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1.
Elife ; 102021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33416497

RESUMO

Shprintzen-Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys-Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-ß signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional corepressor SKI, which is a negative regulator of TGF-b signaling that is rapidly degraded upon ligand stimulation. The molecular consequences of these mutations, however, are not understood. Here we use a combination of structural biology, genome editing and biochemistry to show that SGS mutations in SKI abolish its binding to phosphorylated SMAD2 and SMAD3. This results in stabilization of SKI and consequently attenuation of TGF-ß responses, in both knockin cells expressing an SGS mutation, and in fibroblasts from SGS patients. Thus, we reveal that SGS is associated with an attenuation of TGF-b-induced transcriptional responses, and not enhancement, which has important implications for other Marfan-related syndromes.

2.
Clin Genet ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33415748

RESUMO

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.

3.
Int J Cancer ; 2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33368296

RESUMO

Single-nucleotide polymorphisms (SNPs) in over 180 loci have been associated with breast cancer (BC) through genome-wide association studies involving mostly unselected population-based case-control series. Some of them modify BC risk of women carrying a BRCA1 or BRCA2 (BRCA1/2) mutation and may also explain BC risk variability in BC-prone families with no BRCA1/2 mutation. Here, we assessed the contribution of SNPs of the iCOGS array in GENESIS consisting of BC cases with no BRCA1/2 mutation and a sister with BC, and population controls. Genotyping data were available for 1281 index cases, 731 sisters with BC, 457 unaffected sisters and 1272 controls. In addition to the standard SNP-level analysis using index cases and controls, we performed pedigree-based association tests to capture transmission information in the sibships. We also performed gene- and pathway-level analyses to maximize the power to detect associations with lower-frequency SNPs or those with modest effect sizes. While SNP-level analyses identified 18 loci, gene-level analyses identified 112 genes. Furthermore, 31 Kyoto Encyclopedia of Genes and Genomes and 7 Atlas of Cancer Signaling Network pathways were highlighted (false discovery rate of 5%). Using results from the "index case-control" analysis, we built pathway-derived polygenic risk scores (PRS) and assessed their performance in the population-based CECILE study and in a data set composed of GENESIS-affected sisters and CECILE controls. Although these PRS had poor predictive value in the general population, they performed better than a PRS built using our SNP-level findings, and we found that the joint effect of family history and PRS needs to be considered in risk prediction models.

4.
Clin Genet ; 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-33277917

RESUMO

INTRODUCTION: White-Sutton syndrome is a rare developmental disorder characterized by global developmental delay, intellectual disabilities (ID), and neurobehavioral abnormalities secondary to pathogenic POGZ variants. The purpose of our study was to describe the neurocognitive phenotype of an unbiased national cohort of patients with identified POGZ pathogenic variants. MATERIALS AND METHODS: This study is based on a French collaboration through the AnDDI-Rares network, and includes 19 patients from 18 families with POGZ pathogenic variants. All clinical data and neuropsychological tests were collected from medical files. RESULTS: Among the 19 patients, 14 patients exhibited ID (6 mild, 5 moderate and 3 severe). The 5 remaining patients had learning disabilities and shared a similar neurocognitive profile, including language difficulties, dysexecutive syndrome, attention disorders, slowness and social difficulties. One patient evaluated for autism was found to have moderate autism spectrum disorder. CONCLUSION: This study reveals that the cognitive phenotype of patients with POGZ pathogenic variants can range from learning disabilities to severe ID. It highlights that pathogenic variations in the same genes can be reported in a large spectrum of neurocognitive profiles, and that children with learning disabilities could benefit from next generation sequencing techniques.

5.
Clin Genet ; 2020 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-33368193

RESUMO

Smith-Magenis syndrome (SMS), characterized by dysmorphic features, neurodevelopmental disorder, and sleep disturbance, is due to an interstitial deletion of chromosome 17p11.2 (90%) or to point mutations in the RAI1 gene. In this retrospective cohort, we studied the clinical, cognitive, and behavioral profile of 47 European patients with SMS caused by a 17p11.2 deletion. We update the clinical and neurobehavioral profile of SMS. Intrauterine growth was normal in most patients. Prenatal anomalies were reported in 15%. 60% of our patients older than 10 years were overweight. Prevalence of heart defects (6.5% tetralogy of Fallot, 6.5% pulmonary stenosis), ophthalmological problems (89%), scoliosis (43%), or deafness (32%) were consistent with previous reports. Epilepsy was uncommon (2%). We identified a high prevalence of obstipation (45%). All patients had learning difficulties and developmental delay, but ID range was wide and 10% of patients had IQ in the normal range. Behavioral problems included temper tantrums and other difficult behaviors (84%) and night-time awakenings (86%). Optimal care of SMS children is multidisciplinary and requires important parental involvement. In our series, half of patients were able to follow adapted schooling, but 70% of parents had to adapt their working time, illustrating the medical, social, educative, and familial impact of having a child with SMS.

