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1.
J Med Genet ; 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32817298

RESUMO

BACKGROUND: We describe two unrelated patients who display similar clinical features including telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. METHODS: We performed trio whole exome sequencing and functional analysis using in vitro kinase assays with recombinant proteins. RESULTS: We identified two different de novo mutations in protein kinase D1 (PRKD1, NM_002742.2): c.1774G>C, p.(Gly592Arg) and c.1808G>A, p.(Arg603His), one in each patient. PRKD1 (PKD1, HGNC:9407) encodes a kinase that is a member of the protein kinase D (PKD) family of serine/threonine protein kinases involved in diverse cellular processes such as cell differentiation and proliferation and cell migration as well as vesicle transport and angiogenesis. Functional analysis using in vitro kinase assays with recombinant proteins showed that the mutation c.1808G>A, p.(Arg603His) represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The mutation c.1774G>C, p.(Gly592Arg) in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation. CONCLUSION: The present cases represent a syndrome, which associates symptoms from several different organ systems: skin, teeth, bones and heart, caused by heterozygous de novo mutations in PRKD1 and expands the clinical spectrum of PRKD1 mutations, which have hitherto been linked to syndromic congenital heart disease and limb abnormalities.

2.
Eur J Med Genet ; 63(4): 103822, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31805394

RESUMO

We report that recessive inheritance of a post-GPI attachment to proteins 2 (PGAP2) gene variant results in the hyperphosphatasia with neurologic deficit (HPMRS) phenotype described by Mabry et al., in 1970. HPMRS, or Mabry syndrome, is now known to be one of 21 inherited glycosylphosphatidylinositol (GPI) deficiencies (IGDs), or GPI biosynthesis defects (GPIBDs). Bi-allelic mutations in at least six genes result in HPMRS phenotypes. Disruption of four phosphatidylinositol glycan (PIG) biosynthesis genes, PIGV, PIGO, PIGW and PIGY, expressed in the endoplasmic reticulum, result in HPMRS 1, 2, 5 and 6; disruption of the PGAP2 and PGAP3 genes, necessary for stabilizing the association of GPI anchored proteins (AP) with the Golgi membrane, result in HPMRS 3 and 4. We used exome sequencing to identify a novel homozygous missense PGAP2 variant NM_014489.3:c.881C > T, p.Thr294Met in two index patients and targeted sequencing to identify this variant in an unrelated patient. Rescue assays were conducted in two PGAP2 deficient cell lines, PGAP2 KO cells generated by CRISPR/Cas9 and PGAP2 deficient CHO cells, in order to examine the pathogenicity of the PGAP2 variant. First, we used the CHO rescue assay to establish that the wild type PGAP2 isoform 1, translated from transcript 1, is less active than the wild type PGAP2 isoform 8, translated from transcript 12 (alternatively spliced to omit exon 3). As a result, in our variant rescue assays, we used the more active NM_001256240.2:c.698C > T, p.Thr233Met isoform 8 instead of NM_014489.3:c.881C > T, p.Thr294Met isoform 1. Flow cytometric analysis showed that restoration of cell surface CD59 and CD55 with variant PGAP2 isoform 8, driven by the weak (pTA FLAG) promoter, was less efficient than wild type isoform 8. Therefore, we conclude that recessive inheritance of c.881C > T PGAP2, expressed as the hypomorphic PGAP2 c.698C > T, p.Thr233Met isoform 8, results in prototypical Mabry phenotype, HPMRS3 (GPIBD 8 [MIM: 614207]). This study highlights the need for long-term follow up of individuals with rare diseases in order to ensure that they benefit from innovations in diagnosis and treatment.

