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1.
Int J Endocrinol Metab ; 16(3): e67329, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30323850

RESUMO

Introduction: Schaaf-Yang syndrome (SYS) is caused by truncating point mutations of the paternal allele of MAGEL2, an imprinted gene located in the critical region of Prader-Willi syndrome (PWS). These patients present a phenotype with neurodevelopmental delay, hypotonia, joint contractures, and a particularly high prevalence of autism (up to 75% in affected individuals). The loss of function of MAGEL2 is suggested to contribute to endocrine hypothalamic dysfunction in individuals with PWS. Case Presentation: The current study presented the case of a patient with SYS and a novel de novo truncating mutation of MAGEL2 and phenotypic characteristics typical of this Prader-Willi-like syndrome and also including partial hypopituitarism, hypothyroidism, growth hormone deficiency, and hyperprolactinemia. Conclusions: The clinical and molecular similarities between SYS and PWS suggested the need for a thorough endocrinological follow-up to improve the prognosis and long-term quality of life for patients with SYS.

2.
Am J Med Genet A ; 2018 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-30194818

RESUMO

De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28% of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype-phenotype correlation. In the new cohort of 18 patients, 50% of males had genitourinary anomalies and 61% of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype-phenotype correlations.

3.
Am J Hum Genet ; 103(2): 305-316, 2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30057029

RESUMO

Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.

4.
Eur J Hum Genet ; 26(1): 64-74, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29180823

RESUMO

Whole-gene duplications and missense variants in the HUWE1 gene (NM_031407.6) have been reported in association with intellectual disability (ID). Increased gene dosage has been observed in males with non-syndromic mild to moderate ID with speech delay. Missense variants reported previously appear to be associated with severe ID in males and mild or no ID in obligate carrier females. Here, we report the largest cohort of patients with HUWE1 variants, consisting of 14 females and 7 males, with 15 different missense variants and one splice site variant. Clinical assessment identified common clinical features consisting of moderate to profound ID, delayed or absent speech, short stature with small hands and feet and facial dysmorphism consisting of a broad nasal tip, deep set eyes, epicanthic folds, short palpebral fissures, and a short philtrum. We describe for the first time that females can be severely affected, despite preferential inactivation of the affected X chromosome. Three females with the c.329 G > A p.Arg110Gln variant, present with a phenotype of mild ID, specific facial features, scoliosis and craniosynostosis, as reported previously in a single patient. In these females, the X inactivation pattern appeared skewed in favour of the affected transcript. In summary, HUWE1 missense variants may cause syndromic ID in both males and females.

5.
Int J Genomics ; 2017: 4798474, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28630856

RESUMO

We report on three nonrelated patients with intellectual disability and CNVs that give rise to three new chimeric genes. All the genes forming these fusion transcripts may have an important role in central nervous system development and/or in gene expression regulation, and therefore not only their deletion or duplication but also the resulting chimeric gene may contribute to the phenotype of the patients. Deletions and duplications are usually pathogenic when affecting dose-sensitive genes. Alternatively, a chimeric gene may also be pathogenic by different gain-of-function mechanisms that are not restricted to dose-sensitive genes: the emergence of a new polypeptide that combines functional domains from two different genes, the deregulated expression of any coding sequence by the promoter region of a neighboring gene, and/or a putative dominant-negative effect due to the preservation of functional domains of partially truncated proteins. Fusion oncogenes are well known, but in other pathologies, the search for chimeric genes is disregarded. According to our findings, we hypothesize that the frequency of fusion transcripts may be much higher than suspected, and it should be taken into account in the array-CGH analyses of patients with intellectual disability.

