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1.
Hum Mutat ; 40(8): 1057-1062, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31033088

RESUMO

Moebius syndrome (MBS) is a congenital disorder caused by paralysis of the facial and abducens nerves. Although a number of candidate genes have been suspected, so far only mutations in PLXND1 and REV3L are confirmed to cause MBS. Here, we fine mapped the breakpoints of a complex chromosomal rearrangement (CCR) 46,XY,t(7;8;11;13) in a patient with MBS, which revealed 41 clustered breakpoints with typical hallmarks of chromothripsis. Among 12 truncated protein-coding genes, SEMA3A is known to bind to the MBS-associated PLXND1. Intriguingly, the CCR also truncated PIK3CG, which in silico interacts with REVL3 encoded by the other known MBS-gene REV3L, and with the SEMA3A/PLXND1 complex via FLT1. Additional studies of other complex rearrangements may reveal whether the multiple breakpoints in germline chromothripsis may predispose to complex multigenic disorders.

2.
Eur J Hum Genet ; 27(8): 1296-1303, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30903111

RESUMO

Family studies have established that the heritability of blood pressure is significant and genome-wide association studies (GWAS) have identified numerous susceptibility loci, including one within the non-coding part of Rho GTPase-activating protein 42 gene (ARHGAP42) on chromosome 11q22.1. Arhgap42-deficient mice have significantly elevated blood pressure, but the phenotypic effects of human variants in the coding part of the gene are unknown. In a Danish cohort of carriers with apparently balanced chromosomal rearrangements, we identified a family where a reciprocal translocation t(11;18)(q22.1;q12.2) segregated with hypertension and obesity. Clinical re-examination revealed that four carriers (age 50-77 years) have had hypertension for several years along with an increased body mass index (34-43 kg/m2). A younger carrier (age 23 years) had normal blood pressure and body mass index. Mapping of the chromosomal breakpoints with mate-pair and Sanger sequencing revealed truncation of ARHGAP42. A decreased expression level of ARHGAP42 mRNA in the blood was found in the translocation carriers relative to controls and allele-specific expression analysis showed monoallelic expression in the translocation carriers, confirming that the truncated allele of ARHGAP42 was not expressed. These findings support that haploinsufficiency of ARHGAP42 leads to an age-dependent hypertension. The other breakpoint truncated a regulatory domain of the CUGBP Elav-like family member 4 (CELF4) gene on chromosome 18q12.2 that harbours several GWAS signals for obesity. We thereby provide additional support for an obesity locus in the CELF4 domain.

3.
Am J Hum Genet ; 104(2): 213-228, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639323

RESUMO

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

4.
Nat Genet ; 50(10): 1442-1451, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30224647

RESUMO

The etiological spectrum of ultra-rare developmental disorders remains to be fully defined. Chromatin regulatory mechanisms maintain cellular identity and function, where misregulation may lead to developmental defects. Here, we report pathogenic variations in MSL3, which encodes a member of the chromatin-associated male-specific lethal (MSL) complex responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. These variants cause an X-linked syndrome affecting both sexes. Clinical features of the syndrome include global developmental delay, progressive gait disturbance, and recognizable facial dysmorphism. MSL3 mutations affect MSL complex assembly and activity, accompanied by a pronounced loss of H4K16ac levels in vivo. Patient-derived cells display global transcriptome alterations of pathways involved in morphogenesis and cell migration. Finally, we use histone deacetylase inhibitors to rebalance acetylation levels, alleviating some of the molecular and cellular phenotypes of patient cells. Taken together, we characterize a syndrome that allowed us to decipher the developmental importance of MSL3 in humans.

