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1.
Genet Med ; 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30940925

RESUMO

PURPOSE: A new syndrome with hypotonia, intellectual disability, and eye abnormalities (HIDEA) was previously described in a large consanguineous family. Linkage analysis identified the recessive disease locus, and genome sequencing yielded three candidate genes with potentially pathogenic biallelic variants: transketolase (TKT), transmembrane prolyl 4-hydroxylase (P4HTM), and ubiquitin specific peptidase 4 (USP4). However, the causative gene remained elusive. METHODS: International collaboration and exome sequencing were used to identify new patients with HIDEA and biallelic, potentially pathogenic, P4HTM variants. Segregation analysis was performed using Sanger sequencing. P4H-TM wild-type and variant constructs without the transmembrane region were overexpressed in insect cells and analyzed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blot. RESULTS: Five different homozygous or compound heterozygous pathogenic P4HTM gene variants were identified in six new and six previously published patients presenting with HIDEA. Hypoventilation, obstructive and central sleep apnea, and dysautonomia were identified as novel features associated with the phenotype. Characterization of three of the P4H-TM variants demonstrated yielding insoluble protein products and, thus, loss-of-function. CONCLUSIONS: Biallelic loss-of-function P4HTM variants were shown to cause HIDEA syndrome. Our findings enable diagnosis of the condition, and highlight the importance of assessing the need for noninvasive ventilatory support in patients.

2.
Acta Neuropathol ; 135(5): 727-742, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29423877

RESUMO

A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. In the affected children, neuropathology revealed increased angiomatosis-like leptomeningeal, cortical and superficial white matter vascularisation and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver. A whole-exome sequencing of the two unrelated families with the affected children revealed the transmission of two heterozygous variants in the NHL repeat-containing protein 2 (NHLRC2); an amino acid substitution p.Asp148Tyr and a frameshift 2-bp deletion p.Arg201GlyfsTer6. NHLRC2 is highly conserved and expressed in multiple organs and its function is unknown. It contains a thioredoxin-like domain; however, an insulin turbidity assay on human recombinant NHLRC2 showed no thioredoxin activity. In patient-derived fibroblasts, NHLRC2 levels were low, and only p.Asp148Tyr was expressed. Therefore, the allele with the frameshift deletion is likely non-functional. Development of the Nhlrc2 null mouse strain stalled before the morula stage. Morpholino knockdown of nhlrc2 in zebrafish embryos affected the integrity of cells in the midbrain region. This is the first description of a fatal, early-onset disease; we have named it FINCA disease based on the combination of pathological features that include fibrosis, neurodegeneration, and cerebral angiomatosis.

3.
Blood ; 129(16): 2266-2279, 2017 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-28202457

RESUMO

Several monogenic causes of familial myelodysplastic syndrome (MDS) have recently been identified. We studied 2 families with cytopenia, predisposition to MDS with chromosome 7 aberrations, immunodeficiency, and progressive cerebellar dysfunction. Genetic studies uncovered heterozygous missense mutations in SAMD9L, a tumor suppressor gene located on chromosome arm 7q. Consistent with a gain-of-function effect, ectopic expression of the 2 identified SAMD9L mutants decreased cell proliferation relative to wild-type protein. Of the 10 individuals identified who were heterozygous for either SAMD9L mutation, 3 developed MDS upon loss of the mutated SAMD9L allele following intracellular infections associated with myeloid, B-, and natural killer (NK)-cell deficiency. Five other individuals, 3 with spontaneously resolved cytopenic episodes in infancy, harbored hematopoietic revertant mosaicism by uniparental disomy of 7q, with loss of the mutated allele or additional in cisSAMD9L truncating mutations. Examination of 1 individual indicated that somatic reversions were postnatally selected. Somatic mutations were tracked to CD34+ hematopoietic progenitor cell populations, being further enriched in B and NK cells. Stimulation of these cell types with interferon (IFN)-α or IFN-γ induced SAMD9L expression. Clinically, revertant mosaicism was associated with milder disease, yet neurological manifestations persisted in 3 individuals. Two carriers also harbored a rare, in trans germ line SAMD9L missense loss-of-function variant, potentially counteracting the SAMD9L mutation. Our results demonstrate that gain-of-function mutations in the tumor suppressor SAMD9L cause cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with -7/del(7q), whereas hematopoietic revertant mosaicism commonly ameliorated clinical manifestations. The findings suggest a role for SAMD9L in regulating IFN-driven, demand-adapted hematopoiesis.