6.
J Med Genet ; 54(2): 87-92, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27620904

RESUMO

BACKGROUND: Intellectual disability is a very complex condition where more than 600 genes have been reported. Due to this extraordinary heterogeneity, a large proportion of patients remain without a specific diagnosis and genetic counselling. The need for new methodological strategies in order to detect a greater number of mutations in multiple genes is therefore crucial. METHODS: In this work, we screened a large panel of 1256 genes (646 pathogenic, 610 candidate) by next-generation sequencing to determine the molecular aetiology of syndromic intellectual disability. A total of 92 patients, negative for previous genetic analyses, were studied together with their parents. Clinically relevant variants were validated by conventional sequencing. RESULTS: A definitive diagnosis was achieved in 29 families by testing the 646 known pathogenic genes. Mutations were found in 25 different genes, where only the genes KMT2D, KMT2A and MED13L were found mutated in more than one patient. A preponderance of de novo mutations was noted even among the X linked conditions. Additionally, seven de novo probably pathogenic mutations were found in the candidate genes AGO1, JARID2, SIN3B, FBXO11, MAP3K7, HDAC2 and SMARCC2. Altogether, this means a diagnostic yield of 39% of the cases (95% CI 30% to 49%). CONCLUSIONS: The developed panel proved to be efficient and suitable for the genetic diagnosis of syndromic intellectual disability in a clinical setting. Next-generation sequencing has the potential for high-throughput identification of genetic variations, although the challenges of an adequate clinical interpretation of these variants and the knowledge on further unknown genes causing intellectual disability remain to be solved.


Assuntos
Exoma/genética , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Deficiência Intelectual/genética , Feminino , Humanos , Deficiência Intelectual/patologia , Masculino , Mutação
7.
Pediatr Res ; 80(6): 809-815, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27500536

RESUMO

BACKGROUND: Mutations in the X-linked gene MED12 cause at least three different, but closely related, entities of syndromic intellectual disability. Recently, a new syndrome caused by MED13L deleterious variants has been described, which shows similar clinical manifestations including intellectual disability, hypotonia, and other congenital anomalies. METHODS: Genotyping of 1,256 genes related with neurodevelopment was performed by next-generation sequencing in three unrelated patients and their healthy parents. Clinically relevant findings were confirmed by conventional sequencing. RESULTS: Each patient showed one de novo variant not previously reported in the literature or databases. Two different missense variants were found in the MED12 or MED13L genes and one nonsense mutation was found in the MED13L gene. CONCLUSION: The phenotypic consequences of these mutations are closely related and/or have been previously reported in one or other gene. Additionally, MED12 and MED13L code for two closely related partners of the mediator kinase module. Consequently, we propose the concept of a common MED12/MED13L clinical spectrum, encompassing Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, Ohdo syndrome, MED13L haploinsufficiency syndrome, and others.


Assuntos
Deficiência Intelectual/genética , Complexo Mediador/genética , Mutação , Anormalidades Múltiplas/genética , Substituição de Aminoácidos , Criança , Códon sem Sentido , Análise Mutacional de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Proteínas Mutantes/genética , Mutação de Sentido Incorreto , Fenótipo , Síndrome , Adulto Jovem
8.
Hum Mutat ; 37(8): 804-11, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27159028

RESUMO

Intellectual disability (ID) is a heterogeneous disorder with an unknown molecular etiology in many cases. Previously, X-linked ID (XLID) studies focused on males because of the hemizygous state of their X chromosome. Carrier females are generally unaffected because of the presence of a second normal allele, or inactivation of the mutant X chromosome in most of their cells (skewing). However, in female ID patients, we hypothesized that the presence of skewing of X-inactivation would be an indicator for an X chromosomal ID cause. We analyzed the X-inactivation patterns of 288 females with ID, and found that 22 (7.6%) had extreme skewing (>90%), which is significantly higher than observed in the general population (3.6%; P = 0.029). Whole-exome sequencing of 19 females with extreme skewing revealed causal variants in six females in the XLID genes DDX3X, NHS, WDR45, MECP2, and SMC1A. Interestingly, variants in genes escaping X-inactivation presumably cause both XLID and skewing of X-inactivation in three of these patients. Moreover, variants likely accounting for skewing only were detected in MED12, HDAC8, and TAF9B. All tested candidate causative variants were de novo events. Hence, extreme skewing is a good indicator for the presence of X-linked variants in female patients.