5.
Am J Hum Genet ; 102(6): 1090-1103, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29805044

RESUMO

The 6%-9% risk of an untoward outcome previously established by Warburton for prenatally detected de novo balanced chromosomal rearrangements (BCRs) does not account for long-term morbidity. We performed long-term follow-up (mean 17 years) of a registry-based nationwide cohort of 41 individuals carrying a prenatally detected de novo BCR with normal first trimester screening/ultrasound scan. We observed a significantly higher frequency of neurodevelopmental and/or neuropsychiatric disorders than in a matched control group (19.5% versus 8.3%, p = 0.04), which was increased to 26.8% upon clinical follow-up. Chromosomal microarray of 32 carriers revealed no pathogenic imbalances, illustrating a low prognostic value when fetal ultrasound scan is normal. In contrast, mate-pair sequencing revealed disrupted genes (ARID1B, NPAS3, CELF4), regulatory domains of known developmental genes (ZEB2, HOXC), and complex BCRs associated with adverse outcomes. Seven unmappable autosomal-autosomal BCRs with breakpoints involving pericentromeric/heterochromatic regions may represent a low-risk group. We performed independent phenotype-aware and blinded interpretation, which accurately predicted benign outcomes (specificity = 100%) but demonstrated relatively low sensitivity for prediction of the clinical outcome in affected carriers (sensitivity = 45%-55%). This sensitivity emphasizes the challenges associated with prenatal risk prediction for long-term morbidity in the absence of phenotypic data given the still immature annotation of the morbidity genome and poorly understood long-range regulatory mechanisms. In conclusion, we upwardly revise the previous estimates of Warburton to a morbidity risk of 27% and recommend sequencing of the chromosomal breakpoints as the first-tier diagnostic test in pregnancies with a de novo BCR.

6.
Am J Med Genet A ; 173(9): 2381-2394, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28650583

RESUMO

The autosomal dominant von Hippel-Lindau disease (vHL) is associated with a lifelong risk of tumor development, especially retinal and CNS hemangioblastomas, pheochromocytoma, and renal cell carcinoma. Knowledge of paediatric vHL development is limited, and current surveillance guidelines are based on expert opinions. We aimed to describe the course of vHL development in children and adolescents, focusing on age at first manifestation, manifestation frequencies, and types. The prevalence of vHL diagnosis as well as manifestations in childhood were evaluated based on 99 patients, who had started surveillance before 18 years: 37 Danish patients from the national vHL research database and 62 international patients reported in 15 articles. Overall, 70% (69 of 99) developed manifestations before 18 years (median age at first manifestation: 12 years (range: 6-17 years)). Thirty per cent (30 of 99) had developed more than one manifestation type; the most frequent were retinal (34%) and CNS (30%) hemangioblastomas. Among the 37 Danish patients, 85% (97 of 116) of their tumors were asymptomatic. Vision outcome is significantly improved in hemangioblastomas that are treated while still asymptomatic. We agree with current guidelines that retinal surveillance be performed from birth. The patients had their first CNS hemangioblastomas at the median ages of 13-14 years (range: 6-17 years). Further, 11% (4 of 37) of the Danish patients had CNS surgery in their teenage years. Although the cohort is too small to make definite conclusions about specific initiation ages, regular CNS surveillance from vHL patients' teenage years seems clinically relevant.


Assuntos
Neoplasias do Sistema Nervoso Central/fisiopatologia , Hemangioblastoma/fisiopatologia , Doença de von Hippel-Lindau/fisiopatologia , Adolescente , Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/etiologia , Criança , Dinamarca/epidemiologia , Feminino , Hemangioblastoma/epidemiologia , Hemangioblastoma/etiologia , Humanos , Masculino , Doença de von Hippel-Lindau/complicações , Doença de von Hippel-Lindau/epidemiologia
7.
Eur J Hum Genet ; 24(12): 1783-1791, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27406248

RESUMO

Variants in the ZIC3 gene are rare, but have demonstrated their profound clinical significance in X-linked heterotaxy, affecting in particular male patients with abnormal arrangement of thoracic and visceral organs. Several reports have shown relevance of ZIC3 gene variants in both familial and sporadic cases and with a predominance of mutations detected in zinc-finger domains. No studies so far have assessed the functional consequences of ZIC3 variants in an in vivo model organism. A study population of 348 patients collected over more than 10 years with a large variety of congenital heart disease including heterotaxy was screened for variants in the ZIC3 gene. Functional effects of three variants were assessed both in vitro and in vivo in the zebrafish. We identified six novel pathogenic variants (1,7%), all in either male patients with heterotaxy (n=5) or a female patient with multiple male deaths due to heterotaxy in the family (n=1). All variants were located within the zinc-finger domains or leading to a truncation before these domains. Truncating variants showed abnormal trafficking of mutated ZIC3 proteins, whereas the missense variant showed normal trafficking. Overexpression of wild-type and mutated ZIC protein in zebrafish showed full non-functionality of the two frame-shift variants and partial activity of the missense variant compared with wild-type, further underscoring the pathogenic character of these variants. Concluding, we greatly expanded the number of causative variants in ZIC3 and delineated the functional effects of three variants using in vitro and in vivo model systems.


