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1.
J Med Genet ; 56(8): 526-535, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30923172

RESUMO

BACKGROUND: Balanced chromosomal rearrangements associated with abnormal phenotype are rare events, but may be challenging for genetic counselling, since molecular characterisation of breakpoints is not performed routinely. We used next-generation sequencing to characterise breakpoints of balanced chromosomal rearrangements at the molecular level in patients with intellectual disability and/or congenital anomalies. METHODS: Breakpoints were characterised by a paired-end low depth whole genome sequencing (WGS) strategy and validated by Sanger sequencing. Expression study of disrupted and neighbouring genes was performed by RT-qPCR from blood or lymphoblastoid cell line RNA. RESULTS: Among the 55 patients included (41 reciprocal translocations, 4 inversions, 2 insertions and 8 complex chromosomal rearrangements), we were able to detect 89% of chromosomal rearrangements (49/55). Molecular signatures at the breakpoints suggested that DNA breaks arose randomly and that there was no major influence of repeated elements. Non-homologous end-joining appeared as the main mechanism of repair (55% of rearrangements). A diagnosis could be established in 22/49 patients (44.8%), 15 by gene disruption (KANSL1, FOXP1, SPRED1, TLK2, MBD5, DMD, AUTS2, MEIS2, MEF2C, NRXN1, NFIX, SYNGAP1, GHR, ZMIZ1) and 7 by position effect (DLX5, MEF2C, BCL11B, SATB2, ZMIZ1). In addition, 16 new candidate genes were identified. Systematic gene expression studies further supported these results. We also showed the contribution of topologically associated domain maps to WGS data interpretation. CONCLUSION: Paired-end WGS is a valid strategy and may be used for structural variation characterisation in a clinical setting.

2.
J Med Genet ; 2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30287593

RESUMO

BACKGROUND: The clinical significance of 16p13.11 duplications remains controversial while frequently detected in patients with developmental delay (DD), intellectual deficiency (ID) or autism spectrum disorder (ASD). Previously reported patients were not or poorly characterised. The absence of consensual recommendations leads to interpretation discrepancy and makes genetic counselling challenging. This study aims to decipher the genotype-phenotype correlations to improve genetic counselling and patients' medical care. METHODS: We retrospectively analysed data from 16 013 patients referred to 12 genetic centers for DD, ID or ASD, and who had a chromosomal microarray analysis. The referring geneticists of patients for whom a 16p13.11 duplication was detected were asked to complete a questionnaire for detailed clinical and genetic data for the patients and their parents. RESULTS: Clinical features are mainly speech delay and learning disabilities followed by ASD. A significant risk of cardiovascular disease was noted. About 90% of the patients inherited the duplication from a parent. At least one out of four parents carrying the duplication displayed a similar phenotype to the propositus. Genotype-phenotype correlations show no impact of the size of the duplicated segment on the severity of the phenotype. However, NDE1 and miR-484 seem to have an essential role in the neurocognitive phenotype. CONCLUSION: Our study shows that 16p13.11 microduplications are likely pathogenic when detected in the context of DD/ID/ASD and supports an essential role of NDE1 and miR-484 in the neurocognitive phenotype. Moreover, it suggests the need for cardiac evaluation and follow-up and a large study to evaluate the aortic disease risk.

3.
Am J Med Genet A ; 170(7): 1912-7, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27119754

RESUMO

Chromosomal microarray analysis has become a powerful diagnostic tool in the investigation of patients with intellectual disability leading to the discovery of dosage sensitive genes implicated in the manifestation of various genomic disorders. Interstitial deletions of the short arm of chromosome 10 represent rare genetic abnormalities, especially those encompassing the chromosomal region 10p11-p12. To date, only 10 postnatal cases with microdeletion of this region have been described, and all patients shared a common phenotype, including intellectual disability, abnormal behavior, distinct dysmorphic features, visual impairment, and cardiac malformations. WAC was suggested to be the main candidate gene for intellectual disability associated with 10 p11-p12 deletion syndrome. Here, we describe a new case of de novo 10p11.23-p12.1 microdeletion in a patient with intellectual disability, abnormal behavior, and distinct dysmorphic features. Our observation allows us to redefine the smallest region of overlap among patients reported so far, with a size of 80 Kb and which contains only the WAC gene. These findings strengthen the hypothesis that haploinsufficency of WAC gene might be likely responsible for intellectual disability and behavior disorders. Our data also led us to propose a clinical pathway for patients with this recognizable genetic syndrome depending on the facial dysmorphisms. © 2016 Wiley Periodicals, Inc.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Transtornos Mentais/genética , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 10/genética , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/fisiopatologia , Masculino , Transtornos Mentais/fisiopatologia , Mutação
4.
Am J Med Genet A ; 167(6): 1252-61, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25847481