Assuntos
Variação Genética , Deficiência Intelectual/genética , Análise de Sequência de DNA/métodos , Inativação do Cromossomo X , Proteínas de Transporte/genética , Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , RNA Helicases DEAD-box/genética , Exoma , Feminino , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Proteínas Nucleares/genética
9.
Am J Hum Genet ; 97(6): 922-32, 2015 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-26637982

RESUMO

We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single-nucleotide changes, but they also demonstrated a severe neurodegeneration phenotype. Functional analysis with RNA-seq for one of the families suggested that the phenotype is associated with downregulation of a set of genes notably enriched with genes regulated by E-box proteins. In addition, knockdown and mutant studies of this gene in zebrafish have shown a quantifiable, albeit small, effect on a neuronal phenotype. Our results suggest that mutations in TAF1 play a critical role in the development of this X-linked ID syndrome.


Assuntos
Deficiências do Desenvolvimento/genética , Histona Acetiltransferases/genética , Deficiência Intelectual/genética , Doenças Neurodegenerativas/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Adolescente , Animais , Criança , Pré-Escolar , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Modelos Animais de Doenças , Elementos E-Box , Facies , Família , Regulação da Expressão Gênica , Histona Acetiltransferases/metabolismo , Humanos , Lactente , Padrões de Herança , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Mutação , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Linhagem , Fenótipo , Transdução de Sinais , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Fator de Transcrição TFIID/metabolismo , Adulto Jovem , Peixe-Zebra
11.
Pediatr Res ; 78(5): 533-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26200704

RESUMO

BACKGROUND: Only 15 point mutations in NFIX gene have been reported so far, nine of them cause the Marshall-Smith syndrome (MSS) and the remaining mutations lead to an overgrowth disorder with a less severe phenotype, defined as Sotos-like. METHODS: The clinical findings in three patients with MSS and two patients with a Sotos-like phenotype are presented. Analysis of the NFIX gene was performed both by conventional or next-generation sequencing. RESULTS: Five de novo mutations in NFIX gene were identified, four of them not previously reported. Two frameshift mutations and a donor-splice one caused MSS, while two missense mutations in the DNA binding/dimerisation domain entailed an overgrowth syndrome with some clinical features resembling Sotos syndrome, accompanied by a marfanoid habitus, very low BMI, long narrow face, or arachnodactyly. CONCLUSION: Marshall-Smith mutations are scattered through exons 6-10 of NFIX gene, while most point mutations causing an overgrowth syndrome are clustered in exon 2. Clinical features of this overgrowth syndrome may well be considered an intermediate phenotype between Sotos and Marfan syndromes.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Mutação , Fatores de Transcrição NFI/genética , Displasia Septo-Óptica/genética , Síndrome de Sotos/genética , Anormalidades Múltiplas/diagnóstico , Sequência de Aminoácidos , Sequência de Bases , Doenças do Desenvolvimento Ósseo/diagnóstico , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Análise Mutacional de DNA/métodos , Éxons , Evolução Fatal , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Fenótipo , Displasia Septo-Óptica/diagnóstico , Síndrome de Sotos/diagnóstico , Adulto Jovem
12.
Am J Med Genet A ; 167A(10): 2265-71, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26097044

RESUMO

Severe variants of fibrodysplasia ossificans progressiva (FOP) affect <2% of all FOP patients worldwide, but provide an unprecedented opportunity to probe the phenotype-genotype relationships that propel the pathology of this disabling disease. We evaluated two unrelated children who had severe reduction deficits of the hands and feet with absence of nails, progressive heterotopic ossification, hypoplasia of the brain stem, motor and cognitive developmental delays, facial dysmorphology, small malformed teeth, and abnormal hair development. One child had sensorineural hearing loss, microcytic anemia, and a tethered spinal cord and the other had a patent ductus arteriosus and gonadal dysgenesis with sex reversal (karyotype 46, XY female). Both children had an identical mutation in ACVR1 c.772A>G; p.Arg258Gly (R258G), not previously described in FOP. Although many, if not most, FOP mutations directly perturb the structure of the GS regulatory subdomain and presumably the adjacent αC helix, substitution with glycine at R258 may directly alter the position of the helix in the kinase domain, eliminating a key aspect of the autoinhibitory mechanism intrinsic to the wild-type ACVR1 kinase. The high fidelity phenotype-genotype relationship in these unrelated children with the most severe FOP phenotype reported to date suggests that the shared features are due to the dysregulated activity of the mutant kinase during development and postnatally, and provides vital insight into the structural biology and function of ACVR1 as well as the design of small molecule inhibitors.


