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1.
Clin Genet ; 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31573083

RESUMO

Children with Neurofibromatosis Type 1 (NF1) may exhibit an incomplete clinical presentation, making difficult to reach a clinical diagnosis. A phenotypic overlap may exist with children with other RASopathies or with other genetic conditions if only multiple café-au-lait macules (CALMs) are present. The syndromes that can converge in these inconclusive phenotypes have different clinical courses. In this context, an early genetic testing has been proposed to be clinically useful to manage these patients. We present the validation and implementation into diagnostics of a custom NGS panel (I2HCP) for testing patients with a clinical suspicion of a RASopathy (n=48) and children presenting multiple CALMs (n=102). We describe the mutational spectrum and the detection rates identified in these two groups of individuals. We identified pathogenic variants in 21 out of 48 patients with clinical suspicion of RASopathy, with mutations in NF1 accounting for 10% of cases. Furthermore, we identified pathogenic mutations mainly in the NF1 gene, but also in SPRED1, in more than 50% of children with multiple CALMs, exhibiting a NF1 mutational spectrum different from a group of clinically diagnosed NF1 patients (n=80). An NGS panel strategy for the genetic testing of these two phenotype-defined groups outperforms previous strategies. This article is protected by copyright. All rights reserved.

2.
Mol Genet Genomic Med ; 7(1): e00511, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30548424

RESUMO

BACKGROUND: Patients affected by Angelman syndrome (AS) present severe intellectual disability, lack of speech, ataxia, seizures, abnormal electroencephalography (EEG), and a characteristic behavioral phenotype. Around 10% of patients with a clinical diagnosis of AS (AS-like) do not have an identifiable molecular defect. Some of these patients harbor alternative genetic defects that present overlapping features with AS. METHODS: Trio whole-exome sequence was performed on patient and parent's DNA extracted from peripheral blood. Exome data were filtered according to a de novo autosomal dominant inheritance. cDNA analysis was carried out to assess the effect of the splice site variant. RESULTS: We identified a novel heterozygous SMARCE1 splicing variant that leads to an exon skipping in a patient with an Angelman-like phenotype. Missense variants in the SMARCE1 gene are known to cause Coffin-Siris syndrome (CSS), which is a rare congenital syndrome. Clinical reevaluation of the patient confirmed the presence of characteristic clinical features of CSS, many of them overlapping with AS. CONCLUSIONS: Taking into account the novel finding reported in this study, we consider that CSS should be added to the expanding list of differential diagnoses for AS.


Assuntos
Síndrome de Angelman/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Fenótipo , Adolescente , Síndrome de Angelman/patologia , Exoma , Humanos , Masculino , Mutação de Sentido Incorreto , Processamento de RNA
5.
Behav Genet ; 2018 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-29882083

RESUMO

A genetic analysis of unexplained mild-moderate intellectual disability and co-morbid psychiatric or behavioural disorders is not systematically conducted in adults. A cohort of 100 adult patients affected by both phenotypes were analysed in order to identify the presence of copy number variants (CNVs) responsible for their condition identifying a yield of 12.8% of pathogenic CNVs (19% when including clinically recognizable microdeletion syndromes). Moreover, there is a detailed clinical description of an additional 11% of the patients harbouring possible pathogenic CNVs-including a 7q31 deletion (IMMP2L) in two unrelated patients and duplications in 3q29, 9p24.2p24.1 and 15q14q15.1-providing new evidence of its contribution to the phenotype. This study adds further proof of including chromosomal microarray analysis (CMA) as a mandatory test to improve the diagnosis in the adult patients in psychiatric services.

6.
Br J Psychiatry ; 212(5): 287-294, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29693535

RESUMO

BACKGROUND: Copy number variants (CNVs) are established risk factors for neurodevelopmental disorders. To date the study of CNVs in psychiatric illness has focused on single disorder populations. The role of CNVs in individuals with intellectual disabilities and psychiatric comorbidities are less well characterised.AimsTo determine the type and frequency of CNVs in adults with intellectual disabilities and comorbid psychiatric disorders. METHOD: A chromosomal microarray analysis of 599 adults recruited from intellectual disabilities psychiatry services at three European sites. RESULTS: The yield of pathogenic CNVs was high - 13%. Focusing on established neurodevelopmental disorder risk loci we find a significantly higher frequency in individuals with intellectual disabilities and comorbid psychiatric disorder (10%) compared with healthy controls (1.2%, P<0.0001), schizophrenia (3.1%, P<0.0001) and intellectual disability/autism spectrum disorder (6.5%, P < 0.00084) populations. CONCLUSIONS: In the largest sample of adults with intellectual disabilities and comorbid psychiatric disorders to date, we find a high rate of pathogenic CNVs. This has clinical implications for the use of genetic investigations in intellectual disability psychiatry.Declaration of interestNone.