RESUMO

Tetrasomy 9p is a generic term describing the presence of a supernumerary chromosome incorporating two copies of the 9p arm. Two varieties exist: isodicentric chromosome 9p (i(9p)), where the two 9p arms are linked by a single centromeric region, and pseudodicentric 9p (idic(9p)), where one active and one inactive centromere are linked together by a proximal segment of 9q that may incorporate euchromatic material. In living patients, i(9p) and idic(9p) are usually present in a mosaic state. Fifty-four cases, including fetuses, have been reported, of which only two have been molecularly characterized using array-CGH. Tetrasomy 9p leads to a variable phenotype ranging from multiple congenital anomalies with severe intellectual disability and growth delay to subnormal cognitive and physical developments. Hypertelorism, abnormal ears, microretrognathia and bulbous nose are the most common dysmorphic traits. Microcephaly, growth retardation, joint dislocation, scoliosis, cardiac and renal anomalies were reported in several cases. Those physical anomalies are often, but not universally, accompanied by intellectual disability. The most recurrent breakpoints, defined by conventional cytogenetics, are 9p10, 9q12 and 9q13. We report on 12 new patients with tetrasomy 9p (3 i(9p), 8 idic(9p) and one structurally uncharacterized), including the first case of parental germline mosaicism. All rearrangements have been characterized by DNA microarray. Based on our results and a review of the literature, we further delineate the prenatal and postnatal clinical spectrum of this imbalance. Our results show poor genotype-phenotype correlations and underline the need of precise molecular characterization of the supernumerary marker.


Assuntos
Anormalidades Múltiplas/genética , Aneuploidia , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Trissomia , Anormalidades Múltiplas/patologia , Adolescente , Criança , Pré-Escolar , Bandeamento Cromossômico , Cromossomos Humanos Par 9 , Deficiências do Desenvolvimento/patologia , Feminino , Feto , Estudos de Associação Genética , Heterogeneidade Genética , Humanos , Deficiência Intelectual/patologia , Cariotipagem , Masculino , Mosaicismo , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Síndrome
6.
Am J Clin Pathol ; 142(2): 248-53, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25015868

RESUMO

OBJECTIVES: We report here the unusual association of Silver-Russell syndrome (SRS) and cerebellar dysplasia with trisomy 7 mosaicism and maternal uniparental disomy of chromosome 7 [UPD(7)m]. METHODS: Low-level trisomy 7 mosaicism was diagnosed prenatally on amniocytes, and UPD(7)m was confirmed after birth. RESULTS: Medical examination at birth showed dysmorphic facial features of SRS. Cytogenetic analysis on several tissues and cells confirmed mosaic trisomy 7. Unusual severe psychomotor retardation, hypotonia, and choreoathetoid movement were noted at 6 months. Brain magnetic resonance imaging showed both cerebellar hypoplasia and dysplasia. CONCLUSIONS: This unusual association of SRS and dysplasia of the cerebellum might be related to the presence of the trisomy 7 mosaicism on the cerebellum. Our observation strengthens the hypothesis that the phenotype observed in patients with SRS with UPD(7)m might also result from an undetected low level of trisomy 7 mosaicism that could best be revealed by performing cytogenetic investigations.


Assuntos
Encéfalo/patologia , Síndrome de Silver-Russell/genética , Trissomia/genética , Dissomia Uniparental/genética , Adulto , Cerebelo/anormalidades , Cromossomos Humanos Par 7/genética , Análise Citogenética , Deficiências do Desenvolvimento/diagnóstico , Feminino , Humanos , Mosaicismo , Malformações do Sistema Nervoso/diagnóstico , Síndrome de Silver-Russell/complicações , Síndrome de Silver-Russell/diagnóstico
7.
Am J Med Genet A ; 158A(8): 2015-20, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22753018

RESUMO

Histone deacetylase 4 (HDAC4) serves important roles in multiple human systems, including neurological, cardiac, and skeletal functions. Mutation or deletion of HDAC4 causes brachydactyly mental retardation syndrome (BDMR), a disorder that includes intellectual disability, behavioral abnormalities, autism spectrum disorder, and craniofacial and skeletal anomalies, including brachydactyly type E. We present a case of familial BDMR, including a parent with mild symptoms of the disorder and a child exhibiting a more severe phenotype. Cytogenetic testing showed a cryptic balanced translocation in the mother that resulted in a 2q37.1 monosomy and a 10q26.1 trisomy in the son. Gene expression analyses demonstrated 67% HDAC4 expression in the mother and 23% HDAC4 expression in the son relative to normal controls, lending evidence to the hypothesis that HDAC4 modulates severity of this disorder in a dosage-dependent manner.