3.
Cancer Res ; 80(3): 624-638, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31723001

RESUMO

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Predisposição Genética para Doença , Genômica/métodos , Mutação , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Associação Genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Adulto Jovem
4.
J Clin Endocrinol Metab ; 104(10): 4630-4638, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31180485

RESUMO

CONTEXT: Molecular mechanisms causing the broad phenotypic diversity of external masculinization in individuals with 45,X/46,XY mosaicism are poorly understood. OBJECTIVE: Analysis of androgen receptor (AR) expression and function as a putative influencing factor for the genital phenotype in patients with 45,X/46,XY mosaicism. DESIGN: Measurement of AR mRNA expression levels, AR activity [DHT-mediated APOD (apolipoprotein D) induction] and cellular 45,X/46,XY ratios in genital skin fibroblasts from individuals with 45,X/46,XY mosaicism and male reference individuals, and determination of the external virilization scale from individuals with 45,X/46,XY mosaicism. SETTING: University hospital endocrine research laboratory. Patients or Other Participants: 30 genital skin fibroblast cultures (GFs) from male reference individuals and 15 GFs from individuals with 45,X/46,XY mosaicism. INTERVENTION: None. MAIN OUTCOME MEASURES: Determination of AR mRNA expression and AR activity in male reference GFs and 45,X/46,XY GFs and correlation of the obtained data with the cellular 45,X/46,XY ratios and the patients' external virilization scale. RESULTS: In 6 of 15 45,X/46,XY GFs, AR mRNA expression and AR activity were significantly lower compared with those in the 46,XY reference GFs. In this subgroup of reduced AR mRNA expression, a positive trend was seen between AR mRNA expression and the percentage of XY-positive cells. Furthermore, we found a positive correlation between AR activity and the external virilization scale in the 15 45,X/46,XY GF samples (P = 0.03). CONCLUSION: Our results suggest that AR expression and AR activity might influence the phenotypic variability seen in patients with 45,X/46,XY mosaicism.


Assuntos
Fibroblastos/metabolismo , Mosaicismo , RNA Mensageiro/metabolismo , Receptores Androgênicos/genética , Pele/citologia , Adolescente , Apolipoproteínas D , Pré-Escolar , Feminino , Prepúcio do Pênis , Genitália , Disgenesia Gonadal Mista , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Masculino , Cultura Primária de Células , Receptores Androgênicos/metabolismo , Escroto , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual , Vulva , Adulto Jovem
5.
Clin Epigenetics ; 11(1): 89, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186048

RESUMO

BACKGROUND: Cardiac disease modelling using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) requires thorough insight into cardiac cell type differentiation processes. However, current methods to discriminate different cardiac cell types are mostly time-consuming, are costly and often provide imprecise phenotypic evaluation. DNA methylation plays a critical role during early heart development and cardiac cellular specification. We therefore investigated the DNA methylation pattern in different cardiac tissues to identify CpG loci for further cardiac cell type characterization. RESULTS: An array-based genome-wide DNA methylation analysis using Illumina Infinium HumanMethylation450 BeadChips led to the identification of 168 differentially methylated CpG loci in atrial and ventricular human heart tissue samples (n = 49) from different patients with congenital heart defects (CHD). Systematic evaluation of atrial-ventricular DNA methylation pattern in cardiac tissues in an independent sample cohort of non-failing donor hearts and cardiac patients using bisulfite pyrosequencing helped us to define a subset of 16 differentially methylated CpG loci enabling precise characterization of human atrial and ventricular cardiac tissue samples. This defined set of reproducible cardiac tissue-specific DNA methylation sites allowed us to consistently detect the cellular identity of hiPSC-CM subtypes. CONCLUSION: Testing DNA methylation of only a small set of defined CpG sites thus makes it possible to distinguish atrial and ventricular cardiac tissues and cardiac atrial and ventricular subtypes of hiPSC-CMs. This method represents a rapid and reliable system for phenotypic characterization of in vitro-generated cardiomyocytes and opens new opportunities for cardiovascular research and patient-specific therapy.