Assuntos
Anormalidades Múltiplas/patologia , Receptores de Ativinas Tipo I/genética , Mutação , Miosite Ossificante/patologia , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/enzimologia , Anormalidades Múltiplas/genética , Receptores de Ativinas Tipo I/metabolismo , Substituição de Aminoácidos , Feminino , Expressão Gênica , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Cariótipo , Modelos Moleculares , Miosite Ossificante/diagnóstico , Miosite Ossificante/enzimologia , Miosite Ossificante/genética , Fenótipo , Estrutura Terciária de Proteína , Índice de Gravidade de Doença
13.
Biomed Res Int ; 2015: 341986, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26106604

RESUMO

Alterations of epigenetic mechanisms, and more specifically imprinting modifications, could be responsible of neurodevelopmental disorders such as intellectual disability (ID) or autism together with other associated clinical features in many cases. Currently only eight imprinting syndromes are defined in spite of the fact that more than 200 genes are known or predicted to be imprinted. Recent publications point out that some epimutations which cause imprinting disorders may affect simultaneously different imprinted loci, suggesting that DNA-methylation may have been altered more globally. Therefore, we hypothesised that the detection of altered methylation patterns in known imprinting loci will indirectly allow identifying new syndromes due to epimutations among patients with unexplained ID. In a screening for imprinting alterations in 412 patients with syndromic ID/autism we found five patients with altered methylation in the four genes studied: MEG3, H19, KCNQ1OT1, and SNRPN. Remarkably, the cases with partial loss of methylation in KCNQ1OT1 and SNRPN present clinical features different to those associated with the corresponding imprinting syndromes, suggesting a multilocus methylation defect in accordance with our initial hypothesis. Consequently, our results are a proof of concept that the identification of epimutations in known loci in patients with clinical features different from those associated with known syndromes will eventually lead to the definition of new imprinting disorders.


Assuntos
Impressão Genômica , Transtornos do Neurodesenvolvimento/genética , Proteínas Centrais de snRNP/genética , Adulto , Criança , Pré-Escolar , Metilação de DNA/genética , Epigênese Genética , Feminino , Dosagem de Genes/genética , Humanos , Masculino , Mutação , Transtornos do Neurodesenvolvimento/patologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética
14.
Am J Med Genet A ; 167(7): 1614-20, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25858326

RESUMO

This paper describes the presence of an interstitial pure duplication of 19p13.3 (4.95 Mb) in a patient with intellectual disability studied by array-CGH which was initially considered as a de novo alteration. The discovery of the same chromosomal alteration in a first-degree cousin of this patient led us to investigate the presence of insertional translocations, which were consequently found in three family generations. The same duplication was found in three intellectually disabled patients and among the translocation carrier family members a very high incidence of miscarriages are reported. A review of other published cases has allowed us to find three other patients with a similar pure duplication, all of them sharing some common clinical findings such as intrauterine growth retardation, microcephaly, motor and speech delay, moderate to severe intellectual disability, and dysmorphic features. These findings allow us to suggest the presence of a new microduplication syndrome in chromosomal region 19p13.3.


Assuntos
Anormalidades Múltiplas/genética , Transtornos Cromossômicos/genética , Duplicação Cromossômica/genética , Cromossomos Humanos Par 19/genética , Deficiência Intelectual/genética , Microcefalia/genética , Hibridização Genômica Comparativa , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Síndrome
15.
Am J Med Genet A ; 167(6): 1342-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25900314

