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1.
Hum Mutat ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31502745

RESUMO

Congenital limb malformations (CLM) comprise many conditions affecting limbs and more than 150 associated genes have been reported. Due to this large heterogeneity, a high proportion of patients remains without a molecular diagnosis. In the last two decades, advances in high throughput sequencing have allowed new methodological strategies in clinical practice. Herein, we report the screening of 52 genes/regulatory sequences by multiplex high-throughput targeted sequencing, in a series of 352 patients affected with various CLM, over a 3-year period of time. Patients underwent a clinical triage by expert geneticists in CLM. A definitive diagnosis was achieved in 35.2% of patients, the yield varying considerably, depending on the phenotype. We identified 112 single nucleotide variants and 26 copy-number variations, of which 52 are novel pathogenic or likely pathogenic variants. In 6% of patients, variants of uncertain significance have been found in good candidate genes. We showed that multiplex targeted high-throughput sequencing works as an efficient and cost-effective tool in clinical practice for molecular diagnosis of congenital limb malformations. Careful clinical evaluation of patients may maximize the yield of CLM panel testing.

2.
Eur J Hum Genet ; 27(3): 360-368, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30552424

RESUMO

Holt-Oram syndrome (HOS) is an autosomal dominant condition characterised by the association of congenital heart defect (CHD), with or without rhythm disturbances and radial defects, due to TBX5 variants. The diagnosis is challenged by the variability of expression and the large phenotypic overlap with other conditions, like Okihiro syndrome, TAR syndrome or Fanconi disease. We retrospectively reviewed 212 patients referred for suspicion of HOS between 2002 and 2014, who underwent TBX5 screening. A TBX5 variant has been identified in 78 patients, representing the largest molecular series ever described. In the cohort, 61 met the previously described diagnostic criteria and 17 have been considered with an uncertain HOS diagnosis. A CHD was present in 91% of the patients with a TBX5 variant, atrial septal defects being the most common (61.5%). The genotype-phenotype study highlights the importance of some critical features in HOS: the septal characteristic of the CHD, the bilateral and asymmetric characteristics of the radial defect and the presence of shoulder or elbow mobility defect. Besides, 21 patients presented with an overlapping condition. Among them, 13 had a typical HOS presentation. We discuss the strategies that could be adopted to improve the molecular delineation of the remaining typical patients.


Assuntos
Anormalidades Múltiplas/genética , Cardiopatias Congênitas/genética , Comunicação Interatrial/genética , Deformidades Congênitas das Extremidades Inferiores/genética , Fenótipo , Proteínas com Domínio T/genética , Deformidades Congênitas das Extremidades Superiores/genética , Anormalidades Múltiplas/patologia , Diagnóstico Diferencial , Cardiopatias Congênitas/patologia , Comunicação Interatrial/patologia , Humanos , Lactente , Deformidades Congênitas das Extremidades Inferiores/patologia , Mutação , Deformidades Congênitas das Extremidades Superiores/patologia
3.
Am J Med Genet B Neuropsychiatr Genet ; 177(4): 397-405, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29603867

RESUMO

Recurrent deletions and duplications at the 2q13 locus have been associated with developmental delay (DD) and dysmorphisms. We aimed to undertake detailed clinical characterization of individuals with 2q13 copy number variations (CNVs), with a focus on behavioral and psychiatric phenotypes. Participants were recruited via the Unique chromosomal disorder support group, U.K. National Health Service Regional Genetics Centres, and the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) database. A review of published 2q13 patient case reports was undertaken to enable combined phenotypic analysis. We present a new case series of 2q13 CNV carriers (21 deletion, 4 duplication) and the largest ever combined analysis with data from published studies, making a total of 54 deletion and 23 duplication carriers. DD/intellectual disabilities was identified in the majority of carriers (79% deletion, 70% duplication), although in the new cases 52% had an IQ in the borderline or normal range. Despite the median age of the new cases being only 9 years, 64% had a clinical psychiatric diagnosis. Combined analysis found attention deficit hyperactivity disorder (ADHD) to be the most frequent diagnosis (48% deletion, 60% duplication), followed by autism spectrum disorders (33% deletion, 17% duplication). Aggressive (33%) and self-injurious behaviors (33%) were also identified in the new cases. CNVs at 2q13 are typically associated with DD with mildly impaired intelligence, and a high rate of childhood psychiatric diagnoses-particularly ADHD. We have further characterized the clinical phenotype related to imbalances of the 2q13 region and identified it as a region of interest for the neurobiological investigation of ADHD.

