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1.
Sci Rep ; 8(1): 17201, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30464253

RESUMO

Genetic integrity of induced pluripotent stem cells (iPSCs) is essential for their validity as disease models and for potential therapeutic use. We describe the comprehensive analysis in the ForIPS consortium: an iPSC collection from donors with neurological diseases and healthy controls. Characterization included pluripotency confirmation, fingerprinting, conventional and molecular karyotyping in all lines. In the majority, somatic copy number variants (CNVs) were identified. A subset with available matched donor DNA was selected for comparative exome sequencing. We identified single nucleotide variants (SNVs) at different allelic frequencies in each clone with high variability in mutational load. Low frequencies of variants in parental fibroblasts highlight the importance of germline samples. Somatic variant number was independent from reprogramming, cell type and passage. Comparison with disease genes and prediction scores suggest biological relevance for some variants. We show that high-throughput sequencing has value beyond SNV detection and the requirement to individually evaluate each clone.


Assuntos
Bancos de Espécimes Biológicos/normas , Técnicas de Cultura de Células/métodos , Técnicas de Cultura de Células/normas , Perfil Genético , Células-Tronco Pluripotentes Induzidas/fisiologia , Impressões Digitais de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem , Análise de Sequência de DNA
2.
Genet Med ; 20(6): 630-638, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29758562

RESUMO

PurposeShort stature is a common condition of great concern to patients and their families. Mostly genetic in origin, the underlying cause often remains elusive due to clinical and genetic heterogeneity.MethodsWe systematically phenotyped 565 patients where common nongenetic causes of short stature were excluded, selected 200 representative patients for whole-exome sequencing, and analyzed the identified variants for pathogenicity and the affected genes regarding their functional relevance for growth.ResultsBy standard targeted diagnostic and phenotype assessment, we identified a known disease cause in only 13.6% of the 565 patients. Whole-exome sequencing in 200 patients identified additional mutations in known short-stature genes in 16.5% of these patients who manifested only part of the symptomatology. In 15.5% of the 200 patients our findings were of significant clinical relevance. Heterozygous carriers of recessive skeletal dysplasia alleles represented 3.5% of the cases.ConclusionA combined approach of systematic phenotyping, targeted genetic testing, and whole-exome sequencing allows the identification of the underlying cause of short stature in at least 33% of cases, enabling physicians to improve diagnosis, treatment, and genetic counseling. Exome sequencing significantly increases the diagnostic yield and consequently care in patients with short stature.


Assuntos
Estatura/genética , Feminino , Testes Genéticos , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Análise de Sequência de DNA/métodos , Sequenciamento do Exoma/métodos
3.
Sci Rep ; 7(1): 12225, 2017 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-28939912

RESUMO

Short stature is a common pediatric disorder affecting 3% of the population. However, the clinical variability and genetic heterogeneity prevents the identification of the underlying cause in about 80% of the patients. Recently, heterozygous mutations in the ACAN gene coding for the proteoglycan aggrecan, a main component of the cartilage matrix, were associated with idiopathic short stature. To ascertain the prevalence of ACAN mutations and broaden the phenotypic spectrum in patients with idiopathic short stature we performed sequence analyses in 428 families. We identified heterozygous nonsense mutations in four and potentially disease-causing missense variants in two families (1.4%). These patients presented with a mean of -3.2 SDS and some suggestive clinical characteristics. The results suggest heterozygous mutations in ACAN as a common cause of isolated as well as inherited idiopathic short stature.