RESUMO

The NSDHL gene encodes 3ß-hydroxysteroid dehydrogenase involved in one of the later steps of the cholesterol biosynthetic pathway. Mutations in this gene can cause CHILD syndrome (OMIM 308050) and CK syndrome (OMIM 300831). CHILD syndrome is an X-linked dominant, male lethal disorder caused by mutations in the NSDHL gene that result in the loss of the function of the NSDHL protein. CK syndrome is an allelic X-linked recessive disorder. So far, 13 patients with CK syndrome from two families have been reported on. We present a new five-generation family with affected males manifesting clinical features of CK syndrome. Next generation sequencing was targeted to a custom panel of 542 genes with known or putative implication on intellectual disability. Missense mutation p.Gly152Asp was identified in the NSDHL gene in the DNA sample of the affected male. Mutation carrier status was confirmed for all the obligate carriers in the family. The clinical features of the affected males in the family manifested as weak fetal movements, severe intellectual disability, seizures, spasticity, atrophy of optic discs, microcephaly, plagiocephaly, skeletal abnormalities, and minor facial anomalies, including a high nasal bridge, strabismus, and micrognathia. A highly significant preferential transmission of the mutation was observed in this and previous families segregating CK syndrome. Our report expands the clinical spectrum of this syndrome to include weak fetal movements, spasticity, and plagiocephaly, and transmission ratio distortion. The various findings in these patients increase our understanding of the diversity of the clinical presentation of cholesterol biosynthesis disorders.


Assuntos
3-Hidroxiesteroide Desidrogenases/genética , Anormalidades Múltiplas/genética , Epilepsia Tônico-Clônica/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Eritrodermia Ictiosiforme Congênita/genética , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/genética , Mutação de Sentido Incorreto , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Alelos , Epilepsia Tônico-Clônica/diagnóstico , Epilepsia Tônico-Clônica/patologia , Feminino , Expressão Gênica , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Eritrodermia Ictiosiforme Congênita/diagnóstico , Eritrodermia Ictiosiforme Congênita/patologia , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/patologia , Lituânia , Masculino , Linhagem
16.
J Clin Immunol ; 35(2): 168-81, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25721700

RESUMO

MECP2 (methyl CpG binding protein 2) duplication causes syndromic intellectual disability. Patients often suffer from life-threatening infections, suggesting an additional immunodeficiency. We describe for the first time the detailed infectious and immunological phenotype of MECP2 duplication syndrome. 17/27 analyzed patients suffered from pneumonia, 5/27 from at least one episode of sepsis. Encapsulated bacteria (S.pneumoniae, H.influenzae) were frequently isolated. T-cell immunity showed no gross abnormalities in 14/14 patients and IFNy-secretion upon ConA-stimulation was not decreased in 6/7 patients. In 6/21 patients IgG2-deficiency was detected - in 4/21 patients accompanied by IgA-deficiency, 10/21 patients showed low antibody titers against pneumococci. Supra-normal IgG1-levels were detected in 11/21 patients and supra-normal IgG3-levels were seen in 8/21 patients - in 6 of the patients as combined elevation of IgG1 and IgG3. Three of the four patients with IgA/IgG2-deficiency developed multiple severe infections. Upon infections pronounced acute-phase responses were common: 7/10 patients showed CRP values above 200 mg/l. Our data for the first time show systematically that increased susceptibility to infections in MECP2 duplication syndrome is associated with IgA/IgG2-deficiency, low antibody titers against pneumococci and elevated acute-phase responses. So patients with MECP2 duplication syndrome and low IgA/IgG2 may benefit from prophylactic substitution of sIgA and IgG.


Assuntos
Duplicação Gênica , Infecção/etiologia , Retardo Mental Ligado ao Cromossomo X/complicações , Retardo Mental Ligado ao Cromossomo X/imunologia , Proteína 2 de Ligação a Metil-CpG/genética , Fenótipo , Proteínas da Fase Aguda/metabolismo , Adolescente , Adulto , Proteína C-Reativa/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Genótipo , Humanos , Imunidade Celular , Imunidade Humoral , Imunoglobulinas/sangue , Imunoglobulinas/imunologia , Infecção/diagnóstico , Infecção/tratamento farmacológico , Masculino , Retardo Mental Ligado ao Cromossomo X/diagnóstico , Pessoa de Meia-Idade , Adulto Jovem
17.
Med. clín (Ed. impr.) ; 142(12): 531-537, jun. 2014. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-122582

