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1.
BMC Neurosci ; 22(1): 56, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34525970

RESUMO

BACKGROUND: NRXN1 deletions are identified as one of major rare risk factors for autism spectrum disorder (ASD) and other neurodevelopmental disorders. ASD has 30% co-morbidity with epilepsy, and the latter is associated with excessive neuronal firing. NRXN1 encodes hundreds of presynaptic neuro-adhesion proteins categorized as NRXN1α/ß/γ. Previous studies on cultured cells show that the short NRXN1ß primarily exerts excitation effect, whereas the long NRXN1α which is more commonly deleted in patients involves in both excitation and inhibition. However, patient-derived models are essential for understanding functional consequences of NRXN1α deletions in human neurons. We recently derived induced pluripotent stem cells (iPSCs) from five controls and three ASD patients carrying NRXN1α+/- and showed increased calcium transients in patient neurons. METHODS: In this study we investigated the electrophysiological properties of iPSC-derived cortical neurons in control and ASD patients carrying NRXN1α+/- using patch clamping. Whole genome RNA sequencing was carried out to further understand the potential underlying molecular mechanism. RESULTS: NRXN1α+/- cortical neurons were shown to display larger sodium currents, higher AP amplitude and accelerated depolarization time. RNASeq analyses revealed transcriptomic changes with significant upregulation glutamatergic synapse and ion channels/transporter activity including voltage-gated potassium channels (GRIN1, GRIN3B, SLC17A6, CACNG3, CACNA1A, SHANK1), which are likely to couple with the increased excitability in NRXN1α+/- cortical neurons. CONCLUSIONS: Together with recent evidence of increased calcium transients, our results showed that human NRXN1α+/- isoform deletions altered neuronal excitability and non-synaptic function, and NRXN1α+/- patient iPSCs may be used as an ASD model for therapeutic development with calcium transients and excitability as readouts.

2.
Per Med ; 18(4): 361-373, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34086508

RESUMO

Aim: Despite a considerable interest in expanded carrier screening (ECS) in the general population, actual uptake of ECS remains low. More insights are needed to better understand the perspectives of reproductive-aged individuals. Materials & methods: Nonpregnant women of reproductive age recruited through public pharmacies throughout Flanders (Belgium) were invited to participate in an online survey. Results: Most participants (63.6%) indicated they would consider ECS for themselves in the future. About one in two participants showed a positive attitude toward ECS. Conclusion: This study reports valuable insights in the perspectives of nonpregnant reproductive-aged women in Flanders (Belgium) regarding ECS that can be used in the ongoing debate on the responsible implementation of ECS.

3.
Sci Rep ; 11(1): 12175, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108542

RESUMO

Craniofacial dysmorphism is associated with thousands of genetic and environmental disorders. Delineation of salient facial characteristics can guide clinicians towards a correct clinical diagnosis and understanding the pathogenesis of the disorder. Abnormal facial shape might require craniofacial surgical intervention, with the restoration of normal shape an important surgical outcome. Facial anthropometric growth curves or standards of single inter-landmark measurements have traditionally supported assessments of normal and abnormal facial shape, for both clinical and research applications. However, these fail to capture the full complexity of facial shape. With the increasing availability of 3D photographs, methods of assessment that take advantage of the rich information contained in such images are needed. In this article we derive and present open-source three-dimensional (3D) growth curves of the human face. These are sequences of age and sex-specific expected 3D facial shapes and statistical models of the variation around the expected shape, derived from 5443 3D images. We demonstrate the use of these growth curves for assessing patients and show that they identify normal and abnormal facial morphology independent from age-specific facial features. 3D growth curves can facilitate use of state-of-the-art 3D facial shape assessment by the broader clinical and biomedical research community. This advance in phenotype description will support clinical diagnosis and the understanding of disease pathogenesis including genotype-phenotype relations.


Assuntos
Anormalidades Múltiplas/patologia , Anormalidades Craniofaciais/patologia , Face/patologia , Imageamento Tridimensional/métodos , Modelos Estatísticos , Atrofia Muscular/patologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antropometria , Estudos de Casos e Controles , Criança , Pré-Escolar , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Face/anormalidades , Feminino , Seguimentos , Gráficos de Crescimento , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Fenótipo , Prognóstico , Adulto Jovem
4.
PLoS Genet ; 17(5): e1009528, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33983923

RESUMO

The analysis of contemporary genomic data typically operates on one-dimensional phenotypic measurements (e.g. standing height). Here we report on a data-driven, family-informed strategy to facial phenotyping that searches for biologically relevant traits and reduces multivariate 3D facial shape variability into amendable univariate measurements, while preserving its structurally complex nature. We performed a biometric identification of siblings in a sample of 424 children, defining 1,048 sib-shared facial traits. Subsequent quantification and analyses in an independent European cohort (n = 8,246) demonstrated significant heritability for a subset of traits (0.17-0.53) and highlighted 218 genome-wide significant loci (38 also study-wide) associated with facial variation shared by siblings. These loci showed preferential enrichment for active chromatin marks in cranial neural crest cells and embryonic craniofacial tissues and several regions harbor putative craniofacial genes, thereby enhancing our knowledge on the genetic architecture of normal-range facial variation.


Assuntos
Identificação Biométrica , Face/anatomia & histologia , Genômica , Imageamento Tridimensional , Herança Multifatorial/genética , Fenótipo , Irmãos , Adolescente , Criança , Pré-Escolar , Anormalidades Craniofaciais/genética , Conjuntos de Dados como Assunto , Europa (Continente)/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Face/anormalidades , Face/embriologia , Feminino , Estudos de Associação Genética , Humanos , Masculino
5.
Artigo em Inglês | MEDLINE | ID: mdl-34030997

RESUMO

OBJECTIVE: The aim of this study was to analyze patients with thrombophilia who underwent oral and/or maxillofacial surgery at our center. STUDY DESIGN: We performed a retrospective analysis of patients with hereditary or acquired thrombophilia who had undergone oral/maxillofacial surgery between January 1, 2000 and December 31, 2019. Data regarding demographic and patient characteristics, surgical treatment modalities, antithrombotic therapies, and complications were analyzed. RESULTS: A total of 76 eligible patients (26 male, 50 female) were included in this study, with a mean follow-up period of 3.8 months (range, 0-51 months). The mean age at time of surgery was 44.7 ± 19.4 years. Seven different hereditary and acquired thrombophilia were identified: factor V Leiden (n = 31; 40.8%), prothrombin G20210A mutation (n = 5; 6.6%), protein C deficiency (n = 4; 5.3%), protein S deficiency (n = 11; 14.5%), antiphospholipid syndrome (n = 10; 13.2%), hyperhomocysteinemia (n = 8; 10.5%), and elevated factor VIII (n = 2; 2.6%). Complications occurred in 9 patients (11.8%) and included postoperative infections (n = 6; 7.9%) and postoperative bleeding (n = 3; 3.9%). CONCLUSION: Our data suggest that oral and/or maxillofacial surgery in patients with a confirmed diagnosis of thrombophilia is not associated with a burden of thrombosis or high complication rates. Furthermore, we formulated a guideline for preoperative antithrombotic therapy for patients with thrombophilia undergoing oral and/or maxillofacial surgery.


Assuntos
Procedimentos Cirúrgicos Bucais , Cirurgia Bucal , Trombofilia , Feminino , Humanos , Masculino , Cirurgiões Bucomaxilofaciais , Estudos Retrospectivos , Fatores de Risco , Trombofilia/complicações
6.
Comput Methods Programs Biomed ; 205: 106093, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33882417

RESUMO

Background and Objective; Genetic risk factors for childhood cancer may also influence facial morphology. 3D photography can be used in the recognition of differences in face shape among individuals. In previous research, 3D facial photography was used to identify increased facial asymmetry and greater deviation from normal facial morphology in a group of individuals with distinct morphological features who had childhood cancer compared to healthy controls. In this study, we aim to determine whether there is a difference in facial morphology between children with cancer without previously selected morphological features and healthy controls, detected with 3D facial photography. METHODS: Facial 3D photographic images were obtained of children with a newly diagnosed malignancy. The resulting sample comprised 13 different cancer types. Patients were excluded if they had a known genetic cause of the cancer. Patients were compared to healthy controls, matched for sex, age and ethnic background. The degree of asymmetry and overall deviation of an individual's face from an age and sex typical control face were measured. RESULTS: A total of 163 patients of European descent were included. No significant difference in asymmetry between patients and controls could be identified. On average, patients deviated more from an age and sex typical face than the controls. CONCLUSION: This study shows that children with cancer deviate more than controls, possibly suggesting a higher prevalence of genetic anomalies within this group. The results suggest that this is not sufficient to discriminate patients from controls. Further research is necessary to explore the patterns of individual variation among the overall deviation of patients and controls.


Assuntos
Imageamento Tridimensional , Neoplasias , Criança , Face , Assimetria Facial/diagnóstico por imagem , Humanos , Fotografação
7.
Nat Genet ; 53(6): 830-839, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33821002

RESUMO

Evidence from model organisms and clinical genetics suggests coordination between the developing brain and face, but the role of this link in common genetic variation remains unknown. We performed a multivariate genome-wide association study of cortical surface morphology in 19,644 individuals of European ancestry, identifying 472 genomic loci influencing brain shape, of which 76 are also linked to face shape. Shared loci include transcription factors involved in craniofacial development, as well as members of signaling pathways implicated in brain-face cross-talk. Brain shape heritability is equivalently enriched near regulatory regions active in either forebrain organoids or facial progenitors. However, we do not detect significant overlap between shared brain-face genome-wide association study signals and variants affecting behavioral-cognitive traits. These results suggest that early in embryogenesis, the face and brain mutually shape each other through both structural effects and paracrine signaling, but this interplay may not impact later brain development associated with cognitive function.


Assuntos
Encéfalo/anatomia & histologia , Face/anatomia & histologia , Padrões de Herança/genética , Adulto , Idoso , Comportamento , Cognição , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Imageamento por Ressonância Magnética , Masculino , Transtornos Mentais/genética , Pessoa de Meia-Idade , Análise Multivariada
8.
Neurogenetics ; 22(3): 207-213, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33683518

RESUMO

A de novo 0.95 Mb 8p21.3 deletion had been identified in an individual with non-syndromic autism spectrum disorder (ASD) through high-resolution copy number variant analysis. Subsequent screening of in-house and publicly available databases resulted in the identification of six additional individuals with 8p21.3 deletions. Through case-based reasoning, we conclude that 8p21.3 deletions are rare causes of non-syndromic neurodevelopmental and neuropsychiatric disorders. Based on literature data, we highlight six genes within the region of minimal overlap as potential ASD genes or genes for neuropsychiatric disorders: DMTN, EGR3, FGF17, LGI3, PHYHIP, and PPP3CC.

9.
Front Genet ; 12: 626403, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33692830

RESUMO

Unaffected relatives of individuals with non-syndromic cleft lip with or without cleft palate (NSCL/P) show distinctive facial features. The presence of this facial endophenotype is potentially an expression of underlying genetic susceptibility to NSCL/P in the larger unselected population. To explore this hypothesis, we first partitioned the face into 63 partially overlapping regions representing global-to-local facial morphology and then defined endophenotypic traits by contrasting the 3D facial images from 264 unaffected parents of individuals with NSCL/P versus 3,171 controls. We observed distinct facial features between parents and controls across 59 global-to-local facial segments at nominal significance (p ≤ 0.05) and 52 segments at Bonferroni corrected significance (p < 1.2 × 10-3), respectively. Next, we quantified these distinct facial features as univariate traits in another dataset of 8,246 unaffected European individuals and performed a genome-wide association study. We identified 29 independent genetic loci that were associated (p < 5 × 10-8) with at least one of the tested endophenotypic traits, and nine genetic loci also passed the study-wide threshold (p < 8.47 × 10-10). Of the 29 loci, 22 were in proximity of loci previously associated with normal facial variation, 18 were near genes that show strong evidence in orofacial clefting (OFC), and another 10 showed some evidence in OFC. Additionally, polygenic risk scores for NSCL/P showed associations with the endophenotypic traits. This study thus supports the hypothesis of a shared genetic architecture of normal facial development and OFC.

10.
Nat Genet ; 53(1): 45-53, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33288918

RESUMO

The human face is complex and multipartite, and characterization of its genetic architecture remains challenging. Using a multivariate genome-wide association study meta-analysis of 8,246 European individuals, we identified 203 genome-wide-significant signals (120 also study-wide significant) associated with normal-range facial variation. Follow-up analyses indicate that the regions surrounding these signals are enriched for enhancer activity in cranial neural crest cells and craniofacial tissues, several regions harbor multiple signals with associations to different facial phenotypes, and there is evidence for potential coordinated actions of variants. In summary, our analyses provide insights into the understanding of how complex morphological traits are shaped by both individual and coordinated genetic actions.


Assuntos
Face/anatomia & histologia , Estudo de Associação Genômica Ampla , Acetilação , Elementos Facilitadores Genéticos/genética , Epistasia Genética , Extremidades/embriologia , Face/embriologia , Loci Gênicos , Histonas/metabolismo , Humanos , Lisina/metabolismo , Metanálise como Assunto , Análise Multivariada , Crista Neural/citologia , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Crânio/embriologia , Reino Unido , Estados Unidos
11.
Am J Hum Genet ; 107(5): 963-976, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33157009

RESUMO

NCKAP1/NAP1 regulates neuronal cytoskeletal dynamics and is essential for neuronal differentiation in the developing brain. Deleterious variants in NCKAP1 have been identified in individuals with autism spectrum disorder (ASD) and intellectual disability; however, its clinical significance remains unclear. To determine its significance, we assemble genotype and phenotype data for 21 affected individuals from 20 unrelated families with predicted deleterious variants in NCKAP1. This includes 16 individuals with de novo (n = 8), transmitted (n = 6), or inheritance unknown (n = 2) truncating variants, two individuals with structural variants, and three with potentially disruptive de novo missense variants. We report a de novo and ultra-rare deleterious variant burden of NCKAP1 in individuals with neurodevelopmental disorders which needs further replication. ASD or autistic features, language and motor delay, and variable expression of intellectual or learning disability are common clinical features. Among inherited cases, there is evidence of deleterious variants segregating with neuropsychiatric disorders. Based on available human brain transcriptomic data, we show that NCKAP1 is broadly and highly expressed in both prenatal and postnatal periods and demostrate enriched expression in excitatory neurons and radial glias but depleted expression in inhibitory neurons. Mouse in utero electroporation experiments reveal that Nckap1 loss of function promotes neuronal migration during early cortical development. Combined, these data support a role for disruptive NCKAP1 variants in neurodevelopmental delay/autism, possibly by interfering with neuronal migration early in cortical development.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Transtorno do Espectro Autista/genética , Deficiência Intelectual/genética , Deficiências da Aprendizagem/genética , Mutação , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Adolescente , Animais , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Criança , Feminino , Expressão Gênica , Genótipo , Células HEK293 , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Deficiências da Aprendizagem/diagnóstico , Deficiências da Aprendizagem/patologia , Masculino , Camundongos , Camundongos Knockout , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Linhagem , Fenótipo , Gravidez , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transcriptoma , Adulto Jovem
12.
Brain ; 143(8): 2437-2453, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32761064

RESUMO

In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.


Assuntos
Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/genética , Deficiências do Desenvolvimento/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Doenças do Sistema Nervoso/genética , Humanos , Mutação , Fenótipo , Transporte Proteico/genética , Transdução de Sinais/genética
14.
J Craniofac Surg ; 31(4): 1091-1097, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32176019

RESUMO

BACKGROUND: Craniofacial syndromes occur in approximately 1 in 5600 to 100,000 infants, often resulting in significant morbidity. Due to the heterogeneity of this patient population, no clear consensus consists on optimal treatment modalities and timing. The aim of this study was to analyze the craniofacial syndrome population that were treated at the University Hospital Leuven. METHODS: A retrospective analysis of patients with a clinical diagnosis of a craniofacial syndrome was performed. Inclusion criteria were patients with a clinical diagnosis of a craniofacial syndrome and that received treatment between "2000-2005" and "2010-2015." Patients with nonsyndromic conditions were excluded. Data regarding patient characteristics, treatment modalities, and treatment outcomes were analyzed. RESULTS: After matching the inclusion criteria, 98 eligible patients, affected by 40 different syndromes were included. In the period of "2000 to 2005," 48 patients were treated, as compared to 50 patients in the period of "2010 to 2015." A statistically significant decrease over time is seen for cleft surgery and orthodontic treatment (P = 0.0017 and P = 0.0015, respectively). No statistically significant differences were found concerning the age at which treatment was received (P = 0.42). Significant associations between treatment modalities were found for orthognathic surgery and distraction osteogenesis (P < 0.0001), orthognathic surgery and orthodontic treatment (P < 0.0001), and between orthodontic treatment and distraction osteogenesis (P = 0.03311). CONCLUSION: A decline in cleft reconstruction surgery and orthodontic treatment for patients with craniofacial syndromes was seen over time. A significant association was found between distraction osteogenesis and orthognathic surgery, possibly due to higher reintervention rates for patients treated at a young age.


Assuntos
Ossos Faciais/cirurgia , Doenças Musculoesqueléticas/cirurgia , Adolescente , Criança , Humanos , Procedimentos Cirúrgicos Ortognáticos , Osteogênese por Distração , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
15.
Hum Reprod Update ; 26(3): 335-355, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32099997

RESUMO

BACKGROUND: Through carrier screening, prospective parents can acquire information about whether they have an increased risk of conceiving a child affected with an autosomal recessive or X-linked condition. Within the last decade, advances in genomic technologies have facilitated a shift from condition-directed carrier screening to expanded carrier screening (ECS). Following the introduction of ECS, several studies have been performed to gauge the interest in this new technology among individuals and couples in the general population. OBJECTIVE AND RATIONALE: The aim of this systematic review was to synthesize evidence from empirical studies that assess the interest in ECS among individuals and couples in the general population. As the availability and accessibility of ECS grow, more couples who are a priori not at risk based on their personal or family history will be presented with the choice to accept or decline such an offer. Their attitudes and beliefs, as well as the perceived usefulness of this screening modality, will likely determine whether ECS is to become a widespread reproductive genetic test. SEARCH METHODS: Four databases (Pubmed, Web of Science, CINAHL, Cochrane Library) were systematically searched to identify English language studies performed between January 2009 and January 2019 using the following search terms: carrier screening, carrier testing, attitudes, intention, interest, views, opinions, perspectives and uptake. Studies were eligible for inclusion if they reported on intentions to undergo a (hypothetical) ECS test, uptake of an actual ECS offer or both. Two researchers performed a multistep selection process independently for validation purposes. OUTCOMES: Twelve empirical studies performed between 2015 and 2019 were included for analysis. The studies originated from the USA (n = 6), the Netherlands (n = 3), Belgium (n = 1), Sweden (n = 1) and Australia (n = 1). The sample size of the studies varied from 80 to 1669. In the included studies, 32%-76% of respondents were interested in a (hypothetical) ECS test, while uptake rates for actual ECS offers ranged from 8% to 50%. The highest overall uptake was observed when ECS was offered to pregnant women (50%). By contrast, studies focusing on the preconception population reported lower overall uptake rates (8-34%) with the exception of one study where women were counseled preconception in preparation for IVF (68.7%). WIDER IMPLICATIONS: Our findings suggest that there may be discrepancies between prospective parents' reported intentions to undergo ECS and their actual uptake, particularly during the preconception period. As ECS is a new and relatively unknown test for most future parents, the awareness and comprehension within the general population could be rather limited. Adequate pre- and post-test counseling services should be made available to couples offered ECS to ensure informed reproductive decision-making, together with guidelines for primary health care professionals. Due to restricted nature of the samples and methods of the underlying primary studies, some of the reported results might not be transferable to a broader population. More research is needed to see if the observed trends also apply to a broader and more diverse population.


Assuntos
Triagem de Portadores Genéticos/métodos , Aconselhamento Genético/métodos , Doenças Genéticas Inatas/diagnóstico , Feminino , Doenças Genéticas Inatas/genética , Humanos , Países Baixos , Pais , Gravidez , Estudos Prospectivos , Reprodução
16.
J Med Genet ; 57(5): 347-355, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31932357

RESUMO

BACKGROUND: Intragenic NRXN1 deletions are susceptibility variants for neurodevelopmental disorders; however, their clinical interpretation is often unclear. Therefore, a literature study and an analysis of 43 previously unpublished deletions are provided. METHODS: The literature cohort covered 629 heterozygous NRXN1 deletions: 148 in controls, 341 in probands and 140 in carrier relatives, and was used for clinical hypothesis testing. Exact breakpoint determination was performed for 43 in-house deletions. RESULTS: The prevalence of exonic NRXN1 deletions in controls was ~1/3000 as compared with ~1/800 in patients with neurodevelopmental/neuropsychiatric disorders. The differential distribution of deletions across the gene between controls and probands allowed to distinguish distinct areas within the gene. Exon 6-24 deletions appeared only twice in over 100000 control individuals, had an estimated penetrance for neurodevelopmental disorders of 32.43%, a de novo rate of 50% and segregated mainly with intellectual disability (ID) and schizophrenia. In contrast, exon 1-5 deletions appeared in 20 control individuals, had an estimated penetrance of 12.59%, a de novo rate of 32.5% and were reported with a broad range of neurodevelopmental phenotypes. Exact breakpoint determination revealed six recurrent intron 5 deletions. CONCLUSION: Exon 6-24 deletions have a high penetrance and are mainly associated with ID and schizophrenia. In contrast, the actual contribution of exon 1-5 deletions to a neurodevelopmental/neuropsychiatric disorder in an individual patient and family remains very difficult to assess. To enhance the clinical interpretation, this study provides practical considerations for counselling and an interactive table for comparing a deletion of interest with the available literature data.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Deleção de Genes , Deficiência Intelectual/genética , Moléculas de Adesão de Célula Nervosa/genética , Esquizofrenia/genética , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Éxons , Feminino , Predisposição Genética para Doença , Humanos , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/patologia , Masculino , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Esquizofrenia/epidemiologia , Esquizofrenia/patologia
17.
Twin Res Hum Genet ; 22(6): 454-459, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31496455

RESUMO

The East Flanders Prospective Twin Survey (EFPTS) is a registry of multiple births in the province of East Flanders, Belgium. Since its start in 1964, over 10,000 twin-pairs have been registered. EFPTS has several unique features: it is population-based and prospective, with the possibility of long-term follow-up; the twins (and higher order multiple births) are recruited at birth; basic perinatal data are recorded; chorion type and zygosity are established; since 1969, placental biopsies have been taken and frozen at -20°C for future research. Since its origin, the EFPTS has included placental data and allows differentiation of three subtypes of monozygotic twins based on the time of the initial zygotic division: the dichorionic-diamniotic pairs (early, with splitting before the fourth day after fertilization), the monochorionic-diamniotic pairs (intermediate, splitting between the fourth- and the seventh-day postfertilization) and the monochorionic-monoamniotic pairs (late, splitting after the eighth day postfertilization). Studies can be initiated taking into account primary biases, those originating 'in utero'. Such studies could throw new light on the consequences of early embryological events and the gene-environment interactions as far as periconceptional and intrauterine environment are concerned.


Assuntos
Doenças em Gêmeos/epidemiologia , Interação Gene-Ambiente , Sistema de Registros/estatística & dados numéricos , Gêmeos Dizigóticos/estatística & dados numéricos , Gêmeos Monozigóticos/estatística & dados numéricos , Bélgica/epidemiologia , Doenças em Gêmeos/genética , Doenças em Gêmeos/patologia , Humanos , Incidência , Prole de Múltiplos Nascimentos , Estudos Prospectivos , Inquéritos e Questionários , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética
18.
Genet Med ; 21(12): 2774-2780, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31197268

RESUMO

PURPOSE: Noninvasive prenatal screening (NIPS) using genome sequencing also reveals maternal copy-number variations (CNVs). Those CNVs can be clinically actionable or harmful to the fetus if inherited. CNVs in the DMD gene potentially causing dystrophinopathies are among the most commonly observed maternal CNVs. We present our experience with maternal DMD gene CNVs detected by NIPS. METHODS: We analyzed the data of maternal CNVs detected in the DMD gene revealed by NIPS. RESULTS: Of 26,123 NIPS analyses, 16 maternal CNVs in the DMD gene were detected (1/1632 pregnant women). Variant classification regarding pathogenicity and phenotypic severity was based on public databases, segregation analysis in the family, and prediction of the effect on the reading frame. Ten CNVs were classified as pathogenic, four as benign, and two remained unclassified. CONCLUSION: NIPS leverages CNV screening in the general population of pregnant women. We implemented a strategy for the interpretation and the return of maternal CNVs in the DMD gene detected by NIPS.


Assuntos
Distrofina/genética , Achados Incidentais , Teste Pré-Natal não Invasivo/ética , Adulto , Variações do Número de Cópias de DNA/genética , Distrofina/metabolismo , Feminino , Feto , Humanos , Teste Pré-Natal não Invasivo/métodos , Gravidez , Diagnóstico Pré-Natal/ética , Diagnóstico Pré-Natal/métodos , Análise de Sequência de DNA/ética , Análise de Sequência de DNA/métodos
19.
Mol Autism ; 10: 52, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31893021

RESUMO

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a high co-morbidity of epilepsy and associated with hundreds of rare risk factors. NRXN1 deletion is among the commonest rare genetic factors shared by ASD, schizophrenia, intellectual disability, epilepsy, and developmental delay. However, how NRXN1 deletions lead to different clinical symptoms is unknown. Patient-derived cells are essential to investigate the functional consequences of NRXN1 lesions to human neurons in different diseases. Methods: Skin biopsies were donated by five healthy donors and three ASD patients carrying NRXN1α +/- deletions. Seven control and six NRXN1α +/- iPSC lines were derived and differentiated into day 100 cortical excitatory neurons using dual SMAD inhibition. Calcium (Ca2+) imaging was performed using Fluo4-AM, and the properties of Ca2+ transients were compared between two groups of neurons. Transcriptome analysis was carried out to undercover molecular pathways associated with NRXN1α +/- neurons. Results: NRXN1α +/- neurons were found to display altered calcium dynamics, with significantly increased frequency, duration, and amplitude of Ca2+ transients. Whole genome RNA sequencing also revealed altered ion transport and transporter activity, with upregulated voltage-gated calcium channels as one of the most significant pathways in NRXN1α +/- neurons identified by STRING and GSEA analyses. Conclusions: This is the first report to show that human NRXN1α +/- neurons derived from ASD patients' iPSCs present novel phenotypes of upregulated VGCCs and increased Ca2+ transients, which may facilitate the development of drug screening assays for the treatment of ASD.


Assuntos
Transtorno do Espectro Autista/patologia , Sinalização do Cálcio , Proteínas de Ligação ao Cálcio/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Moléculas de Adesão de Célula Nervosa/metabolismo , Neurônios/metabolismo , Potenciais de Ação , Canais de Cálcio/metabolismo , Diferenciação Celular , Feminino , Humanos , Transporte de Íons , Cinética , Masculino , Reprodutibilidade dos Testes
20.
J Community Genet ; 10(1): 153-159, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29974402

RESUMO

Screening for fragile X syndrome (FXS) is essential in children with developmental delay or intellectual disability (ID). In addition, using clinical screening checklists remains of high interest in resource-limited settings. We aimed to gain insight into the prevalence of FXS and the distribution of CGG alleles and to evaluate the usefulness of three checklists in specialized institutions in Kinshasa, DR Congo. We recruited 80 males and 25 females from six specialized institutions in Kinshasa and administered a questionnaire comprising items from the following FXS checklists: Hagerman, Maes, and Guruju. FMR1 CGG repeats were assessed for every patient. About 37% of patients were referable for FX testing based on Hagerman's checklist, 35% for Maes', and 43.80% for Guruju's, but none of them was molecularly confirmed to have FXS. Thus, specificities were 62.86, 64.76, and 56.5%, respectively, for Hagerman, Maes, and Guruju, respectively. The mean CGG allele size was 28.55 ± 2.83 (ranges, 17-48). The 29 CGG was the most frequent allele (24.61%). Thus, existing checklists should not be automatically applied to Congolese patients without adjustments. The distribution of CGG repeats and the number of CGG alleles are similar to other African studies.

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