8.
BMC Med Genet ; 18(1): 137, 2017 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-29162042

RESUMO

BACKGROUND: Patients with Angelman syndrome (AS) are affected by severe intellectual disability with absence of speech, distinctive dysmorphic craniofacial features, ataxia and a characteristic behavioral phenotype. AS is caused by the lack of expression in neurons of the UBE3A gene, which is located in the 15q11.2-q13 imprinted region. Functional loss of UBE3A is due to 15q11.2-q13 deletion, mutations in the UBE3A gene, paternal uniparental disomy and genomic imprinting defects. CASE PRESENTATION: We report here two patients with clinical features of AS referred to our hospital for clinical follow-up and genetic diagnosis. Methylation Specific-Multiplex Ligation-Dependent Probe Amplification (MS-MLPA) of the 15q11.2-q13 region was carried out in our laboratory as the first diagnostic tool detecting two novel UBE3A intragenic deletions. Subsequently, the MLPA P336-A2 kit was used to confirm and determine the size of the UBE3A deletion in the two patients. A review of the clinical features of previously reported patients with whole UBE3A gene or partial intragenic deletions is presented here together with these two new patients. CONCLUSION: Although rare, UBE3A intragenic deletions may represent a small fraction of AS patients without a genetic diagnosis. Testing for UBE3A intragenic exonic deletions should be performed in those AS patients with a normal methylation pattern and no mutations in the UBE3A gene.


Assuntos
Síndrome de Angelman/genética , Sequência de Bases , Cromossomos Humanos Par 15 , Impressão Genômica , Deleção de Sequência , Ubiquitina-Proteína Ligases/genética , Síndrome de Angelman/diagnóstico , Síndrome de Angelman/patologia , Pré-Escolar , Éxons , Feminino , Dosagem de Genes , Humanos , Neurônios/metabolismo , Neurônios/patologia , Técnicas de Amplificação de Ácido Nucleico , Kit de Reagentes para Diagnóstico , Ubiquitina-Proteína Ligases/deficiência
9.
Gene ; 628: 109-116, 2017 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-28710037

RESUMO

RNA editing is being recognized as an important post-transcriptional mechanism that may have crucial roles in introducing genetic variation and phenotypic diversity. Despite microRNA editing recurrence, defining its biological relevance is still under extended debate. To better understand microRNA editing function and regulation we performed an exhaustive characterization of the A-to-I site-specific patterns in mir-376a-1, a mammalian microRNA which RNA editing is involved in the regulation of development and in disease. Thorough an integrative approach based on high-throughput small RNA sequencing, Sanger sequencing and computer simulations we explored mir-376a-1 editing in samples from various individuals and primate species including human placenta and macaque, gorilla, chimpanzee and human brain cortex. We observed that mir-376a-1 editing is a common phenomenon in the mature and primary microRNA molecules and it is more frequently detected in brain than in placenta. Primary mir-376a-1 is edited at three positions, -1, +4 and +44. Editing frequency estimations and in silico simulations indicated that editing was not equally recurrent along the three mir-376a-1 sites, nevertheless no epistatic interactions among them were observed. Particularly, the +4 site, located in the seed region of the mature miR-376a-5p, reached the highest editing frequency in all samples. Secondary structure predictions revealed that the +4 position was the one that conferred the highest stability to the mir-376a-1 hairpin. We suggest that molecular stability might partially explain the editing recurrence observed in certain microRNAs and that editing events conferring new functional regulatory roles in particular tissues and species could have been conserved along evolution, as it might be the case of mir-376a-1 in primate brain cortex.