RESUMO

Fundamento y objetivo: Las alteraciones genómicas desequilibradas (duplicaciones o deleciones) causantes de trastornos del neurodesarrollo (TND) son en su mayoría episodios de novo. Sin embargo, también pueden surgir como consecuencia de reordenamientos equilibrados no detectados en uno de los progenitores, cambiando radicalmente el riesgo de recurrencia y el consejo genético de estos casos. La técnica de fluorescence in situ hybridization (FISH, «hibridación in situ fluorescente») permite la identificación y localización de reordenamientos cromosómicos tanto equilibrados como desequilibrados, identificando la ubicación de los segmentos duplicados. En este trabajo se pretende localizar en el genoma los segmentos duplicados detectados en pacientes con TND, e identificar aquellos casos debidos a reordenamientos heredados. Pacientes y método: El estudio se llevó a cabo en 13 pacientes con TND y portadores de duplicaciones génicas detectadas por compared genomic hybridization-array (CGH-array, «hibridación genómica comparada sobre arrays»). Se utilizaron 2 aproximaciones de la técnica FISH: hibridación con sondas de pintado cromosómico y con sondas específicas de cada duplicación. Resultados: En la serie de 13 pacientes con duplicación estudiados, se han encontrado 11 con duplicaciones en tándem, un caso con una traslocación insercional intracromosómica, y otro con una traslocación insercional intercromosómica. Por tanto, 2 de las duplicaciones que se habían considerado de novo habían sido, en realidad, heredadas de forma desequilibrada de un progenitor que era portador equilibrado del reordenamiento. Conclusión: Los resultados ponen de manifiesto la necesidad de caracterizar, mediante la técnica de FISH, los reordenamientos que se detectan por CGH-array, para identificar los casos con un elevado riesgo de recurrencia y realizar un correcto asesoramiento genético (AU)


Background and objective: An important proportion of neurodevelopmental disorders (NDDs) results from unbalanced genomic alterations (duplication or deletion). These chromosomal rearrangements may be considered as de novo, despite they arise as a result of a balanced rearrangement not detected in a phenotypically normal parent. Therefore, if the rearrangements are inherited, the recurrence risk and the genetic counseling of these cases change radically. Fluorescence in situ hybridization (FISH) is a technique that allows detecting both balanced and unbalanced rearrangements, identifying also the location of duplicated segments. We tried to locate in the genome the duplicated segments detected in patients with NDDs in order to identify those cases due to inherited rearrangements. Patients and method: The study was conducted in 13 patients with NDDs and genomic duplications detected by compared genomic hybridization-array (CGH-array). Two approaches of FISH technique were taken: hybridization with painting chromosome probes and with specific probes for each duplication. Results: In the studied series of 13 patients with duplication, 11 patients were found to carry tandemduplications, one with an intrachromosomal insertional translocation, and another with an interchromosomal insertional translocation. Therefore, 2 of the duplications considered de novo were actually an unbalanced rearrangement inherited from a parent who is a balanced carrier. Conclusion: The results illustrate the need to characterize by FISH technique the rearrangements that are detected by CGH-array to identify those cases with a high risk of recurrence (AU)


Assuntos
Humanos , Masculino , Feminino , Duplicação Cromossômica/genética , Duplicações Segmentares Genômicas/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Hibridização in Situ Fluorescente/métodos , Hibridização Genômica Comparativa/métodos , Mutagênese Insercional/métodos , Predisposição Genética para Doença/genética , Marcadores Genéticos/genética , Desequilíbrio Alélico/genética
18.
Eur J Paediatr Neurol ; 18(5): 558-66, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24815074

RESUMO

BACKGROUND: Nowadays the microarray technology allows whole-genome analysis with a high resolution and performance for the genetic diagnosis in any patient with intellectual disability or autism spectrum disorder. However in the immediate future, with the development of massive sequencing systems for application at clinical diagnosis, it will be necessary to have clinical criteria to guide studies. AIM: To perform an exhaustive clinical definition of patients with pathogenic copy number variations in order to establish the clinical criteria most suggestive of this kind of genomic rearrangements. METHOD: We designed and implemented a database to collect 190 different clinical variables (pregnancy, neonatal, facial dysmorphism, congenital anomalies, neurological features and family history) in a series of 246 patients, with developmental delay/intellectual disability. All cases were studied with array comparative genomic hybridization. RESULTS: We have found a pathogenic genomic imbalance in 73 patients. Frequency analysis of all clinical variables showed that growth disorder, abnormalities of hands, low-set ears and hypertelorism are the more frequent features among patients with genomic rearrangements. However other clinical features, such as genital abnormalities and aggressiveness, are more specifically associated with pathogenic copy number variations in spite of their low frequencies in the overall series, yielding higher statistical significance values than other traits. CONCLUSIONS: The genotype-phenotype comparison may be useful to set in the future the main clinical manifestations associated with deletions, duplications and unbalanced translocations. Theses analyses will improve the clinical indications and protocols to implement genomic arrays in the genetic study of patients with neurodevelopment disorders.