Assuntos
Dextrocardia/genética , Deleção de Genes , Doenças Genéticas Ligadas ao Cromossomo X/genética , Síndrome de Heterotaxia/genética , Proteínas de Homeodomínio/genética , Mutação de Sentido Incorreto , Fatores de Transcrição/genética , Animais , Dextrocardia/diagnóstico , Feminino , Feto/patologia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Células HeLa , Síndrome de Heterotaxia/diagnóstico , Proteínas de Homeodomínio/metabolismo , Humanos , Recém-Nascido , Masculino , Gravidez , Transporte Proteico , Fatores de Transcrição/metabolismo , Peixe-Zebra
8.
Am J Med Genet A ; 170(11): 2934-2942, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27409573

RESUMO

17q12 deletions and duplications are two distinct, recurrent chromosomal aberrations usually diagnosed by chromosomal microarray analysis (CMA). The aberrations encompass the genes, HNF1B, LHX1, and ACACA, among others. We here describe a large national cohort of 12 phenotyped patients with 17q12 deletions and 26 phenotyped patients with 17q12 duplications. The total cohort includes 19 index patients and 19 family members. We also reviewed the literature in order to further improve the basis for the counseling. We emphasize that renal disease, learning disability, behavioral abnormalities, epilepsy, autism, schizophrenia, structural brain abnormalities, facial dysmorphism, and joint laxity are features seen in both the 17q12 deletion syndrome and the reciprocal 17q12 duplication syndrome; and we extend the list of features seen in both patient categories to include strabismus, esophageal defects, and duodenal atresia. Delayed language development, learning disability, kidney involvement, and eye dysmorphism and strabismus were the most consistently shared features among patients with 17q12 deletion. Patients with 17q12 duplications were characterized by an extremely wide phenotypic spectrum, including a variable degree of learning disabilities, delayed language development, delayed motor milestones, and a broad range of psychiatric and neurological features. This patient group also included adults achieving an academic degree. Assessing index patients and non-index patients separately, our observations illustrate that an overall milder disease burden is seen, in particular in patients with 17q12 duplications who are ascertained on the duplication rather than the phenotype. This evidence may be useful in prenatal counseling. © 2016 Wiley Periodicals, Inc.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Duplicação Cromossômica , Cromossomos Humanos Par 17 , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Dinamarca , Facies , Humanos , Lactente , Recém-Nascido , Padrões de Herança , Fenótipo , Polimorfismo de Nucleotídeo Único , Sistema de Registros , Síndrome , Adulto Jovem
9.
Eur J Hum Genet ; 24(12): 1761-1770, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27352968

RESUMO

Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C>T/p.(Arg66*)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORß), in four affected family members. In addition, two de novo variants (c.218T>C/p.(Leu73Pro); c.1249_1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5-10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia Generalizada/genética , Membro 2 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Adulto , Criança , Pontos de Quebra do Cromossomo , Deleção Cromossômica , Códon sem Sentido , Deficiências do Desenvolvimento/diagnóstico , Epilepsia Generalizada/diagnóstico , Exoma , Éxons , Feminino , Humanos , Masculino , Linhagem , Síndrome , Translocação Genética
10.
BMC Med Educ ; 16: 98, 2016 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-27012245