Assuntos
Agrecanas/genética , Estatura/genética , Transtornos do Crescimento/genética , Fenótipo , Criança , Análise Mutacional de DNA , Feminino , Testes Genéticos , Heterozigoto , Humanos , Masculino , Mutação , Linhagem
4.
J Clin Invest ; 121(9): 3479-91, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21804188

RESUMO

Epigenetic regulation of gene expression, through covalent modification of histones, is a key process controlling growth and development. Accordingly, the transcription factors regulating these processes are important targets of genetic diseases. However, surprisingly little is known about the relationship between aberrant epigenetic states, the cellular process affected, and their phenotypic consequences. By chromosomal breakpoint mapping in a patient with a Noonan syndrome-like phenotype that encompassed short stature, blepharoptosis, and attention deficit hyperactivity disorder, we identified haploinsufficiency of the histone acetyltransferase gene MYST histone acetyltransferase (monocytic leukemia) 4 (MYST4), as the underlying cause of the phenotype. Using acetylation, whole genome expression, and ChIP studies in cells from the patient, cell lines in which MYST4 expression was knocked down using siRNA, and the Myst4 querkopf mouse, we found that H3 acetylation is important for neural, craniofacial, and skeletal morphogenesis, mainly through its ability to specifically regulating the MAPK signaling pathway. This finding further elucidates the complex role of histone modifications in mammalian development and adds what we believe to be a new mechanism to the pathogenic phenotypes resulting from misregulation of the RAS signaling pathway.


Assuntos
Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Síndrome de Noonan/genética , Animais , Criança , Mapeamento Cromossômico , Análise Mutacional de DNA , Epigênese Genética , Técnicas de Silenciamento de Genes , Haploinsuficiência , Células HeLa , Histonas/metabolismo , Humanos , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Morfogênese/genética , Síndrome de Noonan/patologia , Síndrome de Noonan/fisiopatologia , Fenótipo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo
5.
Eur J Med Genet ; 54(5): e521-4, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21777705

RESUMO

We identified a maternally inherited 14.2Mb duplication 5q22.1-q23.2 in two female siblings and their mother by molecular karyotyping. Both siblings were small for gestational age and presented with pronounced postnatal growth retardation, mild motor delay, congenital heart disease in one of the siblings, and distinct facial dysmorphism. As this duplication is one of the smallest reported 5q duplications, short stature and facial dysmorphism can be attributed to duplications of 5q22, whereas severe mental retardation is not part of the phenotypic spectrum of the 5q22.1-q23.2 region. Congenital heart defects, as observed in other 5q duplications, have a variable penetrance. We compared the facial features of patients with 5q duplications and found some consistent features such as high arched eyebrows, bulbous nasal tip and small lips with thin vermilion border.


Assuntos
Síndrome de Cri-du-Chat/genética , Transtornos do Crescimento/genética , Trissomia/genética , Adolescente , Criança , Bandeamento Cromossômico , Cromossomos Humanos Par 5/genética , Feminino , Estudo de Associação Genômica Ampla , Cardiopatias Congênitas/genética , Humanos , Hibridização in Situ Fluorescente , Polimorfismo de Nucleotídeo Único/genética
6.
J Med Genet ; 47(5): 321-31, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-19948535

RESUMO

BACKGROUND: Tetralogy of Fallot (ToF), the most frequent cyanotic congenital heart disease, is associated with a wide range of intra- and extracardiac phenotypes. In order to get further insight into genotype-phenotype correlation, a large cohort of 230 unselected patients with ToF was comprehensively investigated. METHODS AND RESULTS: 230 patients with ToF were studied by karyotyping, comprehensive 22q11.2 deletion testing and sequencing of TBX1, NKX2.5 and JAG1, as well as molecular karyotyping in selected patients. Pathogenic genetic aberrations were found in 42 patients (18%), with 22q11.2 deletion as the most common diagnosis (7.4%), followed by trisomy 21 (5.2%) and other chromosomal aberrations or submicroscopic copy number changes (3%). Mutations in JAG1 were detected in three patients with Alagille syndrome (1.3%), while NKX2.5 mutations were seen in two patients with non-syndromic ToF (0.9%). One patient showed a recurrent polyalanine stretch elongation within TBX1 which represents a true mutation resulting in loss of transcriptional activity due to cytoplasmatic protein aggregation. CONCLUSION: This study shows that 22q11.2 deletion represents the most common known cause of ToF, and that the associated cardiac phenotype is distinct for obstruction of the proximal pulmonary artery, hypoplastic central pulmonary arteries and subclavian artery anomalies. Atrioventricular septal defect associated with ToF is very suggestive of trisomy 21 and almost excludes 22q11.2 deletion. We report a further patient with a recurrent polyalanine stretch elongation within TBX1 and for the first time link TBX1 cytoplasmatic protein aggregation to congenital heart defects.