Assuntos
Disfunção Cognitiva/diagnóstico , Síndromes de Imunodeficiência/diagnóstico , Mutação , Síndromes Mielodisplásicas/diagnóstico , Pancitopenia/diagnóstico , Proteínas Supressoras de Tumor/genética , Adulto , Alelos , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Proliferação de Células , Criança , Cromossomos Humanos Par 7/química , Disfunção Cognitiva/complicações , Disfunção Cognitiva/genética , Disfunção Cognitiva/imunologia , Feminino , Expressão Gênica , Hematopoese/imunologia , Heterozigoto , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Imunofenotipagem , Interferon Tipo I/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Masculino , Pessoa de Meia-Idade , Mosaicismo , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/imunologia , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Células Mieloides/patologia , Pancitopenia/complicações , Pancitopenia/genética , Pancitopenia/imunologia , Linhagem , Proteínas Supressoras de Tumor/metabolismo
4.
Am J Hum Genet ; 98(4): 735-43, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27058446

RESUMO

Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species.


Assuntos
Corpo Estriado/patologia , Hipercinese/genética , Mutação , Diester Fosfórico Hidrolases/genética , Alelos , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica , Variação Genética , Células HEK293 , Humanos , Hipercinese/diagnóstico , Hipercinese/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Linhagem , Inibidores de Fosfodiesterase/metabolismo , Alinhamento de Sequência
5.
Eur J Paediatr Neurol ; 20(1): 164-7, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26685108

RESUMO

Familial cases of West syndrome have been reported only in Japan. In that study no chromosomal analyses were made. It has been suggested that microarray analysis should be included in the diagnostic evaluation of patients with infantile spasms and developmental delay, when an evaluation for structural brain lesions and metabolic disorders reveal no abnormal findings. We report here the first case of infantile spasms and 15q11.2q13.1 chromosome duplication in two successive generations. The daughter and mother with infantile spasms, and the autistic son had the duplication. The clinical course of infantile spasms was very similar in the mother and daughter. The spasms were primarily considered to be of unknown aetiology. Chromosomal microarray analysis revealed a 6.2 Mb size 15q11.2q13.1 duplication. The duplication belongs to the 15q11q13 duplication syndrome (OMIM 608636) which when maternally derived is characterised by neuro-behavioural disorders like autism, hypotonia, cognitive deficit, language delay and epilepsy. The proportion of patients with unknown aetiology for infantile spasms will decrease when more careful chromosomal studies are made. Our report expands the phenotype of chromosome 15q duplication syndrome and is the first report of this abnormality in two successive generations of infantile spasms.


Assuntos
Espasmos Infantis/genética , Trissomia/genética , Adulto , Transtorno Autístico/genética , Duplicação Cromossômica , Cromossomos Humanos Par 15/genética , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Lactente , Japão , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Fenótipo , Adulto Jovem
6.
Artigo em Inglês | MEDLINE | ID: mdl-25140118

RESUMO

OBJECTIVE: To evaluate the efficacy of first trimester combined screening for Down's syndrome in Northern Finland during the first 10 years of practice. METHODS: During 1 January 2002 to 31 December 2011, 47,896 women participated voluntarily in combined screening during first trimester. The risk cutoff was 1:250. The study period was divided into two time periods; 2002-2006 and 2007-2011. RESULTS: During the first half of the study period, the detection rate (DR) was 77.3% with a 4.9% false-positive rate (FPR). During the latter half, the DR was 77.1% with a 2.8% FPR. CONCLUSIONS: An important issue is the number of invasive procedures needed to detect one case of Down's syndrome. The screening performance improved markedly in the latter five years period since the FPR lowered from 4.9% to 2.8% and the number of invasive procedures needed to detect one case of Down's syndrome lowered from 15 to 11.

