC
February 2017

DIDA: A curated and annotated digenic diseases database.

Nucleic Acids Res 2016 Jan 19;44(D1):D900-7. Epub 2015 Oct 19.

Interuniversity Institute of Bioinformatics in Brussels, Boulevard du Triomphe CP 263, 1050 Brussels, Belgium MLG, Département d'Informatique, Université Libre de Bruxelles, Boulevard du Triomphe, CP 212, 1050 Brussels, Belgium AI lab, Vakgroep Computerwetenschappen, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium

DIDA (DIgenic diseases DAtabase) is a novel database that provides for the first time detailed information on genes and associated genetic variants involved in digenic diseases, the simplest form of oligogenic inheritance. The database is accessible via http://dida.ibsquare.be and currently includes 213 digenic combinations involved in 44 different digenic diseases. These combinations are composed of 364 distinct variants, which are distributed over 136 distinct genes. The web interface provides browsing and search functionalities, as well as documentation and help pages, general database statistics and references to the original publications from which the data have been collected. The possibility to submit novel digenic data to DIDA is also provided. Creating this new repository was essential as current databases do not allow one to retrieve detailed records regarding digenic combinations. Genes, variants, diseases and digenic combinations in DIDA are annotated with manually curated information and information mined from other online resources. Next to providing a unique resource for the development of new analysis methods, DIDA gives clinical and molecular geneticists a tool to find the most comprehensive information on the digenic nature of their diseases of interest.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkv1068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702791PMC
January 2016

Implementation of genomic arrays in prenatal diagnosis: the Belgian approach to meet the challenges.

Eur J Med Genet 2014 Mar 15;57(4):151-6. Epub 2014 Feb 15.

Center for Medical Genetics, Universiteit Antwerpen, Belgium.

After their successful introduction in postnatal testing, genome-wide arrays are now rapidly replacing conventional karyotyping in prenatal diagnostics. While previous studies have demonstrated the advantages of this method, we are confronted with difficulties regarding the technology and the ethical dilemmas inherent to genomic arrays. These include indication for testing, array design, interpretation of variants and how to deal with variants of unknown significance and incidental findings. The experiences with these issues reported in the literature are most often from single centres. Here, we report on a national consensus approach how microarray is implemented in all genetic centres in Belgium. These recommendations are subjected to constant re-evaluation based on our growing experience and can serve as a useful tool for those involved in prenatal diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2014.02.002DOI Listing
March 2014

FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly.

J Med Genet 2013 Sep 28;50(9):585-92. Epub 2013 Jun 28.

Laboratoire de Bioinformatique des Génomes et des Réseaux (BiGRe), Université Libre de Bruxelles (ULB), Brussels, Belgium.

Background: Harstfield syndrome is the rare and unique association of holoprosencephaly (HPE) and ectrodactyly, with or without cleft lip and palate, and variable additional features. All the reported cases occurred sporadically. Although several causal genes of HPE and ectrodactyly have been identified, the genetic cause of Hartsfield syndrome remains unknown. We hypothesised that a single key developmental gene may underlie the co-occurrence of HPE and ectrodactyly.

Methods: We used whole exome sequencing in four isolated cases including one case-parents trio, and direct Sanger sequencing of three additional cases, to investigate the causative variants in Hartsfield syndrome.

Results: We identified a novel FGFR1 mutation in six out of seven patients. Affected residues are highly conserved and are located in the extracellular binding domain of the receptor (two homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Strikingly, among the six novel mutations, three are located in close proximity to the ATP's phosphates or the coordinating magnesium, with one position required for kinase activity, and three are adjacent to known mutations involved in Kallmann syndrome plus other developmental anomalies.

Conclusions: Dominant or recessive FGFR1 mutations are responsible for Hartsfield syndrome, consistent with the known roles of FGFR1 in vertebrate ontogeny and conditional Fgfr1-deficient mice. Our study shows that, in humans, lack of accurate FGFR1 activation can disrupt both brain and hand/foot midline development, and that FGFR1 loss-of-function mutations are responsible for a wider spectrum of clinical anomalies than previously thought, ranging in severity from seemingly isolated hypogonadotropic hypogonadism, through Kallmann syndrome with or without additional features, to Hartsfield syndrome at its most severe end.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2013-101603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756455PMC
September 2013

The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r.

Nat Cell Biol 2012 Jun 10;14(7):659-65. Epub 2012 Jun 10.

Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT, UK.

The H19 large intergenic non-coding RNA (lincRNA) is one of the most highly abundant and conserved transcripts in mammalian development, being expressed in both embryonic and extra-embryonic cell lineages, yet its physiological function is unknown. Here we show that miR-675, a microRNA (miRNA) embedded in H19's first exon, is expressed exclusively in the placenta from the gestational time point when placental growth normally ceases, and placentas that lack H19 continue to grow. Overexpression of miR-675 in a range of embryonic and extra-embryonic cell lines results in their reduced proliferation; targets of the miRNA are upregulated in the H19 null placenta, including the growth-promoting insulin-like growth factor 1 receptor (Igf1r) gene. Moreover, the excision of miR-675 from H19 is dynamically regulated by the stress-response RNA-binding protein HuR. These results suggest that H19's main physiological role is in limiting growth of the placenta before birth, by regulated processing of miR-675. The controlled release of miR-675 from H19 may also allow rapid inhibition of cell proliferation in response to cellular stress or oncogenic signals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncb2521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389517PMC
June 2012

High-throughput analysis of candidate imprinted genes and allele-specific gene expression in the human term placenta.