RESUMO

BACKGROUND: Simulation based learning environments are designed to improve the quality of medical education by allowing students to interact with patients, diagnostic laboratory procedures, and patient data in a virtual environment. However, few studies have evaluated whether simulation based learning environments increase students' knowledge, intrinsic motivation, and self-efficacy, and help them generalize from laboratory analyses to clinical practice and health decision-making. METHODS: An entire class of 300 University of Copenhagen first-year undergraduate students, most with a major in medicine, received a 2-h training session in a simulation based learning environment. The main outcomes were pre- to post- changes in knowledge, intrinsic motivation, and self-efficacy, together with post-intervention evaluation of the effect of the simulation on student understanding of everyday clinical practice were demonstrated. RESULTS: Knowledge (Cohen's d = 0.73), intrinsic motivation (d = 0.24), and self-efficacy (d = 0.46) significantly increased from the pre- to post-test. Low knowledge students showed the greatest increases in knowledge (d = 3.35) and self-efficacy (d = 0.61), but a non-significant increase in intrinsic motivation (d = 0.22). The medium and high knowledge students showed significant increases in knowledge (d = 1.45 and 0.36, respectively), motivation (d = 0.22 and 0.31), and self-efficacy (d = 0.36 and 0.52, respectively). Additionally, 90 % of students reported a greater understanding of medical genetics, 82 % thought that medical genetics was more interesting, 93 % indicated that they were more interested and motivated, and had gained confidence by having experienced working on a case story that resembled the real working situation of a doctor, and 78 % indicated that they would feel more confident counseling a patient after the simulation. CONCLUSIONS: The simulation based learning environment increased students' learning, intrinsic motivation, and self-efficacy (although the strength of these effects differed depending on their pre-test knowledge), and increased the perceived relevance of medical educational activities. The results suggest that simulations can help future generations of doctors transfer new understanding of disease mechanisms gained in virtual laboratory settings into everyday clinical practice.


Assuntos
Aconselhamento Genético , Genética Médica/educação , Interface Usuário-Computador , Currículo , Avaliação Educacional , Feminino , Humanos , Masculino , Motivação , Autoeficácia , Estudantes de Medicina/psicologia
11.
Mol Cytogenet ; 9: 11, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26855673

RESUMO

BACKGROUND: IInterstitial 21q deletions can cause a wide spectrum of symptoms depending on the size and the location of the deletion. It has previously been suggested that the long arm of chromosome 21 can be divided into three regions based on the clinical severity of the patients and deletion of the region from 32.3 Mb to 37.1 Mb was more crucial than the deletion of other regions. CASE PRESENTATION: In this study we describe a female patient with dysmorphic features, hepatomegaly, thick myocardium and psychomotor delay. Conventional karyotyping was initially interpreted as full monosomy 21, but subsequent chromosome microarray analysis suggested an approximately 18 Mb partial monosomy. Re-evaluation of the karyotype and fluorescence in situ hybridization revealed deletion of the proximal 21q11.2-q22.11 segment and insertion of 21q22.11-qter to 12qter. The deletion of the present case overlaps with two of the proposed regions including part of the proposed crucial region. CONCLUSIONS: This report emphasizes the relevance of investigating suspected full monosomies with high resolution methods and FISH in order to investigate the extent of the deletion and the presence of more complex rearrangements.

12.
Bipolar Disord ; 17(2): 205-11, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25053281

RESUMO

OBJECTIVES: Breakpoints of chromosomal abnormalities facilitate identification of novel candidate genes for psychiatric disorders. Genome-wide significant evidence supports the linkage between chromosome 17q25.3 and bipolar disorder (BD). Co-segregation of translocation t(9;17)(q33.2;q25.3) with psychiatric disorders has been reported. We aimed to narrow down these chromosomal breakpoint regions and to investigate the associations between single nucleotide polymorphisms within these regions and BD as well as schizophrenia (SZ) in large genome-wide association study samples. METHODS: We cross-linked Danish psychiatric and cytogenetic case registers to identify an individual with both t(9;17)(q33.2;q25.3) and BD. Fluorescent in situ hybridization was employed to map the chromosomal breakpoint regions of this proband. We accessed the Psychiatric Genomics Consortium BD (n = 16,731) and SZ (n = 21,856) data. Genetic associations between these disorders and single nucleotide polymorphisms within these breakpoint regions were analysed by BioQ, FORGE, and RegulomeDB programmes. RESULTS: Four protein-coding genes [coding for (endonuclease V (ENDOV), neuronal pentraxin I (NPTX1), ring finger protein 213 (RNF213), and regulatory-associated protein of mammalian target of rapamycin (mTOR) (RPTOR)] were found to be located within the 17q25.3 breakpoint region. NPTX1 was significantly associated with BD (p = 0.004), while ENDOV was significantly associated with SZ (p = 0.0075) after Bonferroni correction. CONCLUSIONS: Prior linkage evidence and our findings suggest NPTX1 as a novel candidate gene for BD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Transtorno Bipolar/genética , Proteína C-Reativa/genética , Desoxirribonuclease (Dímero de Pirimidina)/genética , Proteínas do Tecido Nervoso/genética , Esquizofrenia/genética , Ubiquitina-Proteína Ligases/genética , Adenosina Trifosfatases , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 9/genética , Família , Ligação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Hibridização in Situ Fluorescente , Polimorfismo de Nucleotídeo Único , Proteína Regulatória Associada a mTOR , Translocação Genética/genética
13.
J Med Genet ; 51(1): 21-7, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24133203

