Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
Filtros adicionais











Tipo de estudo
Intervalo de ano
1.
Am J Hum Genet ; 101(5): 768-788, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29100089

RESUMO

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Deficiência Intelectual/genética , Mutação/genética , Animais , Encéfalo/patologia , Linhagem Celular , Exoma/genética , Feminino , Ácido Glutâmico/genética , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/patologia , Fosforilação/genética , Transdução de Sinais/genética
2.
J Allergy Clin Immunol ; 139(1): 232-245, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27577878

RESUMO

BACKGROUND: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. OBJECTIVE: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. METHODS: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. RESULTS: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. CONCLUSION: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.


Assuntos
Síndromes de Imunodeficiência/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Feminino , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
3.
Eur J Med Genet ; 59(8): 367-72, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27286923

RESUMO

Missense variants in MED12 cause three partially overlapping dysmorphic X-linked intellectual disability (XLID) syndromes: Lujan-Fryns syndrome (also known as Lujan syndrome), FG syndrome (also known as Opitz-Kaveggia syndrome) and X-linked Ohdo syndrome. We report a family with two severely micrognathic male sibs, a 10½ year old boy and a fetus, in which hemizygosity for a previously unreported missense variant in exon 13 of MED12 (NM_005120.2), c.1862G > A, p.(Arg621Gln) was detected by whole exome sequencing. The affected sibs shared no other rare variant with relevance to the phenotype. X-chromosome inactivation in blood was completely skewed (100:0) in the unaffected heterozygous mother, most likely as a result of preferential inactivation of the X-chromosome harbouring the missense variant in MED12. Neither the unaffected brother nor the unaffected maternal grandfather carried the missense variant in MED12. In the 10½ year old boy, upper airway obstruction secondary to Pierre Robin sequence necessitated a tracheostomy for the first 10 months of life. He has mild to moderate intellectual disability and some dysmorphic features seen in MED12-related syndromes. In addition, he has a horizontal gaze paresis, anomalies of the inner ear, and a cervical block vertebra. This report contributes to the expanding phenotypic range associated with MED12-mutations.


Assuntos
Complexo Mediador/genética , Micrognatismo/diagnóstico , Micrognatismo/genética , Mutação de Sentido Incorreto , Fenótipo , Irmãos , Éxons , Genes Ligados ao Cromossomo X , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Inativação do Cromossomo X
4.
PLoS One ; 11(4): e0153757, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27124303

RESUMO

We report molecular genetic analysis of 42 affected individuals referred with a diagnosis of aniridia who previously screened as negative for intragenic PAX6 mutations. Of these 42, the diagnoses were 31 individuals with aniridia and 11 individuals referred with a diagnosis of Gillespie syndrome (iris hypoplasia, ataxia and mild to moderate developmental delay). Array-based comparative genomic hybridization identified six whole gene deletions: four encompassing PAX6 and two encompassing FOXC1. Six deletions with plausible cis-regulatory effects were identified: five that were 3' (telomeric) to PAX6 and one within a gene desert 5' (telomeric) to PITX2. Sequence analysis of the FOXC1 and PITX2 coding regions identified two plausibly pathogenic de novo FOXC1 missense mutations (p.Pro79Thr and p.Leu101Pro). No intragenic mutations were detected in PITX2. FISH mapping in an individual with Gillespie-like syndrome with an apparently balanced X;11 reciprocal translocation revealed disruption of a gene at each breakpoint: ARHGAP6 on the X chromosome and PHF21A on chromosome 11. In the other individuals with Gillespie syndrome no mutations were identified in either of these genes, or in HCCS which lies close to the Xp breakpoint. Disruption of PHF21A has previously been implicated in the causation of intellectual disability (but not aniridia). Plausibly causative mutations were identified in 15 out of 42 individuals (12/32 aniridia; 3/11 Gillespie syndrome). Fourteen of these mutations presented in the known aniridia genes; PAX6, FOXC1 and PITX2. The large number of individuals in the cohort with no mutation identified suggests greater locus heterogeneity may exist in both isolated and syndromic aniridia than was previously appreciated.