BMC Genet 2010 Apr 19;11:25. Epub 2010 Apr 19.

Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1 SA, UK.

Background: Imprinted genes show expression from one parental allele only and are important for development and behaviour. This extreme mode of allelic imbalance has been described for approximately 56 human genes. Imprinting status is often disrupted in cancer and dysmorphic syndromes. More subtle variation of gene expression, that is not parent-of-origin specific, termed 'allele-specific gene expression' (ASE) is more common and may give rise to milder phenotypic differences. Using two allele-specific high-throughput technologies alongside bioinformatics predictions, normal term human placenta was screened to find new imprinted genes and to ascertain the extent of ASE in this tissue.

Results: Twenty-three family trios of placental cDNA, placental genomic DNA (gDNA) and gDNA from both parents were tested for 130 candidate genes with the Sequenom MassArray system. Six genes were found differentially expressed but none imprinted. The Illumina ASE BeadArray platform was then used to test 1536 SNPs in 932 genes. The array was enriched for the human orthologues of 124 mouse candidate genes from bioinformatics predictions and 10 human candidate imprinted genes from EST database mining. After quality control pruning, a total of 261 informative SNPs (214 genes) remained for analysis. Imprinting with maternal expression was demonstrated for the lymphocyte imprinted gene ZNF331 in human placenta. Two potential differentially methylated regions (DMRs) were found in the vicinity of ZNF331. None of the bioinformatically predicted candidates tested showed imprinting except for a skewed allelic expression in a parent-specific manner observed for PHACTR2, a neighbour of the imprinted PLAGL1 gene. ASE was detected for two or more individuals in 39 candidate genes (18%).

Conclusions: Both Sequenom and Illumina assays were sensitive enough to study imprinting and strong allelic bias. Previous bioinformatics approaches were not predictive of new imprinted genes in the human term placenta. ZNF331 is imprinted in human term placenta and might be a new ubiquitously imprinted gene, part of a primate-specific locus. Demonstration of partial imprinting of PHACTR2 calls for re-evaluation of the allelic pattern of expression for the PHACTR2-PLAGL1 locus. ASE was common in human term placenta.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2156-11-25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2871261PMC
April 2010

Conservation of the H19 noncoding RNA and H19-IGF2 imprinting mechanism in therians.

Nat Genet 2008 Aug 29;40(8):971-6. Epub 2008 Jun 29.

The Babraham Institute, Laboratory of Developmental Genetics and Imprinting, Cambridge CB22 3AT, UK.

Comparisons between eutherians and marsupials suggest limited conservation of the molecular mechanisms that control genomic imprinting in mammals. We have studied the evolution of the imprinted IGF2-H19 locus in therians. Although marsupial orthologs of protein-coding exons were easily identified, the use of evolutionarily conserved regions and low-stringency Bl2seq comparisons was required to delineate a candidate H19 noncoding RNA sequence. The therian H19 orthologs show miR-675 and exon structure conservation, suggesting functional selection on both features. Transcription start site sequences and poly(A) signals are also conserved. As in eutherians, marsupial H19 is maternally expressed and paternal methylation upstream of the gene originates in the male germline, encompasses a CTCF insulator, and spreads somatically into the H19 gene. The conservation in all therians of the mechanism controlling imprinting of the IGF2-H19 locus suggests a sequential model of imprinting evolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.168DOI Listing
August 2008

Non-coding transcripts in the H19 imprinting control region mediate gene silencing in transgenic Drosophila.

EMBO Rep 2007 Nov 19;8(11):1068-73. Epub 2007 Oct 19.

Zentrum fuer Molekulare Biologie Heidelberg, Universitaet Heidelberg, INF 282, 69120 Heidelberg, Germany.

The imprinting control region (ICR) upstream of H19 is the key regulatory element conferring monoallelic expression on H19 and Igf2 (insulin-like growth factor 2). Epigenetic marks in the ICR regulate its interaction with the chromatin protein CCCTC-binding factor and with other control factors to coordinate gene silencing in the imprinting cluster. Here, we show that the H19 ICR is biallelically transcribed, producing both sense and antisense RNAs. We analyse the function of the non-coding transcripts in a Drosophila transgenic system in which the H19 upstream region silences the expression of a reporter gene. We show that knockdown of H19 ICR non-coding RNA (ncRNA) by RNA interference leads to the loss of reporter gene silencing. Our results are, to the best of our knowledge, the first to show that ncRNAs in the H19 ICR are functionally significant, and also indicate that they have a role in regulating gene expression and perhaps epigenetic marks at the H19/Igf2 locus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/sj.embor.7401094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2247386PMC
November 2007

Imprinting weaves its web.