Assuntos
Metilação de DNA , Átrios do Coração/citologia , Cardiopatias Congênitas/patologia , Ventrículos do Coração/citologia , Miócitos Cardíacos/citologia , Células Cultivadas , Ilhas de CpG , Feminino , Átrios do Coração/química , Cardiopatias Congênitas/genética , Ventrículos do Coração/química , Humanos , Células-Tronco Pluripotentes Induzidas/química , Células-Tronco Pluripotentes Induzidas/citologia , Masculino , Modelos Biológicos , Miócitos Cardíacos/química , Especificidade de Órgãos , Análise de Sequência de DNA , Engenharia Tecidual
6.
Genet Med ; 21(12): 2723-2733, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31239556

RESUMO

PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.


Assuntos
Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Transtornos do Neurodesenvolvimento/genética , Animais , Criança , Cromatina/genética , Cromatina/metabolismo , Deficiências do Desenvolvimento/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Humanos , Deficiência Intelectual/genética , Masculino , Mutação/genética , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/metabolismo , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma/métodos , Adulto Jovem
7.
Hum Mutat ; 40(9): 1557-1578, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31131967

RESUMO

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Biologia Computacional/métodos , Mutação de Sentido Incorreto , Neoplasias/diagnóstico , Processamento Alternativo , Detecção Precoce de Câncer , Feminino , Predisposição Genética para Doença , Humanos , Funções Verossimilhança , Masculino , Herança Multifatorial , Neoplasias/genética
8.
Am J Hum Genet ; 104(5): 985-989, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31006513

RESUMO

We report a recurrent CNOT1 de novo missense mutation, GenBank: NM_016284.4; c.1603C>T (p.Arg535Cys), resulting in a syndrome of pancreatic agenesis and abnormal forebrain development in three individuals and a similar phenotype in mice. CNOT1 is a transcriptional repressor that has been suggested as being critical for maintaining embryonic stem cells in a pluripotent state. These findings suggest that CNOT1 plays a critical role in pancreatic and neurological development and describe a novel genetic syndrome of pancreatic agenesis and holoprosencephaly.


Assuntos
Deficiências do Desenvolvimento/etiologia , Holoprosencefalia/etiologia , Doenças do Recém-Nascido/etiologia , Mutação , Doenças do Sistema Nervoso/etiologia , Pâncreas/anormalidades , Pancreatopatias/congênito , Fatores de Transcrição/genética , Sequência de Aminoácidos , Animais , Deficiências do Desenvolvimento/patologia , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Feminino , Holoprosencefalia/patologia , Humanos , Lactente , Recém-Nascido , Doenças do Recém-Nascido/patologia , Masculino , Camundongos , Camundongos Knockout , Doenças do Sistema Nervoso/patologia , Pâncreas/patologia , Pancreatopatias/etiologia , Pancreatopatias/patologia , Linhagem , Fenótipo , Homologia de Sequência , Síndrome
9.
Genet Med ; 21(3): 601-607, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30245509

RESUMO

PURPOSE: TANGO2-related disorders were first described in 2016 and prior to this publication, only 15 individuals with TANGO2-related disorder were described in the literature. Primary features include metabolic crisis with rhabdomyolysis, encephalopathy, intellectual disability, seizures, and cardiac arrhythmias. We assess whether genotype and phenotype of TANGO2-related disorder has expanded since the initial discovery and determine the efficacy of exome sequencing (ES) as a diagnostic tool for detecting variants. METHODS: We present a series of 14 individuals from 11 unrelated families with complex medical and developmental histories, in whom ES or microarray identified compound heterozygous or homozygous variants in TANGO2. RESULTS: The initial presentation of patients with TANGO2-related disorders can be variable, including primarily neurological presentations. We expand the phenotype and genotype for TANGO2, highlighting the variability of the disorder. CONCLUSION: TANGO2-related disorders can have a more diverse clinical presentation than previously anticipated. We illustrate the utility of routine ES data reanalysis whereby discovery of novel disease genes can lead to a diagnosis in previously unsolved cases and the need for additional copy-number variation analysis when ES is performed.