Assuntos
Aniridia/genética , Ataxia Cerebelar/genética , Deficiência Intelectual/genética , Fator de Transcrição PAX6/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos X/genética , Hibridização Genômica Comparativa/métodos , Feminino , Fatores de Transcrição Forkhead/genética , Proteínas Ativadoras de GTPase/genética , Testes Genéticos/métodos , Histona Desacetilases/genética , Proteínas de Homeodomínio/genética , Humanos , Masculino , Mutação/genética , Fatores de Transcrição/genética
5.
Am J Hum Genet ; 98(1): 202-9, 2016 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-26708751

RESUMO

Ion channel proteins are required for both the establishment of resting membrane potentials and the generation of action potentials. Hundreds of mutations in genes encoding voltage-gated ion channels responsible for action potential generation have been found to cause severe neurological diseases. In contrast, the roles of voltage-independent "leak" channels, important for the establishment and maintenance of resting membrane potentials upon which action potentials are generated, are not well established in human disease. UNC80 is a large component of the NALCN sodium-leak channel complex that regulates the basal excitability of the nervous system. Loss-of-function mutations of NALCN cause infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF). We report four individuals from three unrelated families who have homozygous missense or compound heterozygous truncating mutations in UNC80 and persistent hypotonia, encephalopathy, growth failure, and severe intellectual disability. Compared to control cells, HEK293T cells transfected with an expression plasmid containing the c.5098C>T (p.Pro1700Ser) UNC80 mutation found in one individual showed markedly decreased NALCN channel currents. Our findings demonstrate the fundamental significance of UNC80 and basal ionic conductance to human health.


Assuntos
Alelos , Encefalopatias/genética , Proteínas de Transporte/genética , Transtornos do Crescimento/genética , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Hipotonia Muscular/genética , Mutação , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Índice de Gravidade de Doença
6.
Gene ; 518(2): 457-60, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-23370340

RESUMO

Currarino syndrome (CS) is a clinically variable disorder characterized by anorectal, sacral and presacral anomalies. It is associated with loss-of-function mutations in the motor neuron and pancreas homeobox 1 (MNX1) gene. Inheritance is autosomal dominant, expression variable and penetrance incomplete. We describe a Norwegian family with typical CS in which a heterozygous deletion removes the entire MNX1 gene but no other known genes. We also report MNX1 mutations in three other Norwegian families and confirm that the GCC12 repeat (c.373_375[12]) is a normal allelic variant. This work underscores the importance of dosage analysis of MNX1 when Sanger sequencing is negative.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades do Sistema Digestório/genética , Proteínas de Homeodomínio/genética , Deleção de Sequência , Siringomielia/genética , Fatores de Transcrição/genética , Canal Anal/anormalidades , Humanos , Fenótipo , Reto/anormalidades , Sacro/anormalidades
9.
Nat Genet ; 41(12): 1272-4, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19935664

RESUMO

Lymphedema, lymphangiectasias, mental retardation and unusual facial characteristics define the autosomal recessive Hennekam syndrome. Homozygosity mapping identified a critical chromosomal region containing CCBE1, the human ortholog of a gene essential for lymphangiogenesis in zebrafish. Homozygous and compound heterozygous mutations in seven subjects paired with functional analysis in a zebrafish model identify CCBE1 as one of few genes causing primary generalized lymph-vessel dysplasia in humans.


Assuntos
Anormalidades Múltiplas/genética , Linfangiectasia/genética , Linfedema/genética , Mutação , Sequência de Aminoácidos , Animais , Consanguinidade , Genes Recessivos , Heterozigoto , Humanos , Deficiência Intelectual/genética , Masculino , Dados de Sequência Molecular , Linhagem , Fenótipo , Síndrome , Adulto Jovem
10.
Tidsskr Nor Laegeforen ; 129(22): 2358-61, 2009 Nov 19.
Artigo em Norueguês | MEDLINE | ID: mdl-19935936

