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1.
Eur J Hum Genet ; 27(8): 1254-1259, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30936465

RESUMO

De novo DDX3X variants account for 1-3% of syndromic intellectual disability (ID) in females and have been occasionally reported in males. Furthermore, somatic DDX3X variants occur in several aggressive cancers, including medulloblastoma. We report three unrelated females with severe ID, dysmorphic features, and a common brain malformative pattern characterized by malformations of cortical development, callosal dysgenesis, basal ganglia anomalies, and midbrain-hindbrain malformations. A pilocytic astrocytoma was incidentally diagnosed in Patient 1 and trigonocephaly was found in Patient 2. With the use of family based whole exome sequencing (WES), we identified three distinct de novo variants in DDX3X. These findings expand the phenotypic spectrum of DDX3X-related disorders, demonstrating unique neuroradiological features resembling those of the tubulinopathies, and support a role for DDX3X in neuronal development. Our observations further suggest a possible link between germline DDX3X variants and cancer development.

2.
Hum Genet ; 138(3): 257-269, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30806792

RESUMO

Rubinstein-Taybi syndrome (RSTS) is an autosomal-dominant neurodevelopmental disease affecting 1:125,000 newborns characterized by intellectual disability, growth retardation, facial dysmorphisms and skeletal abnormalities. RSTS is caused by mutations in genes encoding for writers of the epigenetic machinery: CREBBP (~ 60%) or its homologous EP300 (~ 10%). No causative mutation is identified in up to 30% of patients. We performed whole-exome sequencing (WES) on eight RSTS-like individuals who had normal high-resolution array CGH testing and were CREBBP- and EP300-mutation -negative, to identify the molecular cause. In four cases, we identified putatively causal variants in three genes (ASXL1, KMT2D and KMT2A) encoding members of the epigenetic machinery known to be associated with the Bohring-Opitz, Kabuki and Wiedemann-Steiner syndromes. Each variant is novel, de novo, fulfills the ACMG criteria and is predicted to result in loss-of-function leading to haploinsufficiency of the epi-gene. In two of the remaining cases, homozygous/compound heterozygous variants in XYLT2 and PLCB4 genes, respectively, associated with spondyloocular and auriculocondylar 2 syndromes and in the latter an additional candidate variant in XRN2, a gene yet unrelated to any disease, were detected, but their pathogenicity remains uncertain. These results underscore the broad clinical spectrum of Mendelian disorders of the epigenetic apparatus and the high rate of WES disclosure of the genetic basis in cases which may pose a challenge for phenotype encompassing distinct syndromes. The overlapping features of distinct intellectual disability syndromes reflect common pathogenic molecular mechanisms affecting the complex regulation of balance between open and closed chromatin.


Assuntos
Estudos de Associação Genética , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/genética , Sequenciamento Completo do Exoma , Proteína de Ligação a CREB/genética , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Proteína p300 Associada a E1A/genética , Epigênese Genética , Facies , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Fenótipo
3.
Neuron ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30449657

RESUMO

Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule-associated protein that is predominantly expressed in post-mitotic neurons and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions, we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant-negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.

6.
Eur J Paediatr Neurol ; 21(6): 902-906, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28754298

RESUMO

BACKGROUND: SHANK3 mutations are responsible for Phelan-McDermid syndrome but they are also associated with autism and/or intellectual disability. CASE REPORT: We report a family with four affected individuals including the 37 year-old mother, her 12 year-old male monozygotic twins and 8 year-old daughter harboring a novel SHANK3 interstitial microdeletion. All four members presented with intellectual disability of variable severity. The twins showed brain abnormalities similar to Unidentified Bright Objects (UBOs), typically detected in patients with Neurofibromatosis type 1 (NF1), but they did not display causative mutations in NF1 gene. CONCLUSION: To date, this is the first report of an affected individual with SHANK3 interstitial deletion able to reproduce. Moreover, we found a previously unreported possible association between SHANK3 deletion and UBOs-like lesions in the brain.