Assuntos
MicroRNAs/metabolismo , Edição de RNA , Estabilidade de RNA , Animais , Córtex Cerebral/metabolismo , Epistasia Genética , Feminino , Gorilla gorilla , Macaca , MicroRNAs/genética , Conformação de Ácido Nucleico , Pan troglodytes , Placenta/metabolismo , Gravidez
10.
PLoS One ; 11(9): e0163468, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27685845

RESUMO

CONTEXT: Prader-Willi syndrome (PWS) is characterized by severe hyperphagia. Brain-derived neurotrophic factor (BDNF) and leptin are reciprocally involved in energy homeostasis. OBJECTIVES: To analyze the role of BDNF and leptin in satiety in genetic subtypes of PWS. DESIGN: Experimental study. SETTING: University hospital. SUBJECTS: 90 adults: 30 PWS patients; 30 age-sex-BMI-matched obese controls; and 30 age-sex-matched lean controls. INTERVENTIONS: Subjects ingested a liquid meal after fasting ≥10 hours. MAIN OUTCOME MEASURES: Leptin and BDNF levels in plasma extracted before ingestion and 30', 60', and 120' after ingestion. Hunger, measured on a 100-point visual analogue scale before ingestion and 60' and 120' after ingestion. RESULTS: Fasting BDNF levels were lower in PWS than in controls (p = 0.05). Postprandially, PWS patients showed only a truncated early peak in BDNF, and their BDNF levels at 60' and 120' were lower compared with lean controls (p<0.05). Leptin was higher in PWS patients than in controls at all time points (p<0.001). PWS patients were hungrier than controls before and after eating. The probability of being hungry was associated with baseline BDNF levels: every 50-unit increment in BDNF decreased the odds of being hungry by 22% (OR: 0.78, 95%CI: 0.65-0.94). In uniparental disomy, the odds of being hungry decreased by 66% (OR: 0.34, 90%CI: 0.13-0.9). Postprandial leptin patterns did no differ among genetic subtypes. CONCLUSIONS: Low baseline BDNF levels and lack of postprandial peak may contribute to persistent hunger after meals. Uniparental disomy is the genetic subtype of PWS least affected by these factors.

11.
J Clin Immunol ; 36(4): 388-96, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27026170

RESUMO

The complement system plays a central role in defense to encapsulated bacteria through opsonization and membrane attack complex (MAC) dependent lysis. The three activation pathways (classical, lectin, and alternative) converge in the cleavage of C5, which initiates MAC formation and target lysis. C5 deficiency is associated to recurrent infections by Neisseria spp. In the present study, complement deficiency was suspected in three families of North-African origin after one episode of invasive meningitis due to a non-groupable and two uncommon Meningococcal serotypes (E29, Y). Activity of alternative and classical pathways of complement were markedly reduced and the measurement of terminal complement components revealed total C5 absence. C5 gene analysis revealed two novel mutations as causative of the deficiency: Family A propositus carried a homozygous deletion of two adenines in the exon 21 of C5 gene, resulting in a frameshift and a truncated protein (c.2607_2608del/p.Ser870ProfsX3 mutation). Families B and C probands carried the same homozygous deletion of three consecutive nucleotides (CAA) in exon 9 of the C5 gene, leading to the deletion of asparagine 320 (c.960_962del/p.Asn320del mutation). Family studies confirmed an autosomal recessive inheritance pattern. Although sharing the same geographical origin, families B and C were unrelated. This prompted us to investigate this mutation prevalence in a cohort of 768 North-African healthy individuals. We identified one heterozygous carrier of the p.Asn320del mutation (allelic frequency = 0.065 %), indicating that this mutation is present at low frequency in North-African population.


Assuntos
Complemento C5/deficiência , Complemento C5/genética , Síndromes de Imunodeficiência/genética , África , Criança , Pré-Escolar , Complemento C5/metabolismo , Feminino , Humanos , Síndromes de Imunodeficiência/metabolismo , Lactente , Masculino , Mutação , Linhagem
12.
Cytogenet Genome Res ; 146(2): 109-14, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26280689

RESUMO

Most apparent balanced chromosomal inversions are usually clinically asymptomatic; however, infertility, miscarriages, and mental retardation have been reported in inversion carriers. We present a small family with a paracentric inversion 1q42.13q43 detected in routine prenatal diagnosis. Molecular cytogenetic methods defined the size of the inversion as 11.7 Mb and excluded other unbalanced chromosomal alterations in the patients. Our findings suggest that intellectual disability is caused by dysfunction, disruption, or position effects of genes located at or near the breakpoints involved in this inversion.