7.
Eur J Med Genet ; 56(7): 389-96, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23707653

RESUMO

We present two siblings (a boy and a girl) with a submicroscopic 4 Mb duplication at 22q13.1q13.2. Both children manifested infantile hypotonia and delayed motor milestones, congenital heart defect, growth deficiency, and strikingly similar and distinctive craniofacial dysmorphism including brachycephaly, blepharophimosis, short broad-based nose and wide mouth with thin upper lip. The boy had also a submucous cleft palate. Both had fair skin and hair compared with their parents. Both had moderate mental retardation associated with a short attention span. A 4-Mb interstitial duplication at 22q13.1q13.2 was detected by whole genome microarray comparative genomic hybridisation (array CGH) in both children. The duplication was confirmed by fluorescence in situ hybridisation (FISH) analysis. Their parents had normal array CGH results. FISH analysis revealed that the father was a carrier of a balanced interchromosomal submicroscopic insertion of 22q13 into chromosome 11q23, explaining the unbalanced aberration detected in both children. This report narrows down the critical region at 22q13.1q13.2, which is associated with mental retardation, pre- and post-natal growth retardation, hippocampal malformation, psychiatric symptoms such as short attention span and facial dysmorphism including hypertelorism, epicanthal folds and low set/abnormal ears.


Assuntos
Duplicação Cromossômica , Cromossomos Humanos Par 22/genética , Anormalidades Craniofaciais/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Pré-Escolar , Hibridização Genômica Comparativa , Anormalidades Craniofaciais/diagnóstico , Feminino , Cardiopatias Congênitas/diagnóstico , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Irmãos
8.
Am J Perinatol ; 29(3): 211-6, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21833895

RESUMO

We analyzed the frequency and possible causes of false-negative (Fn) screening results in first-trimester combined Down syndrome screening in Finland. During the study period (May 1, 2002, to December 31, 2008), 76,949 voluntary women with singleton pregnancies participated in screening. Maternal age at screening, week of gestation, levels of pregnancy-associated plasma protein-A (PAPP-A), free ß-human chorionic gonadotropin (fß-hCG), and nuchal translucency (NT) measurement were compared and statistically analyzed between true-positive (Tp) and Fn cases. There were a total of 188 Down syndrome cases (1:409) in the screened population; 154 confirmed Tp and 34 Fn cases. Most Fn cases (n = 25) occurred at 12 + 0 to 13 + 6 weeks' gestation and only nine Fn cases presented between 10 and 11 weeks' gestation. According to the logistic regression analysis, the NT measurement was the most powerful discriminating factor in Fn screening results and accounted for 37.2% of Fn results. The second most important factor was fß-hCG, adding 14.0% to R(2), followed by PAPP-A, which contributed a further 14.3%. The chosen parameters explain 83.9% of Fn results, but 16.1% remain due to unknown factor(s). All investigated parameters contributed to Fn screening results, but fetal NT was the most discriminating factor leading to an Fn screening result.


Assuntos
Gonadotropina Coriônica Humana Subunidade beta/sangue , Síndrome de Down/diagnóstico , Medição da Translucência Nucal/estatística & dados numéricos , Proteína Plasmática A Associada à Gravidez/análise , Diagnóstico Pré-Natal/estatística & dados numéricos , Adulto , Reações Falso-Negativas , Feminino , Finlândia , Humanos , Idade Materna , Gravidez , Primeiro Trimestre da Gravidez , Diagnóstico Pré-Natal/normas
9.
Acta Obstet Gynecol Scand ; 90(8): 885-9, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21539522

RESUMO

OBJECTIVE: To examine the performance of first-trimester combined screening after adding the specific algorithms for trisomies 18 and 13 in the Down syndrome screening program for chromosomal abnormalities other than trisomy 21 and to determine the outcomes of such pregnancies. DESIGN: A retrospective study. SETTING: Oulu University Hospital, Finland. POPULATION: Pregnant women (n=56 076) participating voluntarily in first-trimester combined Down syndrome screening in Northern and Eastern Finland during the study period 1 June 2002 to 31 December 2008. METHODS: The data of all known cases of chromosomal abnormalities other than trisomy 21 were collected. MAIN OUTCOME MEASURES: Risk algorithms for trisomies 21, 18 and 13 were used for the calculation of patient-specific risks for certain chromosomal abnormalities. Algorithms were based on maternal age, crown-rump length, nuchal translucency, and measurement of free ß-human chorionic gonadotrophin and pregnancy-associated plasma protein-A. Detection rates and false-positive rates were calculated. RESULTS: A total of 27 cases of trisomy 18, 11 cases of trisomy 13 and 30 cases of other chromosomal abnormalities were analyzed. The algorithm for Down syndrome detected 55.6% of trisomy 18 cases, 36.4% of trisomy 13 cases and 60.0% of other chromosomal abnormalities. When specific risk algorithms were added, the detection rates improved for trisomy 18 (74.0%) and for trisomy 13 (54.5%), with only a slight increase of the false-positive rate of 0.2%. The detection rate for other chromosomal abnormalities did not improve. CONCLUSIONS: Adding the trisomy 18 algorithm to the Down screening program resulted in the detection of five additional trisomy 18 cases.


Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos/diagnóstico , Diagnóstico Pré-Natal/métodos , Algoritmos , Estatura Cabeça-Cóccix , Feminino , Finlândia , Humanos , Medição da Translucência Nucal , Gravidez , Primeiro Trimestre da Gravidez , Risco , Ultrassonografia Pré-Natal
10.
Acta Obstet Gynecol Scand ; 90(6): 642-7, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21355862

RESUMO

OBJECTIVE: To evaluate the performance of first-trimester combined screening in 5-year periods according to maternal age in a low-risk population. DESIGN: A prospective study. SETTING: Multicenter study in Finland. POPULATION: A total of 76949 voluntary women with singleton pregnancies participated in first-trimester combined screening in public healthcare between 1 May 2002 and 31 December 2008. METHODS: The serum samples were analyzed using the PerkinElmer AutoDELFIA® time-resolved fluoroimmunoassay kit for the measurement of pregnancy-associated plasma protein-A and free beta-human chorionic gonadotropin. Nuchal translucency was measured by trained personnel (midwives or physicians) in a university or central hospital. MAIN OUTCOME MEASURES: Performance, detection rate, false positive rate and the number of invasive procedures needed to detect a single case of Down's syndrome were analyzed. RESULTS: There was a direct connection between maternal age and the prevalence of Down's syndrome with a low prevalence in young women being 1:1 193 in the 25-29 age group and 1:150 in the 35-39 age group. Consequently, for a fixed false positive rate of 5%, the number of invasive procedures needed to detect one case of Down's syndrome is higher in younger women to achieve the same detection rate. CONCLUSIONS: In combined first trimester screening the risk for Down's syndrome is individual, varying with maternal age. This should be taken into consideration when counseling women.


Assuntos
Síndrome de Down/sangue , Síndrome de Down/diagnóstico , Idade Materna , Diagnóstico Pré-Natal/métodos , Adulto , Biomarcadores/sangue , Gonadotropina Coriônica Humana Subunidade beta/sangue , Diagnóstico Precoce , Reações Falso-Positivas , Feminino , Finlândia , Idade Gestacional , Humanos , Pessoa de Meia-Idade , Medição da Translucência Nucal , Gravidez , Primeiro Trimestre da Gravidez , Proteína Plasmática A Associada à Gravidez/metabolismo , Prevalência , Estudos Prospectivos , Fatores de Risco
11.
Cancer Lett ; 302(2): 113-8, 2011 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-21236561