Assuntos
Aberrações Cromossômicas , Variações do Número de Cópias de DNA/genética , Genoma/genética , Deficiência Intelectual/genética , Fenótipo , Criança , Bases de Dados Genéticas , Deficiências do Desenvolvimento/diagnóstico , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/etiologia , Masculino , Análise em Microsséries
19.
Am J Med Genet A ; 164A(4): 918-23, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24458433

RESUMO

Here we report on two unrelated male patients with syndromic intellectual disability (ID) due to duplication at Xq13.3-q21.1, a region of about 6 Mb and 25 genes. Among these, the most outstanding is ATRX, the causative gene of X-linked alpha-thalassemia/mental retardation. ATRX belongs to the growing list of genes implied in chromatin remodeling causing ID. Many these genes, such as MECP2, are dose-sensitive so that not only deletions and point mutations, but also duplications cause ID. Both patients have severe ID, absent expressive speech, early hypotonia, behavior problems (hyperactivity, repetitive self-stimulatory behavior), postnatal growth deficiency, microcephaly, micrognathia, cryptorchidism, low-set, posteriorly angulated ears, and downslanting palpebral fissures. These findings are also usually present among patients with loss-of-function mutations of the ATRX gene. Completely skewed X inactivation was observed in the only informative carrier mother, a constant finding among female carriers of inactivating point mutations of this gene. Participation of other duplicated genes cannot be excluded; nevertheless we propose that the increased dosage of ATRX is the major pathogenic mechanism of this X-linked disorder, a syndrome reminiscent of MECP2 duplication.


Assuntos
Cromossomos Humanos X , DNA Helicases/genética , Duplicação Gênica , Deficiência Intelectual/genética , Retardo Mental Ligado ao Cromossomo X/genética , Proteínas Nucleares/genética , Adolescente , Criança , Feminino , Humanos , Masculino , Mutação , Inativação do Cromossomo X , Proteína Nuclear Ligada ao X , Talassemia alfa/genética
20.
Med Clin (Barc) ; 142(12): 531-7, 2014 Jun 16.
Artigo em Espanhol | MEDLINE | ID: mdl-23790573

RESUMO

BACKGROUND AND OBJECTIVE: An important proportion of neurodevelopmental disorders (NDDs) results from unbalanced genomic alterations (duplication or deletion). These chromosomal rearrangements may be considered as de novo, despite they arise as a result of a balanced rearrangement not detected in a phenotypically normal parent. Therefore, if the rearrangements are inherited, the recurrence risk and the genetic counseling of these cases change radically. Fluorescence in situ hybridization (FISH) is a technique that allows detecting both balanced and unbalanced rearrangements, identifying also the location of duplicated segments. We tried to locate in the genome the duplicated segments detected in patients with NDDs in order to identify those cases due to inherited rearrangements. PATIENTS AND METHOD: The study was conducted in 13 patients with NDDs and genomic duplications detected by compared genomic hybridization-array (CGH-array). Two approaches of FISH technique were taken: hybridization with painting chromosome probes and with specific probes for each duplication. RESULTS: In the studied series of 13 patients with duplication, 11 patients were found to carry tandem duplications, one with an intrachromosomal insertional translocation, and another with an interchromosomal insertional translocation. Therefore, 2 of the duplications considered de novo were actually an unbalanced rearrangement inherited from a parent who is a balanced carrier. CONCLUSION: The results illustrate the need to characterize by FISH technique the rearrangements that are detected by CGH-array to identify those cases with a high risk of recurrence.


Assuntos
Duplicação Cromossômica , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Testes Genéticos/métodos , Hibridização in Situ Fluorescente , Doenças do Sistema Nervoso/genética , Criança , Pré-Escolar , Humanos , Masculino , Linhagem , Risco , Translocação Genética
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