Assuntos
Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Adolescente , Translocador Nuclear Receptor Aril Hidrocarboneto/fisiologia , Encefalopatias/genética , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/genética , Exoma , Família , Feminino , Genótipo , Humanos , Deficiência Intelectual/genética , Masculino , Linhagem , Fenótipo , Convulsões/genética , Sequenciamento Completo do Exoma/métodos
12.
Arch Gynecol Obstet ; 297(1): 147-152, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28993866

RESUMO

PURPOSE: Mutations in the CDH1 gene are linked both to diffuse gastric cancer and invasive lobular carcinoma (ILC). A high mutation rate is found in families fulfilling the diagnostic criteria for hereditary diffuse gastric cancer. Aim of this study was to clarify whether or not there is a significant contribution of CDH1 mutations in hereditary breast-/ovarian cancer (HBOC). METHODS: Ninety-seven unrelated probands fulfilling the diagnostic criteria for HBOC (96 affected, 1 unaffected) but tested negative for pathogenic BRCA1/2 mutations were screened for CDH1 mutations by denaturing high performance liquid chromatography (DHPLC) and subsequent Sanger sequencing of suspicious and positive DHPLC results. RESULTS: In total, we found two potentially pathogenic CDH1 alterations, c.1774G > A, pAla592Thr, and c.2512 A > G, p.Ser838Gly, classified as variants of unknown significance according to ClinVar. In addition, we detected a high number of known CDH1 polymorphisms (n = 62), some of them more frequent in patients with lobular (55%) than in those with invasive ductal carcinoma (27%). CONCLUSION: Although none of the probands studied carried a clearly pathogenic CDH1 mutation, CDH1 could be considered a potential breast cancer gene, esp. for ILC worth including it in the NGS (next generation sequencing) HBOC panel.


Assuntos
Antígenos CD/metabolismo , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Neoplasias da Mama/genética , Caderinas/metabolismo , Neoplasias Ovarianas/genética , Adulto , Neoplasias da Mama/patologia , Estudos de Coortes , Detecção Precoce de Câncer , Feminino , Predisposição Genética para Doença , Humanos , Mutação , Neoplasias Ovarianas/patologia
13.
Blood ; 130(18): 2027-2031, 2017 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-28827408

RESUMO

The bispecific T-cell engager blinatumomab targeting CD19 can induce complete remission in relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, some patients ultimately relapse with loss of CD19 antigen on leukemic cells, which has been established as a novel mechanism to escape CD19-specific immunotherapies. Here, we provide evidence that CD19-negative (CD19-) relapse after CD19-directed therapy in BCP-ALL may be a result of the selection of preexisting CD19- malignant progenitor cells. We present 2 BCR-ABL1 fusion-positive BCP-ALL patients with CD19- myeloid lineage relapse after blinatumomab therapy and show BCR-ABL1 positivity in their hematopoietic stem cell (HSC)/progenitor/myeloid compartments at initial diagnosis by fluorescence in situ hybridization after cell sorting. By using the same approach with 25 additional diagnostic samples from patients with BCR-ABL1-positive BCP-ALL, we identified HSC involvement in 40% of the patients. Patients (6 of 8) with major BCR-ABL1 transcript encoding P210BCR-ABL1 mainly showed HSC involvement, whereas in most of the patients (9 of 12) with minor BCR-ABL1 transcript encoding P190BCR-ABL1, only the CD19+ leukemia compartments were BCR-ABL1 positive (P = .02). Our data are of clinical importance, because they indicate that both CD19+ cells and CD19- precursors should be targeted to avoid CD19- relapses in patients with BCR-ABL1-positive ALL.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Adulto , Crise Blástica/patologia , Humanos , Imunofenotipagem
14.
Eur J Med Genet ; 59(10): 549-53, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27613244

RESUMO

Williams-Beuren syndrome (WBS) is a relatively common, clinically recognizable microdeletion syndrome. In most cases the typical heterozygous deletion of 1.5 Mb on chromosome 7q11.23 spanning about 26 genes can be identified. Also some larger or smaller atypical deletions have been reported and associated with additional or atypical phenotypic aspects. We report on an individual with typical WBS due to the common deletion and with refractory infantile spasms. Using trio-exome sequencing, we identified a de novo truncating variant c.1200del, p (Lys401Serfs*25) in GABRA1 as the likely cause of the early onset epilepsy. This unique case not only allows to further define the phenotypic spectrum of infantile epileptic encephalopathy associated with rare de novo GABRA1 variants but exemplifies the need for a sensitive review of unclear associations in clinically defined syndromes and for extended diagnostic work-up in individuals with unusual presentations of a genetically confirmed diagnosis.