RESUMO

BACKGROUND: Mutations in genes of the mitogen-activated protein kinase (MAPK) cascade have recently been shown to cause several syndromes characterized by dysmorphic facial features, growth retardation, cognitive impairment, heart disease and cutaneous abnormalities. This signalling pathway involves RAS and RAF proteins, and is central in the regulation of normal growth and the development of cancer. MATERIAL AND METHODS: We have studied 23 Norwegian patients for whom there was a clinical suspicion of Costello, Noonan or cardio-facio-cutaneous syndrome. Patients suspected of having Noonan syndrome had previously tested negative for mutations in the tyrosine phosphatase gene PTPN11. The material was examined for mutations in the HRAS, KRAS, RAF1 and BRAF genes. Two patients are described to illustrate diagnostic challenges and the usefulness of genetic testing. RESULTS: Ten of 23 patients (43 %) had mutations affecting the RAS/MAPK signalling pathway. Mutations in HRAS were most common (five cases), while three patients had mutations in KRAS and two in RAF1. Spontaneous mutations were demonstrated in eight cases. Our data indicate an annual incidence of 1-2 new cases of congenital RAS/RAF mutations in Norway. INTERPRETATION: Upon clinical suspicion of syndromes of the RAS/MAPK signalling pathway, molecular genetic analyses may be essential for a correct diagnosis. Certain mutations are associated with an increased cancer risk, exemplifying that results of genetic laboratory testing may influence medical management.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/genética , Sistema de Sinalização das MAP Quinases/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Proteínas ras/genética , Adolescente , Adulto , Pré-Escolar , Síndrome de Costello/genética , Genes ras/genética , Técnicas Genéticas , Humanos , Lactente , Síndrome LEOPARD/genética , Masculino , Síndrome de Noonan/genética , Proteínas Proto-Oncogênicas A-raf/genética , Proteínas Proto-Oncogênicas B-raf/genética , Síndrome
11.
Clin Dysmorphol ; 18(2): 78-82, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19057379

RESUMO

Microduplications in chromosome Xq28, which include the methyl-CPG binding protein (MECP2) gene, cause severe X-linked mental retardation. Serious recurrent infections are a feature of this condition. Affected males are micro or normocephalic. We report two normocephalic brothers with an approximately 0.5 Mb duplication which includes MECP2 who had rapid head growth in infancy. The younger boy had chronic constipation until the age of 3 years. For both boys, the susceptibility to infection subsided in the second year of life. Whether or not rapid head growth in infancy and/or constipation are frequent features of the phenotype remains to be seen as more patients are described. Susceptibility to infection can remit after early childhood and could theoretically be related to overexpression of the interleukin 1 receptor-associated kinase IRAK1 gene.


Assuntos
Duplicação Gênica , Cabeça/crescimento & desenvolvimento , Infecção/genética , Proteína 2 de Ligação a Metil-CpG/genética , Irmãos , Cromossomos Humanos X , Suscetibilidade a Doenças , Humanos , Lactente , Masculino
12.
Acta Obstet Gynecol Scand ; 87(10): 998-1005, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18798055

RESUMO

OBJECTIVES: The primary aim was to evaluate which investigation performed after sonographic detection of central nervous system (CNS) or skeletal anomalies that had highest diagnostic yield. The secondary aim was to estimate recurrence risk. Design. Retrospective review of patients' records. SETTING: Tertiary fetal medicine referral center. SAMPLE: Pregnancy terminations (n=97) because of CNS or skeletal anomalies during a 17-year period, within 12-24 weeks gestation. METHODS: Two medical geneticists and one genetic counselor reviewed charts independently. MAIN OUTCOME MEASURES: Primary ultrasound diagnosis, change in diagnosis following supplementary examinations in addition to prenatal ultrasound (medical history, autopsy, post-mortem X-ray, karyotyping, targeted DNA analysis and investigations for infection), the most useful method to determine diagnosis, and recurrence risk estimate including inter-rater agreement. RESULTS: Mean gestational age was 19.8 weeks. All three investigators agreed in each case on which investigation constituted the best basis to determine the most precise diagnosis. The examinations performed in addition to prenatal ultrasound provided important diagnostic information in 54 cases (56%) and altered recurrence risk in 22 (23%) cases; in eight of these cases the risk estimate was increased. In nine cases (9%) the investigators disagreed in their estimates of recurrence risk. Kappa for inter-rater agreement was >0.90. CONCLUSIONS: A panel of diagnostic investigations, depending on the organ system involved, allows for a more precise diagnosis and a more reliable estimate of recurrence risk than prenatal ultrasound alone. In some instances, recurrence risk estimation is not straightforward as evidenced by lack of consensus.