6.
Am J Hum Genet ; 107(6): 1170-1177, 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33232677

RESUMO

KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In mice, lysine demethylase 4B is expressed during brain development with high levels in the hippocampus, a region important for learning and memory. To understand how KDM4B variants can lead to GDD in humans, we assessed the effect of KDM4B disruption on brain anatomy and behavior through an in vivo heterozygous mouse model (Kdm4b+/-), focusing on neuroanatomical changes. In mutant mice, the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. This report demonstrates that variants in KDM4B are associated with GDD/ intellectual disability and neuroanatomical defects. Our findings suggest that KDM4B variation leads to a chromatinopathy, broadening the spectrum of this group of Mendelian disorders caused by alterations in epigenetic machinery.

7.
Spec Care Dentist ; 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33202072

RESUMO

AIMS: Cohen syndrome (CS) is an uncommon autosomal recessive disorder due to mutations in vacuolar protein sorting 13B, with an intermittent presence of neutropenia. Contrary to other clinical phenotypic features, oral health has been little investigated in CS. We described oral health and dental hygiene in a cohort of CS patients. METHODS AND RESULTS: Twelve CS patients with neutropenia (<1500/mm3 ) were recruited in the dental department of Dijon University Hospital (France). Patients underwent oral examination, and blood samples were collected. Oral health markers were described and compared between patients with moderate and severe neutropenia (<500/mm3 ). In 12 patients (mean age = 21.1 years, SD = 13.7, six females), 45.5% brushed at least twice daily their teeth, and the same percentage annually visited a dentist. Dental plaque index was high (mean = 1.7, SD = 1.4). So was the number of lost teeth per patient, notably among adults (mean = 13.8, SD = 9.8). Elevated markers of periodontitis were noted as percentage of bleeding dental sites (mean = 70.2%, SD = 45.2%) or Gingival Index (mean = 2.2, SD = 1.0). The severity of neutropenia was correlated to the level of tooth-loss (P = .03). CONCLUSION: This study highlighted in CS patients worrisome oral health and dental follow-up in the context of intellectual disability with behavioural anomalies. More attention is needed by care-givers on oral condition in CS.

8.
Genet Med ; 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33149277

RESUMO

PURPOSE: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority. METHODS: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC. RESULTS: Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype-phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts. CONCLUSION: Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.

9.
Genet Med ; 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33106617

RESUMO

PURPOSE: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. METHODS: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. RESULTS: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. CONCLUSION: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.

10.
Clin Genet ; 98(6): 620-621, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32926417

RESUMO

We report two fetal cases carrying a de novo MID1 mutation and presenting with severe hydrothorax, suggesting the expansion of the phenotype of Opitz GBBB syndrome.

11.
Eur J Med Genet ; 63(12): 104064, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32998064

RESUMO

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with a characteristic behavioural phenotype. A multidisciplinary approach to care is required to prevent multiple medical complications in individuals affected by PWS. The aim of this study was to describe the rehabilitation, medical care, educational and social support provided to school-aged French PWS patients with varying neuropsychological profiles. Data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Nineteen PWS subjects with a mean age of 9.2 years were included. The mean full-scale intellectual quotient (IQ) was 58 (Wechsler scale). There were frequent dissociations between verbal and performance IQ that were not associated with a specific profile. We also observed lower autonomy and communication scores (5.3 years and 5.9 years equivalent, respectively, Vineland scale), the absence of hyperactivity (Conners scale), and the presence of behavioural abnormalities (CBCL scale). Multidisciplinary medical supervision was generally coordinated by the paediatric endocrinologist and did not always include follow-up with all of the recommended specialists, in particular with a paediatric psychiatrist. Analysis of multidisciplinary rehabilitation conducted in public and private-sector establishment revealed failings in psychological support, occupational therapy and dietary follow-up. Regarding education, most children younger than 10 years were in normal schools, while older individuals were often cared for in medico-social institutions. In conclusion, children and adolescents with PWS generally received appropriate care. Though there have been considerable improvements in the management of children with PWS, reference centres should continue reinforcing the coordination of multidisciplinary supervision.

12.
Invest Ophthalmol Vis Sci ; 61(11): 18, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32915983

RESUMO

Purpose: Cohen syndrome (CS) is a rare genetic disorder caused by variants of the VPS13B gene. CS patients are affected with a severe form of retinal dystrophy, and in several cases cataracts also develop. The purpose of this study was to investigate the mechanisms and risk factors for cataract in CS, as well as to report on cataract surgeries in CS patients. Methods: To understand how VPS13B is associated with visual impairments in CS, we generated the Vps13b∆Ex3/∆Ex3 mouse model. Mice from 1 to 3 months of age were followed by ophthalmoscopy and slit-lamp examinations. Phenotypes were investigated by histology, immunohistochemistry, and western blot. Literature analysis was performed to determine specific characteristic features of cataract in CS and to identify potential genotype-phenotype correlations. Results: Cataracts rapidly developed in 2-month-old knockout mice and were present in almost all lenses at 3 months. Eye fundi appeared normal until cataract development. Lens immunostaining revealed that cataract formation was associated with the appearance of large vacuoles in the cortical area, epithelial-mesenchymal transition, and fibrosis. In later stages, cataracts became hypermature, leading to profound retinal remodeling due to inflammatory events. Literature analysis showed that CS-related cataracts display specific features compared to other forms of retinitis pigmentosa-related cataracts, and their onset is modified by additional genetic factors. Corroboratively, we were able to isolate a subline of the Vps13b∆Ex3/∆Ex3 model with delayed cataract onset. Conclusions: VPS13B participates in lens homeostasis, and the CS-related cataract development dynamic is linked to additional genetic factors.

13.
Eur J Med Genet ; 63(11): 104036, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32805448

RESUMO

The MTOR gene encodes the mechanistic target of rapamycin (mTOR), which is a core component of the PI3K-AKT-mTOR signaling pathway. Postzygotic MTOR variants result in various mosaic phenotypes, referred to in OMIM as Smith-Kinsgmore syndrome or focal cortical dysplasia. We report here the case of a patient, with an MTOR mosaic gain-of-function variant (p.Glu2419Lys) in the DNA of 41% skin cells, who received compassionate off-label treatment with everolimus for refractory epilepsy. This 12-year-old-girl presented with psychomotor regression, intractable seizures, hypopigmentation along Blaschko's lines (hypomelanosis of Ito), asymmetric regional body overgrowth, and ocular anomalies, as well as left cerebral hemispheric hypertrophy with some focal underlying migration disorders. In response to the patient's increasingly frequent epileptic seizures, everolimus was initiated (after approval from the hospital ethics committee) at 5 mg/day and progressively increased to 12.5 mg/day. After 5 months of close monitoring (including neuropsychological and electroencephalographic assessment), no decrease in seizure frequency was observed. Though the physiopathological rationale was good, no significant clinical response was noticed under everolimus treatment. A clinical trial would be needed to draw conclusions, but, because the phenotype is extremely rare, it would certainly need to be conducted on an international scale.

14.
Biochem Biophys Res Commun ; 530(3): 520-526, 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32620236

RESUMO

PIK3CA-related overgrowth spectrum is caused by mosaicism mutations in the PIK3CA gene. These mutations, which are also observed in various types of cancer, lead to a constitutive activation of the PI3K/AKT/mTOR pathway, increasing cell proliferation. Heat shock transcription factor 1 (HSF1) is the major stress-responsive transcription factor. Recent findings indicate that AKT phosphorylates and activates HSF1 independently of heat-shock in breast cancer cells. Here, we aimed to investigate the role of HSF1 in PIK3CA-related overgrowth spectrum. We observed a higher rate of proliferation and increased phosphorylation of AKT and p70S6K in mutant fibroblasts than in control cells. We also found elevated phosphorylation and activation of HSF1, which is directly correlated to AKT activation. Specific AKT inhibitors inhibit HSF1 phosphorylation as well as HSF1-dependent gene transcription. Finally, we demonstrated that targeting HSF1 with specific inhibitors reduced the proliferation of mutant cells. As there is currently no curative treatment for PIK3CA-related overgrowth spectrum, our results identify HSF1 as a new potential therapeutic target.

15.
Hum Mutat ; 41(9): 1499-1506, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32598510

RESUMO

PITX1 is a homeobox transcription factor essential for hindlimb morphogenesis. Two PITX1-related human disorders have been reported to date: PITX1 ectopic expression causes Liebenberg syndrome, characterized by malformation of upper limbs showing a "lower limb" appearance; PITX1 deletions or missense variation cause a syndromic picture including clubfoot, tibial hemimelia, and preaxial polydactyly. We report two novel PITX1 missense variants, altering PITX1 transactivation ability, in three individuals from two unrelated families showing a distinct recognizable autosomal dominant syndrome, including first branchial arch, pelvic, patellar, and male genital abnormalities. This syndrome shows striking similarities with the Pitx1-/- mouse model. A partial phenotypic overlap is also observed with Ischiocoxopodopatellar syndrome caused by TBX4 haploinsufficiency, and with the phenotypic spectrum caused by SOX9 anomalies, both genes being PITX1 downstream targets. Our study findings expand the spectrum of PITX1-related disorders and suggest a common pattern of developmental abnormalities in disorders of the PITX1-TBX4-SOX9 signaling pathway.

16.
EMBO J ; 39(13): e104163, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32484994

RESUMO

The relationships between impaired cortical development and consequent malformations in neurodevelopmental disorders, as well as the genes implicated in these processes, are not fully elucidated to date. In this study, we report six novel cases of patients affected by BBSOAS (Boonstra-Bosch-Schaff optic atrophy syndrome), a newly emerging rare neurodevelopmental disorder, caused by loss-of-function mutations of the transcriptional regulator NR2F1. Young patients with NR2F1 haploinsufficiency display mild to moderate intellectual disability and show reproducible polymicrogyria-like brain malformations in the parietal and occipital cortex. Using a recently established BBSOAS mouse model, we found that Nr2f1 regionally controls long-term self-renewal of neural progenitor cells via modulation of cell cycle genes and key cortical development master genes, such as Pax6. In the human fetal cortex, distinct NR2F1 expression levels encompass gyri and sulci and correlate with local degrees of neurogenic activity. In addition, reduced NR2F1 levels in cerebral organoids affect neurogenesis and PAX6 expression. We propose NR2F1 as an area-specific regulator of mouse and human brain morphology and a novel causative gene of abnormal gyrification.

17.
Nat Commun ; 11(1): 2441, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415109

RESUMO

KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients' neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mRNA decay. Although we demonstrate that Kif21b haploinsufficiency leads to an impaired neuronal positioning, the duplication variant might not be pathogenic. Altogether, our data indicate that impaired KIF21B autoregulation and function play a critical role in the pathogenicity of human neurodevelopmental disorder.


Assuntos
Cinesina/genética , Atividade Motora , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Animais , Axônios/metabolismo , Movimento Celular , Proliferação de Células , Córtex Cerebral/embriologia , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Masculino , Camundongos , Mutação de Sentido Incorreto/genética , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Neurônios/metabolismo , Tamanho do Órgão , Organogênese/genética , Linhagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Peixe-Zebra/anatomia & histologia , Peixe-Zebra/genética
18.
Hum Genet ; 139(11): 1381-1390, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32399599

RESUMO

Developmental disorders (DD), characterized by malformations/dysmorphism and/or intellectual disability, affecting around 3% of worldwide population, are mostly linked to genetic anomalies. Despite clinical exome sequencing (cES) centered on genes involved in human genetic disorders, the majority of patients affected by DD remain undiagnosed after solo-cES. Trio-based strategy is expected to facilitate variant selection thanks to rapid parental segregation. We performed a second step trio-ES (not only focusing on genes involved in human disorders) analysis in 70 patients with negative results after solo-cES. All candidate variants were shared with a MatchMaking exchange system to identify additional patients carrying variants in the same genes and with similar phenotype. In 18/70 patients (26%), we confirmed causal implication of nine OMIM-morbid genes and identified nine new strong candidate genes (eight de novo and one compound heterozygous variants). These nine new candidate genes were validated through the identification of patients with similar phenotype and genotype thanks to data sharing. Moreover, 11 genes harbored variants of unknown significance in 10/70 patients (14%). In DD, a second step trio-based ES analysis appears an efficient strategy in diagnostic and translational research to identify highly candidate genes and improve diagnostic yield.


Assuntos
Deficiências do Desenvolvimento/genética , Exoma/genética , Predisposição Genética para Doença/genética , Deficiência Intelectual/genética , Feminino , Genômica/métodos , Humanos , Masculino , Fenótipo , Sequenciamento Completo do Exoma/métodos
19.
Genet Med ; 22(7): 1215-1226, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32376980

RESUMO

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts. METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts. RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts. CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

20.
Clin Genet ; 98(5): 433-444, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32335911

RESUMO

Recent advances in next-generation sequencing (NGS) technologies have revolutionized the field of human genetics. Alongside a broad panel of bioinformatics tools and databases, NGS technologies have unprecedentedly improved the molecular diagnosis rate and the identification of new genes associated with rare disorders. However, about 50% of patients remain without a final diagnosis. Here, we highlight the utility of NGS applications in developmental anomalies and intellectual disability, illustrating their main advantages and pitfalls. Through specific examples, we suggest novel strategies and tools for identifying the molecular bases in the remaining patients, and we outline future challenges.

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