Assuntos
Encéfalo/anormalidades , Transtornos Cromossômicos/genética , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Adulto , Encéfalo/patologia , Criança , Deleção Cromossômica , Transtornos Cromossômicos/patologia , Cromossomos Humanos Par 22/genética , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Mutação , Linhagem
7.
Eur J Hum Genet ; 24(9): 1359-62, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26860062

RESUMO

We report an 8-year-old boy with a complex cerebral malformation, intellectual disability, and complex partial seizures. Whole-exome sequencing revealed a yet unreported de novo variant in the PIK3R2 gene that was recently associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome and bilateral perisylvian polymicrogyria (BPP). Our patient showed cerebral abnormalities (megalencephaly, perisylvian polymicrogyria, and mega corpus callosum) that were consistent with these conditions. Imaging also showed right temporal anomalies suggestive of cortical dysplasia. Until now, only three variants (c.1117G>A (p.(G373R)), c.1126A>G (p.(K376E)) and c.1202T>C (p.(L401P))) affecting the SH2 domain of the PIK3R2 protein have been reported in MPPH and BPP syndromes. In contrast to the variants reported so far, the patient described herein exhibits the c.1669G>C (p.(D557H)) variant that affects a highly conserved residue at the interface with the PI3K catalytic subunit α. The phenotypic spectrum associated with variants in this gene and its pathway are likely to continue to expand as more cases are identified.


Assuntos
Agenesia do Corpo Caloso/genética , Malformações do Desenvolvimento Cortical/genética , Mutação de Sentido Incorreto , Fosfatidilinositol 3-Quinases/genética , Polimicrogiria/genética , Agenesia do Corpo Caloso/diagnóstico , Criança , Humanos , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico , Fenótipo , Fosfatidilinositol 3-Quinases/química , Polimicrogiria/diagnóstico , Síndrome
8.
Am J Hematol ; 90(10): 921-6, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26178367

RESUMO

Dehydrated hereditary stomatocytosis (DHSt) is an autosomal dominant congenital hemolytic anemia with moderate splenomegaly and often compensated hemolysis. Affected red cells are characterized by a nonspecific cation leak of the red cell membrane, reflected in elevated sodium content, decreased potassium content, elevated MCHC and MCV, and decreased osmotic fragility. The majority of symptomatic DHSt cases reported to date have been associated with gain-of-function mutations in the mechanosensitive cation channel gene, PIEZO1. A recent study has identified two families with DHSt associated with a single mutation in the KCNN4 gene encoding the Gardos channel (KCa3.1), the erythroid Ca(2+) -sensitive K(+) channel of intermediate conductance, also expressed in many other cell types. We present here, in the second report of DHSt associated with KCNN4 mutations, two previously undiagnosed DHSt families. Family NA exhibited the same de novo missense mutation as that recently described, suggesting a hot spot codon for DHSt mutations. Family WO carried a novel, inherited missense mutation in the ion transport domain of the channel. The patients' mild hemolytic anemia did not improve post-splenectomy, but splenectomy led to no serious thromboembolic events. We further characterized the expression of KCNN4 in the mutated patients and during erythroid differentiation of CD34+ cells and K562 cells. We also analyzed KCNN4 expression during mouse embryonic development.


Assuntos
Anemia Hemolítica Congênita/genética , Hidropisia Fetal/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Anemia Hemolítica Congênita/cirurgia , Animais , Feminino , Humanos , Hidropisia Fetal/cirurgia , Células K562 , Masculino , Camundongos , Esplenectomia/efeitos adversos , Tromboembolia/etiologia , Tromboembolia/genética
9.
Ital J Pediatr ; 40: 5, 2014 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-24433316

RESUMO

Interstitial deletions of the long arm of chromosome 13 (13q) are related with variable phenotypes, according to the size and the location of the deleted region. The main clinical features are moderate/severe mental and growth retardation, cranio-facial dysmorphism, variable congenital defects and increased susceptibility to tumors. Here we report a 3-year-old girl carrying a de novo 13q13.3-21.32 interstitial deletion. She showed developmental delay, growth retardation and mild dysmorphism including curly hair, high forehead, short nose, thin upper lip and long philtrum. An abnormal mass was surgically removed from her liver resulting in a hemangioendothelioma. Array analysis allowed us to define a deleted region of about 27.87 Mb, which includes the RB1 gene. This is the first report of a 13q deletion associated with infantile hemangioendothelioma of the liver.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 13/genética , Predisposição Genética para Doença , Hemangioendotelioma/genética , Neoplasias Hepáticas/genética , Proteína do Retinoblastoma/genética , Transtornos Cromossômicos/diagnóstico , DNA/análise , Diagnóstico Diferencial , Feminino , Hemangioendotelioma/complicações , Hepatectomia , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirurgia , Fenótipo
10.
Neurogenetics ; 14(1): 77-83, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23274687

RESUMO

GPR56-related bilateral frontoparietal polymicrogyria (BFPP) is a rare recessively inherited disorder of neuronal migration caused by mutations of GPR56. To better delineate the clinical, molecular, and neuroradiological phenotypes associated with BFPP, we performed conventional magnetic resonance imaging and diffusion tensor imaging studies in a series of prospectively enrolled patients carrying novel GPR56 mutations. All subjects with GPR56-related BFPP showed a characteristic morphological pattern, including abnormalities of the cerebellar cortex with cerebellar cysts located at the periphery, a mildly thick corpus callosum, and a flat pons. Significant alterations of myelination and white matter tract abnormalities were documented. The present study confirms the phenotypic overlap between GPR56-related brain dysgenesis and other cobblestone-like syndromes and illustrates the contribution of 3D neuroimaging in the characterization of malformations of cortical development.


Assuntos
Encéfalo/diagnóstico por imagem , Lissencefalia Cobblestone/diagnóstico por imagem , Lissencefalia Cobblestone/genética , Mutação , Receptores Acoplados a Proteínas-G/genética , Sequência de Bases , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Imagem de Tensor de Difusão , Feminino , Estudos de Associação Genética , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Mutação/fisiologia , Fenótipo , Radiografia
11.
Orphanet J Rare Dis ; 7: 4, 2012 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-22236771

RESUMO

Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the more severe neuroimaging findings. Based on the literature and this study we suggest as diagnostic criteria for OFD VI: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of one or more hands or feet; 3) hypothalamic hamartoma.


Assuntos
Imagem por Ressonância Magnética/métodos , Neuroimagem/métodos , Síndromes Orofaciodigitais/diagnóstico , Síndromes Orofaciodigitais/patologia , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Doenças Cerebelares/classificação , Doenças Cerebelares/diagnóstico , Doenças Cerebelares/genética , Doenças Cerebelares/patologia , Cerebelo/anormalidades , Criança , Pré-Escolar , Anormalidades do Olho/classificação , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Doenças Renais Císticas/classificação , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Masculino , Síndromes Orofaciodigitais/classificação , Síndromes Orofaciodigitais/genética , Fenótipo , Polidactilia/diagnóstico , Polidactilia/patologia , Retina/anormalidades , Retina/patologia , Adulto Jovem
12.
Expert Rev Proteomics ; 6(2): 159-69, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19385943

RESUMO

Complete description of the complex network of cellular mechanisms and use of the network to predict the full range of cellular behaviors are major goals of systems biology. A key role in contemporary biology can be played by functional proteomics, which focuses on the elucidation of protein functions and the definition of cellular mechanisms at the molecular level. The attainment of these targets is strictly dependent on the identification of individual proteins within functional complexes in vivo. Isolation of interacting proteins relies on either affinity-based or immunoprecipitation procedures in which the protein bait and its specific partners can be fished out by their specific binding to ligand molecules immobilized on insoluble supports. These approaches led to the final identification of several proteins belonging to distinct complexes endowed with different biological functions. Assignment of each protein to a specific complex constitutes a tremendous problem that can only be partially solved using protein-protein interaction databases and literature information. The development of prefractionation methodologies to separate individual protein complexes while preserving their native interactions might then represent an essential tool for the future of functional proteomics. Prepurification of single complexes can only be pursued under native conditions on the basis of their physicochemical features, such as size, dimension (gel filtration chromatography) and density (gradient ultracentrifugation). Following prefractionation, the complex associated to a specific biological function can be isolated using affinity purification techniques. Functional proteomics approaches able to describe individual proteins belonging to complexes involved in specific cellular functions will have a terrific impact on future systems biology studies.


Assuntos
Proteínas/análise , Proteômica/métodos , Animais , Imunoprecipitação , Modelos Teóricos , Ligação Proteica
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