Assuntos
Braquidactilia/genética , Histona Desacetilases/genética , Deficiência Intelectual/genética , Proteínas Repressoras/genética , Adolescente , Hibridização Genômica Comparativa , Humanos , Lactente , Masculino , Síndrome
8.
Am J Med Genet A ; 158A(3): 617-21, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22302515

RESUMO

We report on a fetus with an isolated short femur detected by ultrasound and a de novo interstitial deletion of chromosome 15. The deletion was diagnosed prenatally by karyotype and further mapped by fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (array-CGH) to bands 15q15.3 to 15q21.3 with a size of 11.11 Mb. Fetal autopsy showed characteristic minor anomalies, urinary abnormalities, and delayed bone maturation, but neither craniosynostosis, nor congenital heart defects as observed in previously reported cases. Despite the existence of ultrasound abnormalities, all five cases reported so far were diagnosed after birth. This is the first case of an interstitial deletion involving chromosomal band 15q15.3-q21.3 diagnosed prenatally and characterized at the molecular level. Our observation suggests the absence of imprinted genes in the area of 15q15-q22 and strengthens the hypothesis that a critical region for craniosynostosis may be mapped outside the deleted region in the present patient.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 15 , Fêmur/anormalidades , Diagnóstico Pré-Natal , Adulto , Hibridização Genômica Comparativa , Evolução Fatal , Feminino , Fêmur/embriologia , Humanos , Hibridização in Situ Fluorescente , Gravidez
9.
Psychiatry Res ; 197(3): 356-7, 2012 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-22365273

RESUMO

22q11.2 deletion syndrome, the most common microdeletion syndrome, exhibits a broad range of phenotypes, implying a cumbersome diagnosis due to atypical or paucisymptomatic presentations. We present two atypical cases of 22q11.2 deletion syndrome and suggest a preferential occurrence of the breakpoints in regions poor in repetitive elements of SINE/Alu family.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Hibridização Genômica Comparativa/métodos , Síndrome de DiGeorge/genética , Genoma Humano/genética , Adolescente , Adulto , Variações do Número de Cópias de DNA/genética , Síndrome de DiGeorge/diagnóstico , Feminino , Humanos , Masculino , Fenótipo , Sequências Repetitivas de Ácido Nucleico/genética
10.
Fetal Diagn Ther ; 31(1): 55-62, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22189057

RESUMO

OBJECTIVES: The aim of this study was to evaluate the relative risk of identifying fetal chromosomal anomalies after finding ultrasonographic (US) abnormalities in a high-risk population who underwent amniocentesis. METHODS: A retrospective review of a cohort of patients with single pregnancies who underwent genetic amniocentesis was undertaken. Univariate and multivariate analysis were used to determine the best correlations between US findings and chromosomal abnormalities. RESULTS: Overall, 191 chromosomal abnormalities were found in 5,604 fetuses (3.4%). Multivariate analysis showed chromosomal abnormalities were significant ly associated with anomalies of the central nervous system (OR = 4.4, 95% CI 2.2-8.7), face and neck (OR = 15.7, 95% CI 9.2-26.8), heart (OR = 5.4, 95% CI 2.6-11.2), abdomen (OR = 5.6, 95% CI 2.9-10.9), extremities (OR = 5.7, 95% CI 2.4-13.4), an increased nuchal fold (OR = 5.2, 95% CI 3.3-8.1), an intrauterine growth restriction (OR = 3.6, 95% CI 1.6-7.9) and a short femur (OR = 4.1, 95% CI 1.4-12.1). CONCLUSIONS: Our results confirm the validity of specific US markers in detecting chromosomal abnormalities in the fetus.


Assuntos
Amniocentese , Aberrações Cromossômicas/estatística & dados numéricos , Transtornos Cromossômicos/diagnóstico , Cariotipagem , Ultrassonografia Pré-Natal , Adulto , Transtornos Cromossômicos/diagnóstico por imagem , Transtornos Cromossômicos/epidemiologia , Estudos de Coortes , Feminino , Humanos , Análise Multivariada , Valor Preditivo dos Testes , Gravidez , Prevalência , Estudos Retrospectivos
11.
Eur J Med Genet ; 53(3): 127-32, 2010 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20302980

RESUMO

Numerous studies have shown that balanced reciprocal or Robertsonian translocations and inversions are associated with reduced or absent sperm production. In contrast, a similar association has been rarely reported for unbalanced translocations. An unbalanced translocation, 45,XY,-15,der(18)t(15;18)(q11.2;q23), was found in two healthy infertile brothers who were referred to our hospital together with their partners for infertility. At least two routine semen analyses and karyotyping were done for each of the brothers. Sperm meiotic segregation was studied for both with a three-color FISH assay using locus-specific probes. Semen analyses showed a severe oligo-astheno-teratozoospermia with remarkably similar profiles in the two brothers. The unbalanced translocation had a deletion of 15pter-15q11.2 as well as a deletion of 18q23-18qter. The meiotic segregation was similar in the two brothers with a prevalence of alternate segregation mode. However, no phenotypic effect in the offspring can be expected only if the normal chromosomes 15 and 18 are transmitted to progeny. According to the sperm FISH results, the theoretical probability of this happening is about 25%. Based on the overall results, genetic and reproductive counselling was offered to both couples. Finally, both couples chose the alternative of donor insemination rather than preimplantation genetic diagnosis. The present study helps delineating a phenotypically silent CNV at the distal part of chromosome 18 long arm and illustrates the advantages of an integrated multidisciplinary genetic, reproductive and psychological approach to give the best possible assistance to couples who are faced with a complex and distressing genetic cause of infertility.


Assuntos
Cromossomos Humanos Par 15 , Cromossomos Humanos Par 18 , Espermatozoides/metabolismo , Translocação Genética , Adulto , Segregação de Cromossomos , Saúde da Família , Aconselhamento Genético , Humanos , Hibridização in Situ Fluorescente , Infertilidade Masculina/genética , Cariotipagem , Masculino , Fenótipo , Técnicas de Reprodução Assistida
12.
Am J Med Genet A ; 149A(3): 437-45, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19206177

RESUMO

Inverted duplications with terminal deletions have been reported for an increasing number of chromosome ends. The best characterized and most frequent rearrangement reported involves the short arm of chromosome 8. It derives from non-allelic homologous recombination (NAHR) between two inverted LCRs (low copy repeats) of the olfactory receptor (OR) gene cluster during maternal meiosis. We report here on the cytogenetic characterization of the first inversion duplication deletion involving the short arm of chromosome 20 (inv dup del 20p) in an 18-month-old boy presenting with clinical signs consistent with 20p trisomy syndrome. This abnormality was suspected on karyotyping, but high-resolution molecular cytogenetic investigations were required to define the breakpoints of the rearrangement and to obtain insight into the mechanism underlying its formation. The duplicated region was estimated to be 18.16 Mb in size, extending from 20p13 to 20p11.22, and the size of the terminal deletion was estimated at 2.02 Mb in the 20p13 region. No single copy region was detected between the deleted and duplicated segments. As neither LCR nor inversion was identified in the 20p13 region, the inv dup del (20p) chromosome abnormality probably did not arise by NAHR. The most likely mechanism involves a break in the 20p13 region, leading to chromosome instability and reparation by U-type exchange or end-to-end fusion.


Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Inversão Cromossômica , Cromossomos Humanos Par 20/genética , Análise Citogenética , Quebra Cromossômica , Cromossomos Artificiais Bacterianos , Deficiências do Desenvolvimento/genética , Corantes Fluorescentes/metabolismo , Humanos , Hibridização in Situ Fluorescente , Indóis/metabolismo , Lactente , Deficiência Intelectual/genética , Cariotipagem , Masculino , Modelos Genéticos , Hibridização de Ácido Nucleico , Recombinação Genética , Trissomia
13.
Am J Med Genet A ; 146A(20): 2651-6, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18798330

RESUMO

Structural chromosomal abnormalities can be associated with infertility through meiosis impairment or the formation of unbalanced gametes. Among these structural abnormalities, complex chromosomal rearrangements (CCR) relate to situations with more than two breakpoints and/or more than two chromosomes involved. Mosaic balanced chromosomal rearrangements are very rare events usually ascertained through infertility, recurrent miscarriages or liveborn abnormal children. Mosaicism for complex chromosome rearrangements (CCRM) has never been described to date. Here we report on two patients with secondary infertility whose karyotype revealed mosaic partially cryptic CCRs, revealed by fluorescence in situ hybridization (FISH). To our knowledge, this is the first report of mosaicism for complex chromosomal rearrangements (CCRM). We discuss the importance of molecular cytogenetic characterization of structural rearrangements to assist in genetic counseling related to the possible use of assisted reproductive technology.


Assuntos
Inversão Cromossômica/genética , Rearranjo Gênico/genética , Mosaicismo , Translocação Genética/genética , Adulto , Aberrações Cromossômicas , Bandeamento Cromossômico , Coloração Cromossômica , Análise Citogenética , Aconselhamento Genético , Humanos , Masculino , Pessoa de Meia-Idade
14.
Prenat Diagn ; 28(4): 313-8, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18306148

RESUMO

OBJECTIVE: To evaluate the medical and economic performance of three strategies for selecting patients eligible for interphase FISH in the prenatal diagnosis of common aneuploidies. METHODS: We evaluated three protocols on the same population that was referred for prenatal diagnosis between June 2001 and December 2006. The number of aneuploidies detected by FISH and the relative cost (reagent and technical staff cost) are reported for each strategy. RESULTS: 2707 women were referred for prenatal diagnosis either because of advanced maternal age over 38 (48%), abnormal maternal serum screening (35%) or prenatal ultrasound anomalies (17%). A total of 4.8% chromosomal anomalies (balanced and unbalanced) were diagnosed after karyotyping. Theoretically, interphase FISH should have detected 79.4% of the unbalanced anomalies. We observed a significant improvement in the trisomy 21 detection by selecting the probes according to the reason for referral. The last protocol adopted, which offers a rapid test to 57% of women undergoing amniocentesis, presents the best aneuploidy detection rate (68% of total aneuploidies, 87% of trisomy 21). CONCLUSION: Selecting probes according to medical criteria patients combined with a technical procedure modification allows medico-economic improvement of interphase FISH in routine diagnosis.


Assuntos
Aneuploidia , Hibridização in Situ Fluorescente , Diagnóstico Pré-Natal/métodos , Adulto , Amniocentese , Técnicas de Apoio para a Decisão , Feminino , Testes Genéticos/economia , Humanos , Cariotipagem , Idade Materna , Gravidez , Complicações na Gravidez/genética , Estudos Retrospectivos
15.
Am J Med Genet A ; 143A(11): 1236-43, 2007 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-17497716

RESUMO

We report here on a 6-year-old boy referred to the laboratory for karyotyping and SHOX microdeletion testing. The most significant clinical findings in this boy were small stature, Madelung deformity, facial dysmorphism, mild mental retardation and behavioral problems. R-, G- and RTBG-banding chromosome analysis showed a normal male karyotype. Fine molecular characterization, by FISH, of terminal Xp microdeletion revealed an associated partial duplication. Further refinement of the molecular analysis indicated an inverted duplication of the Xp22.31-Xp22.32 (13.7 Mb) region including the STS, VCX-A and KAL1 genes, associated with a terminal Xp deletion Xp22.33-Xpter (3.6 Mb) encompassing the SHOX and ARSE genes. Such rearrangements have been characterized for other chromosomal pairs, but this is the first reported male patient involving the short arm of the X chromosome. Molecular analysis of the maternal and patient's microsatellite markers showed interchromatid mispairing leading to non-allelic homologous recombination to be the most likely mechanism underlying this rearrangement. This case highlights the importance of clinically driven FISH investigations in order to uncover cryptic micro-rearrangements.


Assuntos
Deleção Cromossômica , Inversão Cromossômica , Cromossomos Humanos Par 22/genética , Duplicação Gênica , Deficiência Intelectual/genética , Criança , Antebraço/diagnóstico por imagem , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Modelos Genéticos , Radiografia
16.
Eur J Med Genet ; 50(1): 60-5, 2007 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17071147

RESUMO

Familial transmissions of unbalanced chromosomal abnormalities are rare. We report here the first case of a maternally inherited pure partial duplication of the long arm of chromosome 6 [46,XX,dup(6)(q21q22.1)mat]. The proband was referred for karyotyping as she presented intrauterine growth retardation (IUGR), moderate mental retardation and facial dysmorphism. Molecular cytogenetics analysis with various BACs showed a duplication of 5-10 Mb between 6q21 and 6q22.1. The proband's mother was found to have the same chromosome abnormality and a similar phenotype, but less severe dysmorphism. This variability in clinical findings between generations may have several causes, including attenuation with aging, imprinting or mosaicism. Only three other cases of pure partial 6q duplication similar to that of our case have been reported. The available information for all four cases was used to refine the karyotype-phenotype correlations for duplications of the 6q21q22 segment.


Assuntos
Anormalidades Múltiplas/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 6/genética , Duplicação Gênica , Criança , Ossos Faciais/anormalidades , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Tremor/genética
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