Assuntos
Tetralogia de Fallot/genética , Síndrome de Alagille/genética , Síndrome de Alagille/patologia , Sequência de Bases , Proteínas de Ligação ao Cálcio/genética , Criança , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Estudos de Coortes , Primers do DNA/genética , Síndrome de Down/genética , Síndrome de Down/patologia , Feminino , Estudos de Associação Genética , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteína Jagged-1 , Cariotipagem , Masculino , Proteínas de Membrana/genética , Mutação , Proteínas Serrate-Jagged , Proteínas com Domínio T/genética , Tetralogia de Fallot/patologia , Fatores de Transcrição/genética
7.
J Med Genet ; 47(2): 91-8, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19843505

RESUMO

BACKGROUND: The authors observed a patient with a cryptic subtelomeric de novo balanced translocation 46,XY.ish t(11;20)(p15.4;q13.2) presenting with severe mental retardation, muscular hypotonia, seizures, bilateral sensorineural hearing loss, submucous cleft palate, persistent ductus Botalli, unilateral cystic kidney dysplasia and frequent infections. METHODS AND RESULTS: Fluorescence in situ hybridisation mapping and sequencing of the translocation breakpoints showed that no known genes are disrupted at 20q13.2 and that ST5 (suppression of tumorigenicity 5; MIM 140750) is disrupted on 11p15.4. By quantitative PCR from different human tissues, the authors found ST5 to be relatively evenly expressed in fetal tissues. ST5 expression was more pronounced in adult brain, kidney and muscle than in the corresponding fetal tissues, whereas expression in other tissues was generally lower than in the fetal tissue. Using RNA in situ hybridisation in mouse, the authors found that St5 is expressed in the frontal cortex during embryonic development. In adult mouse brain, expression of St5 was especially high in the hippocampal area and cerebellum. CONCLUSION: Hence, the authors suppose that ST5 plays an important role in central nervous system development probably due to disturbance of DENN-domain-mediated vesicle formation and neurotransmitter trafficking. Thus, these findings implicate ST5 in the aetiology of mental retardation, seizures and multiple congenital anomalies.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Proteínas Supressoras de Tumor/genética , Animais , Pré-Escolar , Pontos de Quebra do Cromossomo , Mapeamento Cromossômico , Análise Mutacional de DNA , Proteínas de Ligação a DNA/metabolismo , Embrião de Mamíferos , Dosagem de Genes , Histocitoquímica , Humanos , Hibridização in Situ Fluorescente , Masculino , Camundongos , Especificidade de Órgãos , RNA , Tomografia Óptica , Proteínas Supressoras de Tumor/metabolismo
8.
Eur J Med Genet ; 51(6): 666-71, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18757044

RESUMO

We report on a healthy man with high normal intelligence, minor dysmorphic features and infertility due to hypogonadism and azoospermia. Cytogenetic analysis showed a 6.7Mb duplication in chromosome band 11q24.2q25, which could be confirmed with FISH and molecular karyotyping using an Affymetrix GeneChip Human Mapping 250K Nsp SNP array.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 11 , Infertilidade Masculina/genética , Desempenho Psicomotor , Adulto , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino
10.
Eur J Med Genet ; 51(4): 358-61, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18342594

RESUMO

We report on a female patient carrying a de novo 15Mb duplication of 6q24.1-q25.3 detected by conventional karyotyping and fine-mapped by molecular karyotyping with a 250K SNP array. Pure interstitial duplications of 6q are rarely reported in the literature and none of them exactly mapped by array technique so far. Our patient shows typical aspects of the "duplication 6q" syndrome such as hypertelorism, downslanting palpebral fissures, carp shaped mouth and joint contractures, but milder mental retardation and no growth retardation.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 6/genética , Duplicação Gênica , Adolescente , Adulto , Motivos de Aminoácidos/genética , Pré-Escolar , Ossos Faciais/anormalidades , Feminino , Humanos , Deficiência Intelectual/genética , Articulações/anormalidades , Cariotipagem , Síndrome
11.
Eur J Med Genet ; 50(6): 421-31, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17845869