Assuntos
Epilepsia/genética , Receptores de GABA-A/genética , Espasmos Infantis/genética , Síndrome de Williams/genética , Epilepsia/complicações , Epilepsia/fisiopatologia , Exoma/genética , Humanos , Lactente , Recém-Nascido , Masculino , Espasmos Infantis/complicações , Espasmos Infantis/fisiopatologia , Síndrome de Williams/fisiopatologia
15.
Epigenomics ; 8(6): 801-16, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27323310

RESUMO

AIM: To characterize the genotypic and phenotypic extent of multilocus imprinting disturbances (MLID). MATERIALS & METHODS: We analyzed 37 patients with imprinting disorders (explorative cohort) for DNA methylation changes using the Infinium HumanMethylation450 BeadChip. For validation, three independent cohorts with imprinting disorders or cardinal features thereof were analyzed (84 patients with imprinting disorders, 52 with growth disorder, 81 with developmental delay). RESULTS: In the explorative cohort 21 individuals showed array-based MLID with each one displaying an Angelman or Temple syndrome phenotype, respectively. Epimutations in ZDBF2 and FAM50B were associated with severe MLID regarding number of affected regions. By targeted analysis we identified methylation changes of ZDBF2 and FAM50B also in the three validation cohorts. CONCLUSION: We corroborate epimutations in ZDBF2 and FAM50B as frequent changes in MLID whereas these rarely occur in other patients with cardinal features of imprinting disorders. Moreover, we show cell lineage specific differences in the genomic extent of FAM50B epimutation.


Assuntos
Metilação de DNA , Deficiências do Desenvolvimento/genética , Impressão Genômica , Estudos de Casos e Controles , Proteínas de Ligação a DNA/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Fenótipo , Proteínas/genética , Análise de Sequência de DNA
16.
Neurology ; 86(10): 954-62, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26865513

RESUMO

OBJECTIVE: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. METHODS: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. RESULTS: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features. CONCLUSION: De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.


Assuntos
Encefalopatias/genética , Epilepsia/genética , Proteínas Munc18/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Adulto , Encefalopatias/diagnóstico , Encefalopatias/epidemiologia , Criança , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/epidemiologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/epidemiologia , Adulto Jovem
17.
Epigenomics ; 7(7): 1089-97, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26541061

RESUMO

AIM: To investigate the DNA-methylation levels in the newly described MEG8 differentially methylated region (DMR) in the imprinted cluster in 14q32 in patients with Temple syndrome. PATIENTS & METHODS: We included three patients with Temple syndrome which were studied by Infinium HumanMethylation450 BeadChips, locus-specific bisulfite-pyrosequencing, methylation-specific-MLPA and microsatellite analyses. The tag-CpG of the MEG8-DMR was investigated using the Infinium HumanMethylation450 BeadChip. RESULTS: In all three patients, the identical pattern of DNA-hypermethylation of the MEG8-DMR was observed along with DNA-hypomethylation of the IG-DMR and MEG3-DMR. CONCLUSION: Based on the observed MEG8-DMR DNA-hypermethylation and previously published data, we conclude that DNA-methylation of the MEG3- and MEG8-DMR is functionally dependent on the DNA-methylation pattern of the IG-DMR. The observed combination of epimutations is predicted to be associated with bi-allelic MEG3 and MEG8 expression in individuals with Temple syndrome.