Assuntos
Inversão Cromossômica , Cromossomos Humanos Par 1/genética , Doenças Fetais/genética , Deficiência Intelectual/genética , Diagnóstico Pré-Natal , Pré-Escolar , Bandeamento Cromossômico , Feminino , Doenças Fetais/diagnóstico , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Deficiência Intelectual/diagnóstico , Gravidez
13.
Biomed Res Int ; 2014: 542541, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25136594

RESUMO

High throughput methods such as next generation sequencing are increasingly used in molecular diagnosis. The aim of this study was to develop a workflow for the detection of BRCA1 and BRCA2 mutations using massive parallel sequencing in a 454 GS Junior bench top sequencer. Our approach was first validated in a panel of 23 patients containing 62 unique variants that had been previously Sanger sequenced. Subsequently, 101 patients with familial breast and ovarian cancer were studied. BRCA1 and BRCA2 exon enrichment has been performed by PCR amplification using the BRCA MASTR kit (Multiplicom). Bioinformatic analysis of reads is performed with the AVA software v2.7 (Roche). In total, all 62 variants were detected resulting in a sensitivity of 100%. 71 false positives were called resulting in a specificity of 97.35%. All of them correspond to deletions located in homopolymeric stretches. The analysis of the homopolymers stretches of 6 bp or longer using the BRCA HP kit (Multiplicom) increased the specificity of the detection of BRCA1 and BRCA2 mutations to 99.99%. We show here that massive parallel pyrosequencing can be used as a diagnostic strategy to test for BRCA1 and BRCA2 mutations meeting very stringent sensitivity and specificity parameters replacing traditional Sanger sequencing with a lower cost.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Neoplasias Ovarianas/genética , Análise Mutacional de DNA/métodos , Feminino , Humanos , Sensibilidade e Especificidade
14.
Hum Mutat ; 35(4): 478-85, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24470203

RESUMO

Mandibulofacial dysostosis, Guion-Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs), and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum, and other MFDs. EFTUD2, located on 17q21.31, encodes a component of the major spliceosome and is disease causing in MFDGA, due to heterozygous loss-of-function (LoF) mutations. Here, we describe a series of 36 cases of MFDGA, including 24 previously unreported cases, and we review the literature in order to delineate the clinical spectrum ascribed to EFTUD2 LoF. MFD, external ear anomalies, and intellectual deficiency occur at a higher frequency than microcephaly. We characterize the evolution of the facial gestalt at different ages and describe novel renal and cerebral malformations. The most frequent extracranial malformation in this series is OA, followed by CHDs and skeletal abnormalities. MFDGA is probably more frequent than other syndromic MFDs such as Nager or Miller syndromes. Although the wide spectrum of malformations complicates diagnosis, characteristic facial features provide a useful handle.


Assuntos
Anormalidades Múltiplas/patologia , Anus Imperfurado/patologia , Deformidades Congênitas da Mão/patologia , Perda Auditiva Bilateral/patologia , Deficiência Intelectual/patologia , Disostose Mandibulofacial/patologia , Microcefalia/patologia , Oftalmoplegia/patologia , Fatores de Alongamento de Peptídeos/genética , Fatores de Alongamento de Peptídeos/metabolismo , Ribonucleoproteína Nuclear Pequena U5/genética , Ribonucleoproteína Nuclear Pequena U5/metabolismo , Trombocitopenia/patologia , Anormalidades Múltiplas/genética , Anus Imperfurado/genética , Criança , Pré-Escolar , Diagnóstico Diferencial , Orelha Externa/patologia , Feminino , Deformidades Congênitas da Mão/genética , Haploinsuficiência , Perda Auditiva Bilateral/genética , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Disostose Mandibulofacial/genética , Microcefalia/genética , Mutação , Oftalmoplegia/genética , Fenótipo , Gravidez , Diagnóstico Pré-Natal , Trombocitopenia/genética
15.
Mol Genet Genomic Med ; 2(6): 512-21, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25614873