Dev Cell 2006 Nov;11(5):598-9

Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB22 3AT, United Kingdom.

It has long been recognized that imprinted genes often act in common developmental or physiological pathways. A new knockout of the gene Zac1 reveals just how extensive the transcriptional network of imprinted genes may be.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.devcel.2006.10.013DOI Listing
November 2006

Genetic predictors of ovarian hyperstimulation syndrome in women undergoing in vitro fertilization.

Nat Clin Pract Endocrinol Metab 2006 Nov;2(11):590-1

Fertility Clinic, Erasme Hospital, and Laboratory of Research on Human Reproduction, Free University Brussels, Belgium.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncpendmet0319DOI Listing
November 2006

Understanding ovarian hyperstimulation syndrome.

Endocrine 2005 Apr;26(3):285-90

Fertility Clinic, Hôpital Erasme, Brussels, Belgium.

The ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication of ovarian stimulation treatments. Severe forms are characterized by a massive ovarian enlargement with the formation of multiple ovarian cysts associated with extravascular fluid shifts resulting in the development of ascites, pleural and/or pericardial effusion. The pathophysiology of the syndrome has not been completely elucidated yet. The vascular fluid leakage is thought to result from an increased capillary permeability of mesothelial surfaces under the action of one or several vasoactive ovarian factor(s) produced by the multiple corpora lutea. The paper focuses on the recent identification of mutations in the FSH receptor gene that display an increased sensitivity to hCG and are responsible for the development of spontaneous OHSS occurring during pregnancy. These findings have shed light for the first time on the molecular basis of the pathophysiology of the spontaneous form of the syndrome. As spontaneous and iatrogenic OHSS share similar pathophysiological sequences including massive recruitment and growth of ovarian follicles, extensive luteinization provoked by hCG, and oversecretion of vasogenic molecules by the corpora lutea, they have also opened new research perspectives for the understanding of the much more frequent iatrogenic OHSS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1385/ENDO:26:3:285DOI Listing
April 2005

Premature ovarian aging in mice deficient for Gpr3.

Proc Natl Acad Sci U S A 2005 Jun 13;102(25):8922-6. Epub 2005 Jun 13.

Institut de Recherches en Biologie Humaine et Moléculaire, University of Brussels, Campus Erasme, 808 Route de Lennik, B-1070 Brussels, Belgium.

After becoming competent for resuming meiosis, fully developed mammalian oocytes are maintained arrested in prophase I until ovulation is triggered by the luteotropin surge. Meiotic pause has been shown to depend critically on maintenance of cAMP level in the oocyte and was recently attributed to the constitutive Gs (the heterotrimeric GTP-binding protein that activates adenylyl cyclase) signaling activity of the G protein-coupled receptor GPR3. Here we show that mice deficient for Gpr3 are unexpectedly fertile but display progressive reduction in litter size despite stable age-independent alteration of meiotic pause. Detailed analysis of the phenotype confirms premature resumption of meiosis, in vivo, in about one-third of antral follicles from Gpr3-/- females, independently of their age. In contrast, in aging mice, absence of GPR3 leads to severe reduction of fertility, which manifests by production of an increasing number of nondeveloping early embryos upon spontaneous ovulation and massive amounts of fragmented oocytes after superovulation. Severe worsening of the phenotype in older animals points to an additional role of GPR3 related to protection (or rescue) of oocytes from aging. Gpr3-defective mice may constitute a relevant model of premature ovarian failure due to early oocyte aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0503840102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1150279PMC
June 2005

Glycoprotein hormone receptors: link between receptor homodimerization and negative cooperativity.

EMBO J 2005 Jun 12;24(11):1954-64. Epub 2005 May 12.

IRIBHM, Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium.

The monomeric model of rhodopsin-like G protein-coupled receptors (GPCRs) has progressively yielded the floor to the concept of GPCRs being oligo(di)mers, but the functional correlates of dimerization remain unclear. In this report, dimers of glycoprotein hormone receptors were demonstrated in living cells, with a combination of biophysical (bioluminescence resonance energy transfer and homogenous time resolved fluorescence/fluorescence resonance energy transfer), functional and biochemical approaches. Thyrotropin (TSHr) and lutropin (LH/CGr) receptors form homo- and heterodimers, via interactions involving primarily their heptahelical domains. The large hormone-binding ectodomains were dispensable for dimerization but modulated protomer interaction. Dimerization was not affected by agonist binding. Observed functional complementation indicates that TSHr dimers may function as a single functional unit. Finally, heterologous binding-competition studies, performed with heterodimers between TSHr and LH/CG-TSHr chimeras, demonstrated the unsuspected existence of strong negative cooperativity of hormone binding. Tracer desorption experiments indicated an allosteric behavior in TSHr and, to a lesser extent, in LH/CGr and FSHr homodimers. This study is the first report of homodimerization associated with negative cooperativity in rhodopsin-like GPCRs. As such, it may warrant revisitation of allosterism in the whole GPCR family.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/sj.emboj.7600686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142614PMC
June 2005