RESUMO

BACKGROUND: Since the advent of array-CGH, numerous new microdeletional syndromes have been delineated while others remain to be described. Although 3q29 subtelomeric deletion is a well-described syndrome, there is no report on 3q interstitial deletions. METHODS: We report for the first time seven patients with interstitial deletions at the 3q27.3q28 locus gathered through the Decipher database, and suggest this locus as a new microdeletional syndrome. RESULTS: The patients shared a recognisable facial dysmorphism and marfanoid habitus, associated with psychosis and mild to severe intellectual disability (ID). Most of the patients had no delay in gross psychomotor acquisition, but had severe impaired communicative and adaptive skills. Two small regions of overlap were defined. The first one, located on the 3q27.3 locus and common to all patients, was associated with psychotic troubles and mood disorders as well as recognisable facial dysmorphism. This region comprised several candidate genes including SST, considered a candidate for the neuropsychiatric findings because of its implication in interneuronal migration and differentiation processes. A familial case with a smaller deletion allowed us to define a second region of overlap at the 3q27.3q28 locus for marfanoid habitus and severe ID. Indeed, the common morphological findings in the first four patients included skeletal features from the marfanoid spectrum: scoliosis (4/4), long and thin habitus with leanness (average Body Mass Index of 15 (18.5

Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 3 , Deficiência Intelectual/genética , Transtornos do Humor/genética , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Pré-Escolar , Mapeamento Cromossômico , Hibridização Genômica Comparativa , Facies , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Masculino , Transtornos do Humor/diagnóstico , Fenótipo , Síndrome , Adulto Jovem
14.
Eur J Hum Genet ; 20(12): 1315-9, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22617346

RESUMO

Only 20 patients with deletions of 18q12.2 have been reported in the literature and the associated phenotype includes borderline intellectual disability, behavioral problems, seizures, obesity, and eye manifestations. Here, we report a male patient with a de novo translocation involving chromosomes 12 and 18, with borderline IQ, developmental and behavioral disorders, myopia, obesity, and febrile seizures in childhood. We characterized the rearrangement with Affymetrix SNP 6.0 Array analysis and next-generation mate pair sequencing and found truncation of CELF4 at 18q12.2. This second report of a patient with a neurodevelopmental phenotype and a translocation involving CELF4 supports that CELF4 is responsible for the phenotype associated with deletion of 18q12.2. Our study illustrates the utility of high-resolution genome-wide techniques in identifying neurodevelopmental and neurobehavioral genes, and it adds to the growing evidence, including a transgenic mouse model, that CELF4 is important for human brain development.


Assuntos
Deficiências do Desenvolvimento/genética , Miopia/genética , Obesidade/genética , Proteínas de Ligação a RNA/genética , Convulsões/genética , Adulto , Proteínas CELF , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 18/genética , Deficiências do Desenvolvimento/diagnóstico , Estudos de Associação Genética , Haploinsuficiência , Humanos , Masculino , Miopia/diagnóstico , Obesidade/diagnóstico , Convulsões/diagnóstico , Síndrome , Translocação Genética
15.
Am J Med Genet A ; 155A(1): 203-6, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21204233

RESUMO

Distal interstitial deletions of chromosome 14 involving the 14q24-q23.2 region are rare, and only been reported so far in 20 patients. Ten of these patients were analyzed both clinically and genetically. Here we present a de novo interstitial deletion of chromosome 14q24.3-q32.2 in a male patient with developmental delay, language impairment, plagiocephaly, BPES features (blepharophimosis, ptosis, epicanthus), and congenital heart defect. The deletion breakpoints were fine mapped using fluorescence in situ hybridization (FISH) and the size of the deletion is estimated to be approximately 23 Mb. Based on genotype-phenotype comparisons of the 10 previously published patients and the present case, we suggest that the shortest regions for deletion overlap may include candidate genes for speech impairment, mental retardation, and hypotonia.


Assuntos
Anormalidades Múltiplas/genética , Deficiências do Desenvolvimento/genética , Cardiopatias Congênitas/genética , Fenótipo , Plagiocefalia/genética , Anormalidades Múltiplas/patologia , Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Deficiências do Desenvolvimento/patologia , Cardiopatias Congênitas/patologia , Humanos , Hibridização in Situ Fluorescente , Masculino , Plagiocefalia/patologia
16.
Behav Genet ; 41(1): 125-33, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20798984

RESUMO

Dyslexia is one of the most common neurodevelopmental disorders where likely many genes are involved in the pathogenesis. So far six candidate dyslexia genes have been proposed, and two of these were identified by rare chromosomal translocations in affected individuals. By systematic re-examination of all translocation carriers in Denmark, we have identified 16 different translocations associated with dyslexia. In four families, where the translocation co-segregated with the phenotype, one of the breakpoints concurred (at the cytogenetic level) with either a known dyslexia linkage region--at 15q21 (DYX1), 2p13 (DYX3) and 1p36 (DYX8)--or an unpublished linkage region at 19q13. As a first exploitation of this unique cohort, we identify three novel candidate dyslexia genes, ZNF280D and TCF12 at 15q21, and PDE7B at 6q23.3, by molecular mapping of the familial translocation with the 15q21 breakpoint.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/genética , Dislexia/genética , Estudos de Associação Genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Translocação Genética/genética , Dedos de Zinco/genética , Adulto , Amniocentese , Criança , Mapeamento Cromossômico , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 6/genética , Estudos de Coortes , Dinamarca , Feminino , Triagem de Portadores Genéticos , Humanos , Cariotipagem , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Gravidez
17.
Am J Med Genet A ; 152A(12): 3115-9, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21082657

RESUMO

We describe a chromosome rearrangement, ins(7;13)(q32q34;q32), which segregates in a three generation family, giving rise to three individuals with an unbalanced rearrangement. Two of the individuals, a sister and a brother, were investigated further in this study. They had minor facial dysmorphism and neuropsychiatric disorders including mental retardation, language delay and epilepsy. The sister had primary amenorrhea. Array CGH revealed a 12.2 Mb deletion at 7q34-q36.2 including more than 60 genes where CNTNAP2 and NOBOX are of special interest. Comparison of the clinical and cytogenetic findings of our patients with previously reported patients, supports that haploinsuffiency of CNTNAP2 can result in language delay and/or autism spectrum disorder. Furthermore, we report on the second women with a deletion involving NOBOX who is affected by primary amenorrhea.


Assuntos
Amenorreia/genética , Deleção Cromossômica , Cromossomos Humanos Par 7 , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Adulto , Células Cultivadas , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Cromossomos Artificiais Bacterianos , Análise Citogenética/métodos , DNA/genética , Feminino , Humanos , Linfócitos/citologia , Masculino , Irmãos
18.
Am J Hum Genet ; 86(6): 839-49, 2010 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-20493459

RESUMO

Congenital heart defects (CHDs) are the most common major developmental anomalies and the most frequent cause for perinatal mortality, but their etiology remains often obscure. We identified a locus for CHDs on 6q24-q25. Genotype-phenotype correlations in 12 patients carrying a chromosomal deletion on 6q delineated a critical 850 kb region on 6q25.1 harboring five genes. Bioinformatics prioritization of candidate genes in this locus for a role in CHDs identified the TGF-beta-activated kinase 1/MAP3K7 binding protein 2 gene (TAB2) as the top-ranking candidate gene. A role for this candidate gene in cardiac development was further supported by its conserved expression in the developing human and zebrafish heart. Moreover, a critical, dosage-sensitive role during development was demonstrated by the cardiac defects observed upon titrated knockdown of tab2 expression in zebrafish embryos. To definitively confirm the role of this candidate gene in CHDs, we performed mutation analysis of TAB2 in 402 patients with a CHD, which revealed two evolutionarily conserved missense mutations. Finally, a balanced translocation was identified, cosegregating with familial CHD. Mapping of the breakpoints demonstrated that this translocation disrupts TAB2. Taken together, these data clearly demonstrate a role for TAB2 in human cardiac development.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Deleção Cromossômica , Cromossomos Humanos Par 6 , Cardiopatias Congênitas/genética , Sequência de Aminoácidos , Animais , Embrião de Mamíferos , Feminino , Técnicas de Silenciamento de Genes , Estudos de Associação Genética , Coração/embriologia , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Translocação Genética , Peixe-Zebra/embriologia
19.
Arthritis Rheum ; 62(3): 658-66, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20187158

RESUMO

OBJECTIVE: In terms of number of X chromosomes, women with Turner's syndrome cytogenetically resemble men. An increased risk of autoimmune diseases has been observed among women with Turner's syndrome. This study was undertaken to investigate whether the autoimmune disease profile in women with Turner's syndrome is characterized by diseases with a female or male predominance. METHODS: Using the Danish Cytogenetic Central Register, the Danish National Patient Register, and the Danish Civil Registration System, we estimated relative risk of 46 different autoimmune diseases in a cohort of 798 Danish women with Turner's syndrome followed up for 12,461 person-years between 1980 and 2004. Standardized incidence ratios (SIRs) of first hospitalization for autoimmune disease and 95% confidence intervals (95% CIs) were used as measures of relative risk. RESULTS: The overall risk of autoimmune disease among women with Turner's syndrome was twice that among Danish women in general (SIR 2.1 [95% CI 1.6-2.7]). For autoimmune diseases with a female predominance, the SIR among women with Turner's syndrome was 1.7 (95% CI 1.2-2.4), whereas the SIR for autoimmune diseases with a male predominance among these women was 3.9 (95% CI 2.5-5.8). Associations were strongest for Hashimoto thyroiditis (SIR 14.6 [95% CI 6.7-27.1]), a strongly female-predominant condition, and type 1 diabetes mellitus (SIR 4.1 [95% CI 2.5-6.3]). CONCLUSION: Women with Turner's syndrome are at excess risk of autoimmune diseases, notably autoimmune diseases characterized by male predominance.


Assuntos
Doenças Autoimunes/complicações , Síndrome de Turner/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
20.
Eur J Hum Genet ; 16(3): 312-9, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18183041

RESUMO

Autism spectrum disorders (ASDs) are a heterogeneous group of disorders with unknown aetiology. Even though ASDs are suggested to be among the most heritable complex disorders, only a few reproducible mutations leading to susceptibility for ASD have been identified. In an attempt to identify ASD susceptibility genes through chromosome rearrangements, we investigated a female patient with childhood autism and high-grade myopia, and an apparently balanced de novo translocation, t(5;18)(q34;q12.2). Further analyses revealed a 3.2 Mb deletion encompassing 17 genes at the 18q break point and an additional deletion of 1.27 Mb containing two genes on chromosome 4q35. Q-PCR analysis of 14 of the 17 genes deleted on chromosome 18 showed that 11 of these genes were expressed in the brain, suggesting that haploinsufficiency of one or more genes may have contributed to the childhood autism phenotype of the patient. Identification of multiple genetic changes in this patient with childhood autism agrees with the most frequently suggested genetic model of ASDs as complex, polygenic disorders.


Assuntos
Transtorno Autístico/genética , Cromossomos Humanos Par 18 , Miopia/genética , Deleção de Sequência , Adulto , Transtorno Autístico/complicações , Criança , Feminino , Humanos , Hibridização In Situ , Miopia/complicações , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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