Assuntos
Cromossomos Humanos Par 14 , Deficiências do Desenvolvimento/genética , Epigênese Genética , Isoformas de RNA/genética , RNA Longo não Codificante/genética , Dissomia Uniparental/genética , Adolescente , Criança , Pré-Escolar , Ilhas de CpG , Metilação de DNA , Deficiências do Desenvolvimento/patologia , Feminino , Impressão Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Repetições de Microssatélites , Reação em Cadeia da Polimerase , Dissomia Uniparental/patologia
18.
Mol Genet Genomic Med ; 3(5): 467-80, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26436113

RESUMO

Seckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice-site mutations c.383+1G>C and c.4005-9A>G in CDK5RAP2 in two consanguineous families with Seckel syndrome. CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly. We establish CDK5RAP2 as a disease-causing gene for Seckel syndrome and show that loss of functional CDK5RAP2 leads to severe defects in mitosis and spindle organization, resulting in cells with abnormal nuclei and centrosomal pattern, which underlines the important role of centrosomal and mitotic proteins in the pathogenesis of the disease. Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK5RAP2 and CEP152. This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152.

19.
Eur J Med Genet ; 58(8): 419-25, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26003415

RESUMO

Despite recent progress in molecular karyotyping and clinical sequencing the cause of intellectual disability in a considerable subset of individuals affected by this phenotype remains elusive. As intellectual disability is also a feature of various imprinting disorders and some monogenic forms of intellectual disability are caused by epigenetic modifiers we hypothesized that changes in DNA methylation might be associated with or even causative in some cases of intellectual disability. Therefore, we performed a DNA methylation analysis of peripheral blood samples from 82 patients with intellectual disability and additional features using the HumanMethylation450 BeadChip. The findings were compared to that of 19 normal controls. Differentially methylated loci were validated by bisulfite pyrosequencing. On a global level, we failed to detect a robust DNA methylation signature segregating individuals with intellectual disability from controls. Using an individual approach, we identified 157 regions showing individual DNA methylation changes in at least one patient. These correlated to 107 genes including genes linked to conditions associated with intellectual disability, namely COLEC11, SHANK2, GLI2 and KCNQ2, as well as imprinted genes like FAM50B and MEG3. The latter was suggestive of an undiagnosed Temple syndrome which could be confirmed by diagnostic tests. Subsequent in-depth analysis of imprinted loci revealed DNA methylation changes at additional imprinted loci, i.e. PPIEL, IGF2R, MEG8 and MCTS2/HM13, in up to five patients. Our findings indicate that imprinting disorders are rare but probably under-diagnosed in patients with intellectual disability and moreover point to DNA methylation changes as potential alternative means to identify deregulated genes involved in the pathogenesis of intellectual disability.


Assuntos
Metilação de DNA , Deficiências do Desenvolvimento/genética , Loci Gênicos , Impressão Genômica , Deficiência Intelectual/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/patologia , Feminino , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Cariótipo , Masculino , Análise em Microsséries , Fenótipo
20.
Int J Gynecol Pathol ; 34(3): 253-6, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25844548

RESUMO

We report a first trimester miscarriage (9 wk gestation) with a macroscopic grape-like aspect due to extensive angiomatoid changes with widened communicating thin-walled villous vessels. Fluorescence in situ hybridization analysis and microsatellite analysis revealed a diandric triploidy of the trophoblastic tissue, so this miscarriage is indeed a genetic partial hydatidiform mole. This is remarkable since the typical morphologic hallmarks of partial hydatidiform mole, especially enhanced trophoblastic proliferation and marked villous cistern formation, were not prominent. The finding of extensive angiomatoid morphology is to our knowledge an undescribed morphology of an early partial hydatidiform mole. It serves as an example of the morphologic variability of this probably underestimated condition that has a slightly elevated risk for the development of gestational trophoblastic disease.


Assuntos
Mola Hidatiforme/patologia , Neoplasias Uterinas/patologia , Aborto Espontâneo , Adulto , Feminino , Humanos , Mola Hidatiforme/irrigação sanguínea , Mola Hidatiforme/genética , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Gravidez , Primeiro Trimestre da Gravidez , Triploidia , Neoplasias Uterinas/genética
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