Assuntos
Anormalidades Múltiplas/diagnóstico por imagem , Sistema Nervoso Central/anormalidades , Aconselhamento Genético , Anormalidades Musculoesqueléticas/diagnóstico por imagem , Anormalidades Múltiplas/diagnóstico , Aborto Induzido , Adulto , Amniocentese , Autopsia , Sistema Nervoso Central/diagnóstico por imagem , Amostra da Vilosidade Coriônica , Feminino , Humanos , Cariotipagem , Anormalidades Musculoesqueléticas/diagnóstico , Gravidez , Radiografia , Recidiva , Estudos Retrospectivos , Fatores de Risco , Ultrassonografia Pré-Natal
13.
Eur J Med Genet ; 50(2): 155-8, 2007 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17324647

RESUMO

We have observed unusual transverse distal phalangeal creases in two patients, one with Costello syndrome (G12S mutation in the HRAS gene) and one with cardio-facio-cutaneous (CFC) syndrome or possibly Noonan syndrome (Q22E mutation in the KRAS gene). This feature along with fetal pads was present in both children at birth and has persisted until age two years. Distal phalangeal creases, when present, may be a good diagnostic handle for syndromes belonging to the RAS signalling pathway.


Assuntos
Falanges dos Dedos da Mão/anormalidades , Síndrome de Noonan/diagnóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/genética , Anormalidades da Pele/genética , Proteínas ras/metabolismo , Pré-Escolar , Feminino , Humanos , Síndrome de Noonan/genética , Anormalidades da Pele/diagnóstico , Proteínas ras/genética
14.
Eur J Med Genet ; 50(2): 159-61, 2007 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17223397

RESUMO

Posterior helical pits are an easily overlooked finding. They are uncommon in the general population although they do occur as an isolated autosomal dominant trait. We have observed posterior helical pits as a feature in three syndromes only: Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome and Rubinstein-Taybi syndrome. We suggest that posterior helical pits, when present, are an excellent diagnostic handle.


Assuntos
Síndrome de Beckwith-Wiedemann/genética , Orelha Externa/anormalidades , Genes Dominantes , Síndrome de Rubinstein-Taybi/genética , Humanos
15.
Healthc Q ; 9(3): 50-4, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16830401

RESUMO

BACKGROUND: We are sick and tired of being redisorganized. OBJECTIVE: To systematically review the empirical evidence for organizational theories and repeated reorganizations. METHODS: We did not find anything worth reading, other than Dilbert, so we fantasized. Unfortunately, our fantasies may well resemble many people's realities. We are sorry about this, but it is not our fault. RESULTS: We discovered many reasons for repeated reorganizations, the most common being 'no good reason'. We estimated that trillions of dollars are being spent on strategic and organizational planning activities each year, thus providing lots of good reasons for hundreds of thousands of people, including us, to get into the business. New leaders who are intoxicated with the prospect of change further fuel perpetual cycles of redisorganization. We identified eight indicators of successful redisorganizations, including large consultancy fees paid to friends and relatives. CONCLUSIONS: We propose the establishment of ethics committees to review all future redisorganization proposals in order to put a stop to uncontrolled, unplanned experimentation inflicted providers and users of the health services.

16.
J R Soc Med ; 98(12): 563-8, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16319441

RESUMO

BACKGROUND: We are sick and tired of being redisorganized. OBJECTIVE: To systematically review the empirical evidence for organizational theories and repeated reorganizations. METHODS: We did not find anything worth reading, other than Dilbert, so we fantasized. Unfortunately, our fantasies may well resemble many people's realities. We are sorry about this, but it is not our fault. RESULTS: We discovered many reasons for repeated reorganizations, the most common being "no good reason". We estimated that trillions of dollars are being spent on strategic and organizational planning activities each year, thus providing lots of good reasons for hundreds of thousands of people, including us, to get into the business. New leaders who are intoxicated with the prospect of change further fuel perpetual cycles of redisorganization. We identified eight indicators of successful redisorganizations, including large consultancy fees paid to friends and relatives. CONCLUSIONS: We propose the establishment of ethics committees to review all future redisorganization proposals in order to put a stop to uncontrolled, unplanned experimentation inflicted on providers and users of the health services.


Assuntos
Reforma dos Serviços de Saúde , Modelos Organizacionais , Senso de Humor e Humor como Assunto , Consultores , Comissão de Ética , Reforma dos Serviços de Saúde/ética , Pesquisa sobre Serviços de Saúde , Inovação Organizacional
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA