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1.
Clin Genet ; 106(3): 234-246, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38561231

RESUMO

Xq28 int22h-1/int22h-2 duplication is the result of non-allelic homologous recombination between int22h-1/int22h-2 repeats separated by 0.5 Mb. It is responsible for a syndromic form of intellectual disability (ID), with recurrent infections and atopic diseases. Minor defects, nonspecific facial dysmorphic features, and overweight have also been described. Half of female carriers have been reported with ID, whereas all reported evaluated born males present mild to moderate ID, suggesting complete penetrance. We collected data on 15 families from eight university hospitals. Among them, 40 patients, 21 females (one fetus), and 19 males (two fetuses), were carriers of typical or atypical Xq28 int22h-1/int22h-2 duplication. Twenty-one individuals were considered asymptomatic (16 females and 5 males), without significantly higher rate of recurrent infections, atopia, overweight, or facial dysmorphism. Approximately 67% live-born males and 23% live-born female carriers of the typical duplication did not have obvious signs of intellectual disability, suggesting previously undescribed incomplete penetrance or low expression in certain carriers. The possibility of a second-hit or modifying factors to this possible susceptibility locus is yet to be studied but a possible observational bias should be considered in assessing such challenging X-chromosome copy number gains. Additional segregation studies should help to quantify this newly described incomplete penetrance.


Assuntos
Cromossomos Humanos X , Deficiência Intelectual , Penetrância , Humanos , Masculino , Feminino , Cromossomos Humanos X/genética , Deficiência Intelectual/genética , Criança , Adulto , Adolescente , Pré-Escolar , Fenótipo , Duplicação Cromossômica/genética , Duplicação Gênica , Linhagem , Adulto Jovem
2.
Hum Mutat ; 42(7): 811-817, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33993607

RESUMO

Heterozygous intragenic loss-of-function mutations of ERF, encoding an ETS transcription factor, were previously reported to cause a novel craniosynostosis syndrome, suggesting that ERF is haploinsufficient. We describe six families harboring heterozygous deletions including, or near to, ERF, of which four were characterized by whole-genome sequencing and two by chromosomal microarray. Based on the severity of associated intellectual disability (ID), we identify three categories of ERF-associated deletions. The smallest (32 kb) and only inherited deletion included two additional centromeric genes and was not associated with ID. Three larger deletions (264-314 kb) that included at least five further centromeric genes were associated with moderate ID, suggesting that deletion of one or more of these five genes causes ID. The individual with the most severe ID had a more telomerically extending deletion, including CIC, a known ID gene. Children found to harbor ERF deletions should be referred for craniofacial assessment, to exclude occult raised intracranial pressure.


Assuntos
Cromossomos Humanos Par 19 , Deficiência Intelectual , Criança , Deleção Cromossômica , Haploinsuficiência , Heterozigoto , Humanos , Deficiência Intelectual/genética , Mutação , Proteínas Repressoras/genética
3.
Clin Genet ; 100(4): 396-404, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34176129

RESUMO

Ephrin receptor and their ligands, the ephrins, are widely expressed in the developing brain. They are implicated in several developmental processes that are crucial for brain development. Deletions in genes encoding for members of the Eph/ephrin receptor family were reported in several neurodevelopmental disorders. The ephrin receptor A7 gene (EPHA7) encodes a member of ephrin receptor subfamily of the protein-tyrosine kinase family. EPHA7 plays a role in corticogenesis processes, determines brain size and shape, and is involved in development of the central nervous system. One patient only was reported so far with a de novo deletion encompassing EPHA7 in 6q16.1. We report 12 additional patients from nine unrelated pedigrees with similar deletions. The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance. Four patients had tiny deletions involving only EPHA7, suggesting a critical role of EPHA7 in a neurodevelopmental disability phenotype. We provide further evidence for EPHA7 deletion as a risk factor for neurodevelopmental disorder and delineate its clinical phenotype.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Haploinsuficiência , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Receptor EphA7/genética , Cromossomos Humanos Par 6 , Hibridização Genômica Comparativa , Feminino , Estudos de Associação Genética/métodos , Humanos , Hibridização in Situ Fluorescente , Padrões de Herança , Masculino , Mutação , Linhagem , Sequenciamento do Exoma
4.
Neurogenetics ; 21(1): 67-72, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31823155

RESUMO

Microdeletions encompassing 14q11.2 locus, involving SUPT16H and CHD8, were shown to cause developmental delay, intellectual disability, autism spectrum disorders and macrocephaly. Variations leading to CHD8 haploinsufficiency or loss of function were also shown to lead to a similar phenotype. Recently, a 14q11.2 microduplication syndrome, encompassing CHD8 and SUPT16H, has been described, highlighting the importance of a tight control of at least CHD8 gene-dosage for a normal development. There have been only a few reports of 14q11.2 microduplications. Patients showed variable neurodevelopmental issues of variable severity. Breakpoints of the microduplications were non-recurrent, making interpretation of the CNV and determination of their clinical relevance difficult. Here, we report on two patients with 14q11.2 microduplication encompassing CHD8 and SUPT16H, one of whom had normal intelligence. Review of previous reports describing patients with comparable microduplications allowed for a more precise delineation of the condition and widening of the phenotypic spectrum.


Assuntos
Encéfalo/patologia , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Duplicação Gênica , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Fatores de Transcrição/genética , Encéfalo/diagnóstico por imagem , Criança , Feminino , Humanos , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Fenótipo
5.
Am J Med Genet B Neuropsychiatr Genet ; 177(4): 397-405, 2018 06.
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.


Assuntos
Cromossomos Humanos Par 2/genética , Deficiências do Desenvolvimento/genética , Transtornos Mentais/genética , Adolescente , Adulto , Criança , Pré-Escolar , Aberrações Cromossômicas , Deleção Cromossômica , Duplicação Cromossômica , Variações do Número de Cópias de DNA/genética , Feminino , Duplicação Gênica/genética , Humanos , Deficiência Intelectual/genética , Masculino , Fenótipo , Reino Unido
6.
Am J Med Genet A ; 173(6): 1690-1693, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28398607

RESUMO

Wilm's tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome, a rare genetic disorder, is caused by the loss of 11p13 region including PAX6 and WT1. We report novel findings in a 28-month-old boy with aniridia, Wilm's tumor, congenital hypothyroidism, and sublingual thyroid ectopia. He was found to have a mosaic 5.28 Mb interstitial deletion of chromosome 11p13 deleting PAX6 and WT1. In order to clarify the mechanism underlying his thyroid dysgenesis, sequence analysis of candidate thyroid developmental genes was performed. We identified a FOXE1: c.532_537delGCCGCC p.(Ala178_Ala179del) variant that predisposes to thyroid ectopia. Taken together, this is the first report of mosaic 11p13 deletion in association with thyroid dysgenesis. We also propose a model of complex interactions of different genetic variants for this particular phenotype in the present patient.


Assuntos
Hipotireoidismo Congênito/genética , Fatores de Transcrição Forkhead/genética , Disgenesia da Tireoide/genética , Síndrome WAGR/genética , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 11 , Hipotireoidismo Congênito/fisiopatologia , Humanos , Hibridização in Situ Fluorescente , Masculino , Mosaicismo , Fator de Transcrição PAX6/genética , Fenótipo , Disgenesia da Tireoide/fisiopatologia , Síndrome WAGR/fisiopatologia , Proteínas WT1/genética
7.
Am J Hematol ; 88(4): 306-11, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23460398

RESUMO

Germline heterozygous alterations of the tumor-suppressor gene neurofibromatosis-1 (NF1) lead to neurofibromatosis type 1, a genetic disorder characterized by a higher risk to develop juvenile myelomonocytic leukemia and/or acute myeloid leukemia (AML). More recently, somatic 17q11 deletions encompassing NF1 have been described in many adult myeloid malignancies. In this context, we aimed to define NF1 involvement in AML. We screened a total of 488 previously untreated de novo AML patients for the NF1 deletion using either array comparative genomic hybridization (aCGH) or real-time quantitative PCR/fluorescence in situ hybridization approaches. We also applied massively parallel sequencing for in depth mutation analysis of NF1 in 20 patients including five NF1-deleted patients. We defined a small ∼0.3 Mb minimal deleted region involving NF1 by aCGH and an overall frequency of NF1 deletion of 3.5% (17/485). NF1 deletion is significantly associated with unfavorable cytogenetics and with monosomal karyotype notably. We discovered six NF1 variants of unknown significance in 7/20 patients of which only one out of four disappeared in corresponding complete remission sample. In addition, only one out of five NF1-deleted patients has an acquired coding mutation in the remaining allele. In conclusion, direct NF1 inactivation is infrequent in de novo AML and may be a secondary event probably involved in leukemic progression.


Assuntos
Deleção de Genes , Leucemia Mieloide Aguda/genética , Neurofibromatose 1/genética , Neurofibromina 1/genética , Adolescente , Adulto , Idoso , Alelos , Hibridização Genômica Comparativa , Feminino , Frequência do Gene , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Neurofibromina 1/deficiência , Reação em Cadeia da Polimerase em Tempo Real
8.
Eur J Hum Genet ; 26(10): 1497-1501, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29899371

RESUMO

Helsmoortel-van der Aa (SWI/SNF autism-related or ADNP syndrome) is an autosomal dominant monogenic syndrome caused by de novo variants in the last exon of ADNP gene and no deletions have been documented to date. We report the first case of a 3 years and 10 months old boy exhibiting typical features of ADNP syndrome, including intellectual disability, autistic traits, facial dysmorphism, hyperlaxity, mood disorder, behavioral problems, and severe chronic constipation. 60K Agilent array-comparative genomic hybridization (CGH) identified a heterozygous interstitial microdeletion at 20q13.13 chromosome region, encompassing ADNP and DPM1. Taking into account the clinical phenotype of previously reported cases with ADNP single-point variants, genotype-phenotype correlation in the proband was established and the diagnosis of Helsmoortel-van der Aa syndrome was made. Our report thus confirms that ADNP haploinsufficiency is associated with Helsmoortel-van der Aa syndrome as well as highlights the utility of whole-genome array-CGH for detection of unbalanced submicroscopic chromosomal rearrangements in routine clinical setting in patients with unexplained intellectual disability and/or syndromic autism.


Assuntos
Transtorno Autístico/genética , Deleção Cromossômica , Proteínas de Homeodomínio/genética , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Transtorno Autístico/fisiopatologia , Pré-Escolar , Cromossomos Humanos Par 20/genética , Hibridização Genômica Comparativa , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Manosiltransferases/genética , Fenótipo
9.
Oncotarget ; 9(5): 6478-6489, 2018 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-29464086

RESUMO

Acute myeloid leukemia (AML) with t(8;21) and inv(16), together referred as core binding factor (CBF)-AML, are recognized as unique entities. Both rearrangements share a common pathophysiology, the disruption of the CBF, and a relatively good prognosis. Experiments have demonstrated that CBF rearrangements were insufficient to induce leukemia, implying the existence of cooperating events. To explore these aberrations, we performed single nucleotide polymorphism (SNP)-array in a well-annotated cohort of 198 patients with CBF-AML. Excluding breakpoint-associated lesions, the most frequent events included loss of a sex chromosome (53%), deletions at 9q21 (12%) and 7q36 (9%) in patients with t(8;21) compared with trisomy 22 (13%), trisomy 8 (10%) and 7q36 deletions (12%) in patients with inv(16). SNP-array revealed novel recurrent genetic alterations likely to be involved in CBF-AML leukemogenesis. ZBTB7A mutations (20% of t(8;21)-AML) were shown to be a target of copy-neutral losses of heterozygosity (CN-LOH) at chromosome 19p. FOXP1 focal deletions were identified in 5% of inv(16)-AML while sequence analysis revealed that 2% carried FOXP1 truncating mutations. Finally, CCDC26 disruption was found in both subtypes (4.5% of the whole cohort) and possibly highlighted a new lesion associated with aberrant tyrosine kinase signaling in this particular subtype of leukemia.

10.
Ann Biol Clin (Paris) ; 74(5): 511-515, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27477825

RESUMO

Cytogenetic evaluation is one the most important criteria for diagnosis and response to treatment in chronic myeloid leukemia, and recent baseline prognostic factors including particular additional clonal cytogenetic abnormalities have been established. The French cytogenetic group in hematology GFCH proposes here an updating of recommendations for cytogenetic assessment of CML in the era of tyrosine kinase inhibitors.