RESUMO

Deletions in the 2p16.3 region that includes the neurexin (NRXN1) gene are associated with intellectual disability and various psychiatric disorders, in particular, autism and schizophrenia. We present three unrelated patients, two adults and one child, in whom we identified an intragenic 2p16.3 deletion within the NRXN1 gene using an oligonucleotide comparative genomic hybridization array. The three patients presented dual diagnosis that consisted of mild intellectual disability and autism and bipolar disorder. Also, they all shared a dysmorphic phenotype characterized by a long face, deep set eyes, and prominent premaxilla. Genetic analysis of family members showed two inherited deletions. A comprehensive neuropsychological examination of the 2p16.3 deletion carriers revealed the same phenotype, characterized by anxiety disorder, borderline intelligence, and dysexecutive syndrome. The cognitive pattern of dysexecutive syndrome with poor working memory and reduced attention switching, mental flexibility, and verbal fluency was the same than those of the adult probands. We suggest that in addition to intellectual disability and psychiatric disease, NRXN1 deletion is a risk factor for a characteristic cognitive and dysmorphic profile. The new cognitive phenotype found in the 2p16.3 deletion carriers suggests that 2p16.3 deletions might have a wide variable expressivity instead of incomplete penetrance.

16.
Prenat Diagn ; 24(11): 908-12, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15565586

RESUMO

OBJECTIVE: To investigate outcomes of ultrasound investigations (US) and invasive diagnostic procedures in cases of congenital malformations (CM), and to compare the use of invasive prenatal test techniques (amniocentesis (AC) versus chorionic villus sampling (CVS)) among European populations. DESIGN: Analysis of data from population-based registries of CM. SUBJECTS: 25 400 cases of CM recorded by 14 EUROCAT registries covering a total population of 1,013,352 births 1995-99. RESULTS: US were performed in 91% of cases, and positively detected CM in 35% of cases. AC was performed in 24% of the cases and CVS in 3% of cases. Thirty-eight percent of invasive tests gave positive results. Fifty-two percent of cases with maternal age > or = 35 years had an invasive test performed compared to 20% of cases with younger mothers. Considerable variation was found between registries in the uptake rate of invasive tests in cases with older maternal age and on the use of invasive tests with only four regions employing CVS techniques in at least a third of the cases having invasive tests. For chromosomal anomalies US gave positive results in 46% of cases with maternal age < 35 years with US performed and in 36% of cases with maternal age > or = 35 years with US performed. CONCLUSION: Prenatal US was performed in 91% of all pregnancies with CM but the test was only positive in a third of the cases. There was large regional variation in the uptake rate of invasive tests with maternal age of 35 years or more. For every CVS carried out there were nine AC tests. US is an important tool in the prenatal diagnosis of chromosomal anomalies in Europe.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/epidemiologia , Aberrações Cromossômicas , Avaliação de Resultados (Cuidados de Saúde) , Diagnóstico Pré-Natal/estatística & dados numéricos , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/etiologia , Adulto , Europa (Continente)/epidemiologia , Feminino , Humanos , Idade Materna , Registros Médicos , Valor Preditivo dos Testes , Gravidez , Diagnóstico Pré-Natal/métodos , Sistema de Registros , Ultrassonografia Pré-Natal/métodos , Ultrassonografia Pré-Natal/estatística & dados numéricos
17.
Am J Med Genet A ; 129A(1): 16-20, 2004 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-15266609

RESUMO

This study evaluated the prenatal diagnosis of Turner syndrome by ultrasound examination in an unselected population from all over Europe. Data from 19 congenital malformation registries from 11 European countries were analyzed. Turner syndrome was diagnosed in 125 cases (7.2%) in a total of 1,738 chromosome abnormalities. Sixty-seven percent of cases were detected prenatally by ultrasound examination due to the presence of congenital defects. The most frequent anomalies were cystic hygroma (59.5%) and hydrops fetalis (19%). The most frequent karyotype was 45,X (81.6%) followed by different types of mosaicism (16.8%). Significant differences in congenital defects (P = 0.0003) were observed between 45,X karyotypes and 45,X mosaicism cases. Prenatal counseling for 45,X mosaicism should take into account the expectation of a milder phenotype. In 78.6% of cases diagnosed by ultrasound examination due to congenital anomalies, the pregnancy was terminated. Prenatal detection of Turner syndrome by ultrasound examination was high in this unselected population.


Assuntos
Síndrome de Turner/diagnóstico , Ultrassonografia Pré-Natal/normas , Adolescente , Adulto , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/diagnóstico por imagem , Europa (Continente) , Feminino , Idade Gestacional , Humanos , Cariotipagem , Idade Materna , Gravidez , Sistema de Registros/estatística & dados numéricos , Sensibilidade e Especificidade , Síndrome de Turner/diagnóstico por imagem , Síndrome de Turner/genética , Ultrassonografia Pré-Natal/métodos
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