RESUMO

The microphthalmia with linear skin defects (MLS or MIDAS) syndrome is a rare X-linked dominant inherited disorder with male lethality, associated with segmental aneuploidy of the Xp22.2 region in most of the cases. However, we recently described heterozygous sequence alterations in a single gene, HCCS, in females with MLS. Beside the classical MLS phenotype, occasional features such as sclerocornea, agenesis of the corpus callosum, and congenital heart defects can occur. Although the majority of cases are sporadic, mother-to-daughter transmission has been observed and a high intra- and interfamilial phenotypic variability exists. We describe an asymptomatic mother and her daughter presenting with the typical features of MLS syndrome. By cytogenetic analysis both females were found to have a terminal Xp deletion with the breakpoint in Xp22.2, mapping near to or within the MSL3L1 gene which is located centromeric to HCCS. FISH analysis revealed that the mother is a mosaic with 45,X(11)/46,X,del(X)(p22.2)(89), while in all cells of the MLS-affected daughter a hybridization pattern consistent with a 46,X,del(X)(p22.2) karyotype was detected. By haplotype analysis we identified the paternal X chromosome of the mother to carry the terminal Xp deletion. X-inactivation studies showed a completely skewed pattern in mother and daughter with the deleted X chromosome to be preferentially inactivated in their peripheral blood cells. We suggest that both chromosomal mosaicism as well as functional X chromosome mosaicism could contribute to the lack of any typical MLS feature in individuals with a heterozygous MLS-associated mutation. The 45,X cell population, that most likely is also present in other tissues of the mother, might have protected her from developing MLS. Nonetheless, a non-random X-inactivation pattern in favor of activity of the wild-type X chromosome in the early blastocyte could also account for the apparent lack of any disease sign in this female.


Assuntos
Cromossomos Humanos X/genética , Microftalmia/genética , Mosaicismo , Anormalidades da Pele/genética , Inativação do Cromossomo X/genética , Adulto , Pré-Escolar , Feminino , Humanos , Masculino , Mães , Núcleo Familiar , Linhagem , Síndrome
12.
J Med Genet ; 44(10): 629-36, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17601928

RESUMO

BACKGROUND: Using array techniques, it was recently shown that about 10% of patients with mental retardation of unknown origin harbour cryptic chromosomal aneusomies. However, data analysis is currently not standardised and little is known about its sensitivity and specificity. METHODS: We have developed an electronic data analysis tool for gene-mapping SNP arrays, a software tool that we call Copy Number Variation Finder (CNVF). Using CNVF, we analysed 104 unselected patients with mental retardation of unknown origin with a genechip mapping 100K SNP array and established an optimised set of analysis parameters. RESULTS: We detected deletions as small as 20 kb when covered by at least three single-nucleotide polymorphisms (SNPs) and duplications as small as 150 kb when covered by at least six SNPs, with only one false-positive signal in six patients. In 9.1% of patients, we detected apparently disease-causing or de novo aberrations ranging in size from 0.4 to 14 Mb. Morphological anomalies in patients with de novo aberrations were equal to that of unselected patients when measured with de Vries score. CONCLUSION: Our standardised CNVF data analysis tool is easy to use and has high sensitivity and specificity. As some genomic regions are covered more densely than others, the genome-wide resolution of the 100K array is about 400-500 kb for deletions and 900-1000 kb for duplications. The detection rate of about 10% of de novo aberrations is independent of selection of patients for particular features. The incidental finding in two patients of heterozygosity for the 250 kb recurrent deletion at the NPH1 locus, associated with autosomal recessive juvenile nephronophthisis, which was inherited from a healthy parent, highlights the fact that inherited aberrations might be disease-related even though not causal for mental retardation.