RESUMO

A portion of familial breast cancer cases are caused by mutations in the same genes that are inactivated in the downstream part of Fanconi anemia (FA) signaling pathway. Here we have assessed the FANCA gene for breast cancer susceptibility by examining blood DNA for aberrations from 100 Northern Finnish breast cancer families using the MLPA method. We identified a novel heterozygous deletion, removing the promoter and 12 exons of the gene in one family. This allele was absent from 124 controls. We conclude that FANCA deletions might contribute to breast cancer susceptibility, potentially in combination with other germline mutations. To our knowledge, this is the first study reporting a large deletion in an upstream FA gene in familial breast cancer.


Assuntos
Neoplasias da Mama/genética , Anemia de Fanconi/genética , Predisposição Genética para Doença , Deleção de Sequência , Feminino , Finlândia/epidemiologia , Humanos , Programas de Rastreamento
12.
Am J Obstet Gynecol ; 196(3): 278.e1-5, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17346554

RESUMO

OBJECTIVE: The purpose of this study was to compare the efficacy of both separate and combined maternal serum testing and fetal nuchal translucency measurement in the first trimester screening for Down syndrome in northern Finland. STUDY DESIGN: The following screening tests were evaluated: measurement of nuchal translucency (NT) alone; serum screening (pregnancy-associated plasma protein A [PAPP-A] and free beta subunit of human chorionic gonadotropin [beta-hCG]) alone; and combined screening (NT plus PAPP-A and free beta-hCG). RESULTS: The participants comprised 7534 pregnant women during the 10+0-12+6 weeks of pregnancy. All 7534 women participated in serum screening, and 4765 women participated in combined screening. In the serum screening-alone group, there were 30 cases of trisomy 21, of which 23 (76%) were detected. In the combined-screening group, there were 24 cases of trisomy 21 and 21 (87.5%) were detected. In the combined-screening group NT alone detected 15 cases of Down syndrome (62%). CONCLUSION: Combined screening is the method of choice for Down syndrome screening.


Assuntos
Gonadotropina Coriônica Humana Subunidade beta/sangue , Síndrome de Down/diagnóstico , Medição da Translucência Nucal , Proteína Plasmática A Associada à Gravidez/análise , Diagnóstico Pré-Natal , Adulto , Feminino , Finlândia , Humanos , Gravidez , Primeiro Trimestre da Gravidez
13.
Am J Med Genet A ; 126A(3): 248-52, 2004 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-15054837

RESUMO

Angelman syndrome (AS) is a neurogenetic disorder associated with a loss of maternal gene expression in chromosome region 15q11-q13 due to either maternal deletion, paternal uniparental disomy (UPD), imprinting mutation, or mutation in the UBE3A gene. UBE3A encodes an ubiquitin-protein ligase and shows brain-specific imprinting. We have done conformation sensitive gel electrophoresis (CSGE) mutation analysis of the UBE3A coding region in nine AS patients, who had shown a normal biparental inheritance and methylation pattern of the 15q11-q13. Disease-causing mutations were identified in five of them: three deletions (1930delAG, 3093delAAGA) and two missense mutations (902A --> C, 975T --> C). Both deletions have also been detected in other AS patients, suggesting these sites may be prone to deletions in the UBE3A gene. All AS cases were sporadic, but a mosaicism for mutation 902A --> C was present in a patient's mother. Screening for the UBE3A mutations in the AS patients was found useful both for the confirmation of diagnosis and genetic counseling. CSGE was found to be a sensitive and simple screening method for these mutations.


Assuntos
Síndrome de Angelman/genética , Mutação , Polimorfismo Conformacional de Fita Simples , Ubiquitina-Proteína Ligases/genética , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Cromossomos Humanos Par 15/genética , Análise Mutacional de DNA , Eletroforese/métodos , Feminino , Finlândia , Humanos , Masculino , Conformação de Ácido Nucleico , Linhagem
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