4.
Eur J Hum Genet ; 26(1): 85-93, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29184170

RESUMO

Syndromes caused by copy number variations are described as reciprocal when they result from deletions or duplications of the same chromosomal region. When comparing the phenotypes of these syndromes, various clinical features could be described as reversed, probably due to the opposite effect of these imbalances on the expression of genes located at this locus. The NFIX gene codes for a transcription factor implicated in neurogenesis and chondrocyte differentiation. Microdeletions and loss of function variants of NFIX are responsible for Sotos syndrome-2 (also described as Malan syndrome), a syndromic form of intellectual disability associated with overgrowth and macrocephaly. Here, we report a cohort of nine patients harboring microduplications encompassing NFIX. These patients exhibit variable intellectual disability, short stature and small head circumference, which can be described as a reversed Sotos syndrome-2 phenotype. Strikingly, such a reversed phenotype has already been described in patients harboring microduplications encompassing NSD1, the gene whose deletions and loss-of-function variants are responsible for classical Sotos syndrome. Even though the type/contre-type concept has been criticized, this model seems to give a plausible explanation for the pathogenicity of 19p13 microduplications, and the common phenotype observed in our cohort.

5.
Eur J Hum Genet ; 25(8): 1011-1014, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28589944

RESUMO

CHES (cerebellar hypoplasia with endosteal sclerosis) syndrome (OMIM#213002) associates hypomyelination, cerebellar atrophy, hypogonadism and hypodontia. So far, only five patients have been described. The condition is of neonatal onset. Patients have severe psychomotor delay and moderate to severe intellectual disability. Inheritance is assumed to be autosomal recessive due to recurrence in sibs, consanguinity of parents and absence of vertical transmission. CHES syndrome is reminiscent of 4H-leukodystrophy, a recessive-inherited affection due to variations in genes encoding subunits of the RNA polymerase III (POLR3A-POLR3B-POLR1C). POLR3B variants have been identified in one CHES patient. Here we report on a novel CHES patient, carrying compound heterozygous variations in POLR3B. This report confirms affiliation of CHES to POLR3-related disorders and suggests that CHES syndrome represents a severe form of 4H-leukodystrophy.


Assuntos
Ataxia Cerebelar/genética , Osteosclerose/genética , RNA Polimerase III/genética , Adolescente , Ataxia Cerebelar/diagnóstico , Heterozigoto , Humanos , Masculino , Mutação de Sentido Incorreto , Osteosclerose/diagnóstico
6.
Genet Med ; 19(9): 1013-1021, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28301459

RESUMO

PURPOSE: Blepharocheilodontic (BCD) syndrome is a rare autosomal dominant condition characterized by eyelid malformations, cleft lip/palate, and ectodermal dysplasia. The molecular basis of BCD syndrome remains unknown. METHODS: We recruited 11 patients from 8 families and performed exome sequencing for 5 families with de novo BCD syndrome cases and targeted Sanger sequencing in the 3 remaining families. RESULTS: We identified five CDH1 heterozygous missense mutations and three CTNND1 heterozygous truncating mutations leading to loss-of-function or haploinsufficiency. Establishment of detailed genotype-phenotype correlations was not possible because of the size of the cohort; however, the phenotype seems to appear more severe in case of CDH1 mutations. Functional analysis of CDH1 mutations confirmed their deleterious impact and suggested accelerated E-cadherin degradation. CONCLUSION: Mutations in CDH1 encoding the E-cadherin were previously reported in hereditary diffuse gastric cancer as well as in nonsyndromic cleft lip/palate. Mutations in CTNND1 have never been reported before. The encoded protein, p120ctn, prevents E-cadherin endocytosis and stabilizes its localization at the cell surface. Conditional deletion of Cdh1 and Ctnnd1 in various animal models induces features reminiscent of BCD syndrome and underlines critical role of the E-cadherin-p120ctn interaction in eyelid, craniofacial, and tooth development. Our data assert BCD syndrome as a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1 and widen the phenotypic spectrum of E-cadherin anomalies.Genet Med advance online publication 09 March 2017.


Assuntos
Caderinas/genética , Cateninas/genética , Fenda Labial/diagnóstico , Fenda Labial/genética , Fissura Palatina/diagnóstico , Fissura Palatina/genética , Ectrópio/diagnóstico , Ectrópio/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/genética , Antígenos CD , Caderinas/química , Caderinas/metabolismo , Cateninas/química , Cateninas/metabolismo , Linhagem Celular , Fenda Labial/metabolismo , Fissura Palatina/metabolismo , Biologia Computacional , Análise Mutacional de DNA , Ectrópio/metabolismo , Éxons , Facies , Feminino , Expressão Gênica , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Modelos Moleculares , Linhagem , Fenótipo , Conformação Proteica , Transporte Proteico , Anormalidades Dentárias/metabolismo
7.
Eur J Med Genet ; 58(3): 140-7, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25596525

RESUMO

Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients. This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease). Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, 'de novo' microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients. Our results support the hypothesis that 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia/genética , Cardiopatias/genética , Deficiência Intelectual/genética , Transtornos Mentais/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Pré-Escolar , Aberrações Cromossômicas , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Estudos de Coortes , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/diagnóstico , Epilepsia/diagnóstico , Feminino , Cardiopatias/congênito , Cardiopatias/diagnóstico , Humanos , Hibridização in Situ Fluorescente , Lactente , Deficiência Intelectual/diagnóstico , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Transtornos Mentais/diagnóstico , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Fenótipo , Distúrbios da Fala/genética , Adulto Jovem
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