Assuntos
Deficiência Intelectual/genética , Polimorfismo de Nucleotídeo Único , Aberrações Cromossômicas , Técnicas Genéticas , Variação Genética , Genoma , Heterozigoto , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos , Sensibilidade e Especificidade , Análise de Sequência de DNA
13.
J Histochem Cytochem ; 55(6): 651-60, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17341473

RESUMO

Sixteen newly established cell lines with small supernumerary marker chromosomes (sSMC) derived from chromosomes 1, 2, 4, 6, 7, 8, 14, 15, 16, 18, 19, 21, and 22 are reported. Two sSMC are neocentric and derived from 15q24.1-qter and 2q35-q36, respectively. Two further cases each present with two sSMC of different chromosomal origin. sSMC were characterized by multicolor fluorescence in situ hybridization for their chromosomal origin and genetic content. Moreover, uniparental disomy of the sister chromosomes of the sSMC was excluded in all nine cases studied for that reason. The 16 cases provide information to establish a refined genotype-phenotype correlation of sSMC and are available for future studies.


Assuntos
Bancos de Espécimes Biológicos , Aberrações Cromossômicas , Coloração Cromossômica/métodos , Linfócitos B/citologia , Linfócitos B/metabolismo , Linfócitos B/virologia , Linhagem Celular Transformada , Transformação Celular Viral , Feminino , Herpesvirus Humano 4/fisiologia , Humanos , Cariotipagem , Masculino , Modelos Genéticos , Dissomia Uniparental
14.
Am J Med Genet A ; 143A(2): 135-41, 2007 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-17163525

RESUMO

Males with deletions of or within Xp22.3-pter display variable contiguous gene syndromes including manifestations of Léri-Weill syndrome, chondrodysplasia punctata, mental retardation, ichthyosis, Kallmann syndrome, and ocular albinism. Herein, we report on a male infant with a large, cytogenetically visible, terminal Xp deletion defined by extensive FISH and STS marker analysis to encompass 9.6 Mb, and findings of all of the disorders mentioned above. His deletion approximates the largest Xp terminal deletion ever reported in a male individual. Since the extent of terminal Xp deletions viable in males is limited by the position of male lethal genes in Xp22.2 at about 10-11 Mb from the telomere, this patient falls into the category of the most severe male terminal Xp deletion phenotype.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Deleção Cromossômica , Cromossomos Humanos X/genética , Albinismo Ocular/genética , Albinismo Ocular/patologia , Condrodisplasia Punctata/genética , Condrodisplasia Punctata/patologia , Humanos , Ictiose/genética , Ictiose/patologia , Hibridização in Situ Fluorescente , Lactente , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Síndrome de Kallmann/genética , Síndrome de Kallmann/patologia , Masculino
15.
Am J Med Genet A ; 140(19): 2063-74, 2006 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-16917849

RESUMO

The underlying cause of mental retardation remains unknown in up to 80% of patients. As chromosomal aberrations are the most common known cause of mental retardation, several new methods based on FISH, PCR, and array techniques have been developed over recent years to increase detection rate of subtle aneusomies initially of the gene rich subtelomeric regions, but nowadays also genome wide. As the reported detection rates vary widely between different reports and in order to compare the diagnostic yield of various investigations, we analyzed the diagnostic yield of conventional karyotyping, subtelomeric screening, molecular karyotyping, X-inactivation studies, and dysmorphological evaluation with targeted laboratory testing in unselected patients referred for developmental delay or mental retardation to our cytogenetic laboratory (n = 600) and to our genetic clinic (n = 570). In the cytogenetic group, 15% of patients showed a disease-related aberration, while various targeted analyses after dysmorphological investigation led to a diagnosis in about 20% in the genetic clinic group. When adding the patients with a cytogenetic aberration to the patient group seen in genetic clinic, an etiological diagnosis was established in about 40% of the combined study group. A conventional cytogenetic diagnosis was present in 16% of combined patients and a microdeletion syndrome was diagnosed in 5.3%, while subtelomeric screening revealed only 1.3% of causes. Molecular karyotyping with a 10 K SNP array in addition revealed 5% of underlying causes, but 29% of all diagnoses would have been detectable by molecular karyotyping. In those patients without a clear diagnosis, 5.6% of mothers of affected boys showed significant (>95%) skewing of X-inactivation suggesting X-linked mental retardation. The most common diagnoses with a frequency of more than 0.5% were Down syndrome (9.2%), common microdeletion 22q11.2 (2.4%), Williams-Beuren syndrome (1.3%), Fragile-X syndrome (1.2%), Cohen syndrome (0.7%), and monosomy 1p36.3 (0.6%). From our data, we suggest the following diagnostic procedure in patients with unexplained developmental delay or mental retardation: (1) Clinical/dysmorphological investigation with respective targeted analyses; (2) In the remaining patients without an etiological diagnosis, we suggest conventional karyotyping, X-inactivation screening in mothers of boys, and molecular karyotyping, if available. If molecular karyotyping is not available, subtelomeric screening should be performed.


Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Pré-Escolar , Aberrações Cromossômicas , Citogenética , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Testes Genéticos , Humanos , Lactente , Recém-Nascido , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Deficiência Intelectual Ligada ao Cromossomo X/genética , Fenótipo , Síndrome , Inativação do Cromossomo X
16.
Mol Genet Metab ; 88(3): 256-60, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16545979

RESUMO

We describe the clinical course, as well as cytogenetic and molecular findings, of a 3-year-old obese boy with psychomotor retardation who exhibited two rare conditions: succinic semialdehyde dehydrogenase deficiency (SSADH deficiency, MIM 271980), a disorder of gamma-aminobutyric acid metabolism with a heterogeneous clinical spectrum, and partial Wilms' tumor, aniridia, genital abnormalities, and mental retardation (WAGR) syndrome, an association between Wilms' tumor, aniridia, genitourinary malformations, and mental retardation due to mutations involving the short arm of chromosome 11, particularly deletions at the chromosomal region 11p13 (MIM 194072). Diagnosis of SSADH deficiency in our patient was established by demonstration of absent enzyme activity in isolated leucocytes, and was associated with a novel missense mutation (c.587G>A; p.Gly196Asp) in the SSADH coding sequence. We further confirmed an incomplete WAGR syndrome in this boy [karyotype 46, XY, del (11) (p13p14.2)] with a normal WT1 (Wilms' tumor) gene and an absence of pathology in the genitourinary tract, but with obesity (WAGR syndrome with obesity, WAGRO syndrome). The patient also exhibited distinctive cerebral anomalies such as increased signals of the globi pallidi, internal hydrocephalus and cerebellar vermian atrophy. However, treatment options for this patient are limited, including supportive treatment, physiotherapy, special educational training, and vigabatrin. In summary, we report the first patient with the exceptional rare findings of both SSADH deficiency and partial WAGR/WAGRO syndrome.


Assuntos
Obesidade/complicações , Succinato-Semialdeído Desidrogenase/genética , Síndrome WAGR/genética , Cerebelo/anormalidades , Pré-Escolar , Humanos , Hidrocefalia/genética , Leucócitos/enzimologia , Masculino , Mutação de Sentido Incorreto , Succinato-Semialdeído Desidrogenase/deficiência , Succinato-Semialdeído Desidrogenase/metabolismo , Síndrome WAGR/complicações , Síndrome WAGR/patologia
18.
Am J Med Genet A ; 132A(2): 185-8, 2005 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-15578616

RESUMO

OTC deficiency, the most common urea cycle defect, is transmitted as a partially dominant X-linked trait. The most severe form of the disease, however, is usually restricted to males. We report on monozygotic female twins with severe neonatal-onset OTC deficiency and a de novo balanced reciprocal translocation t(X;5)(p21.1;q11). Disruption of the OTC gene on the derivative X-chromosome was confirmed by FISH analysis. Consistent inactivation of the normal X could be demonstrated by RGB staining. Manifestation of X-linked recessive disorders in females due to a balanced reciprocal X-autosome translocation has previously been described in Duchenne muscular dystrophy and several other disorders but not in OTC deficiency. This report emphasizes the importance of chromosome analysis in any female manifesting severe OTC deficiency.