Assuntos
Análise Citogenética/normas , Hematologia/normas , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Aberrações Cromossômicas , Análise Citogenética/métodos , Análise Citogenética/tendências , França , Hematologia/organização & administração , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Monitorização Fisiológica/métodos , Monitorização Fisiológica/normas , Sociedades Médicas , Translocação Genética
11.
Expert Rev Hematol ; 8(1): 43-56, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25348871

RESUMO

Core-binding factor acute myeloid leukemia (CBF-AML) - including AML with t(8;21) and AML with inv(16) - accounts for about 15% of adult AML and is associated with a relatively favorable prognosis. Nonetheless, relapse incidence may reach 40% in these patients. In this context, identification of prognostic markers is considered of great interest. Due to similarities between their molecular and prognostic features, t(8;21) and inv(16)-AML are usually grouped and reported together in clinical studies. However, considerable experimental evidences have highlighted that they represent two distinct entities and should be considered separately for further studies. This review summarizes recent laboratory and clinical findings in this particular subset of AML and how they could be used to improve management of patients in routine practice.


Assuntos
Fatores de Ligação ao Core/metabolismo , Leucemia Mieloide Aguda/metabolismo , Animais , Fatores de Ligação ao Core/genética , Humanos , Leucemia Mieloide Aguda/genética , Prognóstico
12.
Clin Case Rep ; 3(10): 814-6, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26509013

RESUMO

Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with poor prognosis that should be investigated in routine practice. Single-nucleotide polymorphism (SNP)-array provides a useful method to detect such cases showing a highly characteristic profile.

13.
Eur J Med Genet ; 56(2): 88-92, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23202277

RESUMO

Split-hand/foot malformation (SHFM) with long-bone deficiency (SHFLD, MIM#119100) is a rare condition characterised by SHFM associated with long-bone malformation usually involving the tibia. Previous published data reported several unrelated patients with 17p13.3 duplication and SHFLD. Recently, BHLHA9 has been proposed to be the major candidate gene responsible for this limb malformation. Here we report two new patients affected with ectrodactyly harbouring a 17p13.3 duplication detected by array-CGH. Both duplications contain 3 genes including BHLHA9 and are inherited from an unaffected parent. One of the patients presents a complete radial agenesis, expanding the phenotype of SHFLD3.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Duplicação Gênica , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/genética , Fenótipo , Pré-Escolar , Cromossomos Humanos Par 17 , Hibridização Genômica Comparativa , Feminino , Humanos , Lactente , Masculino , Recombinação Genética , Tíbia/anormalidades
14.
Eur J Med Genet ; 56(3): 163-70, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23279911

RESUMO

The increased use of array-CGH and SNP-arrays for genetic diagnosis has led to the identification of new microdeletion/microduplication syndromes and enabled genotype-phenotype correlations to be made. In this study, nine patients with 9q21 deletions were investigated and compared with four previously Decipher reported patients. Genotype-phenotype comparisons of 13 patients revealed several common major characteristics including significant developmental delay, epilepsy, neuro-behavioural disorders and recognizable facial features including hypertelorism, feature-less philtrum, and a thin upper lip. The molecular investigation identified deletions with different breakpoints and of variable lengths, but the 750 kb smallest overlapping deleted region includes four genes. Among these genes, RORB is a strong candidate for a neurological phenotype. To our knowledge, this is the first published report of 9q21 microdeletions and our observations strongly suggest that these deletions are responsible for a new genetic syndrome characterised by mental retardation with speech delay, epilepsy, autistic behaviour and moderate facial dysmorphy.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 9/genética , Epilepsia/genética , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Anormalidades Múltiplas/genética , Adolescente , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Microanálise por Sonda Eletrônica , Feminino , Estudos de Associação Genética , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular , Cariótipo , Masculino , Análise em Microsséries , Proteínas de Neoplasias/genética , Membro 2 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Fenótipo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Pró-Proteína Convertases/genética , Proteínas/genética , Serina Endopeptidases/genética , Canais de Cátion TRPM/genética
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