Assuntos
Cromossomos Humanos Par 5/genética , Cromossomos Humanos X/genética , Doenças em Gêmeos/genética , Doença da Deficiência de Ornitina Carbomoiltransferase , Translocação Genética , Idade de Início , Pré-Escolar , Doenças em Gêmeos/enzimologia , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Cariotipagem , Modelos Genéticos , Ornitina Carbamoiltransferase/genética , Irmãos , Gêmeos/genética
19.
Int J Oncol ; 24(1): 127-36, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14654949

RESUMO

Routine cytogenetic analysis provides important information of diagnostic and prognostic relevance for hematological malignancies. In spite of this, poorly spread metaphase chromosomes and highly rearranged karyotypes with numerous marker chromosomes, are often difficult to interpret. In order to improve the definition of chromosomal breakpoints multicolor banding (MCB) was applied on 45 bone marrow samples from patients suffering from hematological malignancies like myelodysplastic syndrome (MDS), acute myelocytic leukemia (AML), chronic myelocytic leukemia (CML) or acute lymphoblastic leukemia (ALL). The breakpoints defined by GTG banding were confirmed by MCB in 8 cases, while in the remaining 37 cases the breakpoints had to be redefined. In 20/45 cases the breakpoints could only be characterized after application of MCB. In summary, 73 different breakpoints were characterized, thereof 33 were previously undescribed. Eleven cases showed known acquired aberrations and 21 cases had previously described aberration types such as del(5q-), del(7q-), del(13q-) or t(1;5) as sole rearrangement or in connection with other complex ones. In a total of 11 cases 19 breakpoints as described before were involved in hematological malignancies, while in 14 cases 33 breakpoints were identified which have not been described previously. Thus, MCB has proven to be a powerful and reliable method for screening of chromosomal aberrations, which considerably increased the accuracy of cytogenetic diagnosis.


Assuntos
Aberrações Cromossômicas , Quebra Cromossômica/genética , Neoplasias Hematológicas/genética , Adulto , Criança , Bandeamento Cromossômico , Deleção Cromossômica , Neoplasias Hematológicas/patologia , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Translocação Genética
20.
Am J Hum Genet ; 73(6): 1341-54, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14628291

RESUMO

Nonsyndromic X-linked mental retardation (MRX) is defined by an X-linked inheritance pattern of low IQ, problems with adaptive behavior, and the absence of additional specific clinical features. The 13 MRX genes identified to date account for less than one-fifth of all MRX, suggesting that numerous gene defects cause the disorder in other families. In a female patient with severe nonsyndromic mental retardation and a de novo balanced translocation t(X;7)(p11.3;q11.21), we have cloned the DNA fragment that contains the X-chromosomal and the autosomal breakpoint. In silico sequence analysis provided no indication of a causative role for the chromosome 7 breakpoint in mental retardation (MR), whereas, on the X chromosome, a zinc-finger gene, ZNF41, was found to be disrupted. Expression studies indicated that ZNF41 transcripts are absent in the patient cell line, suggesting that the mental disorder in this patient results from loss of functional ZNF41. Moreover, screening of a panel of patients with MRX led to the identification of two other ZNF41 mutations that were not found in healthy control individuals. A proline-to-leucine amino acid exchange is present in affected members of one family with MRX. A second family carries an intronic splice-site mutation that results in loss of specific ZNF41 splice variants. Wild-type ZNF41 contains a highly conserved transcriptional repressor domain that is linked to mechanisms of chromatin remodeling, a process that is defective in various other forms of MR. Our results suggest that ZNF41 is critical for cognitive development; further studies aim to elucidate the specific mechanisms by which ZNF41 alterations lead to MR.


Assuntos
Cromossomos Humanos X/genética , Transtornos Cognitivos/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Mutação/genética , Sequência de Bases , Northern Blotting , Southern Blotting , Montagem e Desmontagem da Cromatina/genética , Cromatografia Líquida de Alta Pressão , Mapeamento Cromossômico , Primers do DNA , Feminino , Expressão Gênica/genética , Humanos , Hibridização in Situ Fluorescente , Fatores de Transcrição Kruppel-Like , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA
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