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Steroid hormone receptors are ligand-binding transcription factors essential for mammalian physiology. The androgen receptor (AR) binds androgens mediating gene expression for sexual, somatic and behavioural functions, and is involved in various conditions including androgen insensitivity syndrome and prostate cancer1. Here we identified functional mutations in the formin and actin nucleator DAAM2 in patients with androgen insensitivity syndrome. DAAM2 was enriched in the nucleus, where its localization correlated with that of the AR to form actin-dependent transcriptional droplets in response to dihydrotestosterone. DAAM2 AR droplets ranged from 0.02 to 0.06 µm3 in size and associated with active RNA polymerase II. DAAM2 polymerized actin directly at the AR to promote droplet coalescence in a highly dynamic manner, and nuclear actin polymerization is required for prostate-specific antigen expression in cancer cells. Our data uncover signal-regulated nuclear actin assembly at a steroid hormone receptor necessary for transcription.
Assuntos
Actinas , Forminas , Proteínas Nucleares , Receptores Androgênicos , Transcrição Gênica , Humanos , Actinas/metabolismo , Síndrome de Resistência a Andrógenos/genética , Síndrome de Resistência a Andrógenos/metabolismo , Androgênios/farmacologia , Androgênios/metabolismo , Forminas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Polimerização/efeitos dos fármacos , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , RNA Polimerase II/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esteroides/metabolismo , Esteroides/farmacologia , Testosterona/análogos & derivados , Transcrição Gênica/efeitos dos fármacosRESUMO
Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions1-3. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus4,5. This suggests that mutations in disordered proteins may alter condensate properties and function6-8. Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.
Assuntos
Nucléolo Celular , Proteína HMGB1 , Humanos , Arginina/genética , Arginina/metabolismo , Nucléolo Celular/genética , Nucléolo Celular/metabolismo , Nucléolo Celular/patologia , Proteína HMGB1/química , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Proteínas Intrinsicamente Desordenadas/química , Proteínas Intrinsicamente Desordenadas/genética , Proteínas Intrinsicamente Desordenadas/metabolismo , Síndrome , Mutação da Fase de Leitura , Transição de FaseRESUMO
Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways.
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Variações do Número de Cópias de DNA/genética , Haploinsuficiência/genética , Cardiopatias Congênitas/genética , Bases de Dados Genéticas , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Predisposição Genética para Doença/genética , Genômica/métodos , Humanos , Canais Iônicos/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genéticaRESUMO
[This corrects the article DOI: 10.1371/journal.pgen.1009679.].
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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.
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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 , SíndromeRESUMO
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.
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Braquidactilia/genética , Displasia Ectodérmica/genética , Mutação , Proteína Quinase C/genética , Telangiectasia/genética , Adolescente , Braquidactilia/enzimologia , Displasia Ectodérmica/enzimologia , Feminino , Células HEK293 , Humanos , Masculino , Síndrome , Telangiectasia/enzimologia , Sequenciamento do Exoma , Adulto JovemRESUMO
The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified.
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Heterogeneidade Genética , Proteínas de Homeodomínio/genética , Deformidades Congênitas dos Membros/genética , Mutação , Fatores de Transcrição/genética , Enzimas Ativadoras de Ubiquitina/genética , Sequência de Bases , Estudos de Coortes , Variações do Número de Cópias de DNA , Expressão Gênica , Testes Genéticos , Humanos , Lactente , Deformidades Congênitas dos Membros/metabolismo , Deformidades Congênitas dos Membros/patologia , Masculino , Linhagem , Fatores de Transcrição/deficiência , Enzimas Ativadoras de Ubiquitina/deficiência , Sequenciamento Completo do GenomaRESUMO
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.
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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/genéticaRESUMO
The original version of this Article contained an error in the spelling of the author J. Lawrence Merritt, which was incorrectly given as Lawrence Merritt. This has now been corrected in both the PDF and HTML versions of the Article.
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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 do Exoma/métodosRESUMO
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 do Exoma/métodos , Adulto JovemRESUMO
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.
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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 , ImunofenotipagemRESUMO
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.
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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/patologiaRESUMO
Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. We describe the identification of homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs(∗)22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), c.269A>G (p.Glu90Gly), and c.700T>C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction we showed that the mutation c.298G>T is probably a founder mutation. Due to the spectrum of the amino acid changes, we suggest that loss of function in TGDS is the underlying mechanism of Catel-Manzke syndrome. TGDS (dTDP-D-glucose 4,6-dehydrogenase) is a conserved protein belonging to the SDR family and probably plays a role in nucleotide sugar metabolism.
Assuntos
Deformidades Congênitas da Mão/genética , Oxirredutases/genética , Síndrome de Pierre Robin/genética , Adolescente , Adulto , Sequência de Aminoácidos , Pré-Escolar , Exoma/genética , Feminino , Deformidades Congênitas da Mão/enzimologia , Haplótipos , Heterozigoto , Homozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Oxirredutases/metabolismo , Linhagem , Síndrome de Pierre Robin/enzimologia , Alinhamento de Sequência , Análise de Sequência de DNA , Adulto JovemRESUMO
Deletion 1p36 syndrome is recognized as the most common terminal deletion syndrome. Here, we describe the loss of a gene within the deletion that is responsible for the cardiomyopathy associated with monosomy 1p36, and we confirm its role in nonsyndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). With our own data and publically available data from array comparative genomic hybridization (aCGH), we identified a minimal deletion for the cardiomyopathy associated with 1p36del syndrome that included only the terminal 14 exons of the transcription factor PRDM16 (PR domain containing 16), a gene that had previously been shown to direct brown fat determination and differentiation. Resequencing of PRDM16 in a cohort of 75 nonsyndromic individuals with LVNC detected three mutations, including one truncation mutant, one frameshift null mutation, and a single missense mutant. In addition, in a series of cardiac biopsies from 131 individuals with DCM, we found 5 individuals with 4 previously unreported nonsynonymous variants in the coding region of PRDM16. None of the PRDM16 mutations identified were observed in more than 6,400 controls. PRDM16 has not previously been associated with cardiac disease but is localized in the nuclei of cardiomyocytes throughout murine and human development and in the adult heart. Modeling of PRDM16 haploinsufficiency and a human truncation mutant in zebrafish resulted in both contractile dysfunction and partial uncoupling of cardiomyocytes and also revealed evidence of impaired cardiomyocyte proliferative capacity. In conclusion, mutation of PRDM16 causes the cardiomyopathy in 1p36 deletion syndrome as well as a proportion of nonsyndromic LVNC and DCM.
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Cardiomiopatia Dilatada/genética , Transtornos Cromossômicos/genética , Mapeamento Cromossômico/métodos , Proteínas de Ligação a DNA/genética , Miocárdio Ventricular não Compactado Isolado/genética , Fatores de Transcrição/genética , Animais , Cardiomiopatia Dilatada/patologia , Estudos de Casos e Controles , Proliferação de Células , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Hibridização Genômica Comparativa , Éxons , Mutação da Fase de Leitura , Humanos , Mutação de Sentido Incorreto , Contração Miocárdica , Miócitos Cardíacos , Peixe-Zebra/embriologia , Peixe-Zebra/genéticaRESUMO
Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. De novo dominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies.
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Anormalidades Múltiplas/genética , Montagem e Desmontagem da Cromatina/genética , Face/anormalidades , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Hipotricose/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Deleção de Sequência/genética , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Proteínas de Transporte/genética , Criança , Pré-Escolar , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Exoma/genética , Face/patologia , Fácies , Feminino , Deformidades Congênitas do Pé/patologia , Deformidades Congênitas da Mão/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hipotricose/patologia , Lactente , Recém-Nascido , Deficiência Intelectual/patologia , Cariotipagem , Masculino , Micrognatismo/patologia , Mutação de Sentido Incorreto , Pescoço/patologia , Proteínas Repressoras , Proteína SMARCB1 , Fatores de Transcrição/genéticaRESUMO
Coffin-Siris syndrome (CSS) and Nicolaides-Baraitser syndrome (NCBRS) are rare intellectual disability/congenital malformation syndromes that represent distinct entities but show considerable clinical overlap. They are caused by mutations in genes encoding members of the BRG1- and BRM-associated factor (BAF) complex. However, there are a number of patients with the clinical diagnosis of CSS or NCBRS in whom the causative mutation has not been identified. In this study, we performed trio-based whole-exome sequencing (WES) in ten previously described but unsolved individuals with the tentative diagnosis of CSS or NCBRS and found causative mutations in nine out of ten individuals. Interestingly, our WES analysis disclosed overlapping differential diagnoses including Wiedemann-Steiner, Kabuki, and Adams-Oliver syndromes. In addition, most likely causative de novo mutations were identified in GRIN2A and SHANK3. Moreover, trio-based WES detected SMARCA2 and SMARCA4 deletions, which had not been annotated in a previous Haloplex target enrichment and next-generation sequencing of known CSS/NCBRS genes emphasizing the advantages of WES as a diagnostic tool. In summary, we discuss the phenotypic and diagnostic challenges in clinical genetics, establish important differential diagnoses, and emphasize the cardinal features and the broad clinical spectrum of BAF complex disorders and other disorders caused by mutations in epigenetic landscapers.
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Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Exoma , Face/anormalidades , Deformidades Congênitas do Pé/diagnóstico , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Hipotricose/diagnóstico , Hipotricose/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Micrognatismo/diagnóstico , Micrognatismo/genética , Mutação , Pescoço/anormalidades , Adulto , Idoso de 80 Anos ou mais , Criança , DNA Helicases/genética , Diagnóstico Diferencial , Fácies , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Receptores de N-Metil-D-Aspartato/genética , Fatores de Transcrição/genéticaRESUMO
Mandibulofacial dysostosis with microcephaly (MFDM) is a rare sporadic syndrome comprising craniofacial malformations, microcephaly, developmental delay, and a recognizable dysmorphic appearance. Major sequelae, including choanal atresia, sensorineural hearing loss, and cleft palate, each occur in a significant proportion of affected individuals. We present detailed clinical findings in 12 unrelated individuals with MFDM; these 12 individuals compose the largest reported cohort to date. To define the etiology of MFDM, we employed whole-exome sequencing of four unrelated affected individuals and identified heterozygous mutations or deletions of EFTUD2 in all four. Validation studies of eight additional individuals with MFDM demonstrated causative EFTUD2 mutations in all affected individuals tested. A range of EFTUD2-mutation types, including null alleles and frameshifts, is seen in MFDM, consistent with haploinsufficiency; segregation is de novo in all cases assessed to date. U5-116kD, the protein encoded by EFTUD2, is a highly conserved spliceosomal GTPase with a central regulatory role in catalytic splicing and post-splicing-complex disassembly. MFDM is the first multiple-malformation syndrome attributed to a defect of the major spliceosome. Our findings significantly extend the range of reported spliceosomal phenotypes in humans and pave the way for further investigation in related conditions such as Treacher Collins syndrome.
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GTP Fosfo-Hidrolases/genética , Haploinsuficiência/genética , Disostose Mandibulofacial/genética , Microcefalia/genética , Ribonucleoproteína Nuclear Pequena U5/genética , Anormalidades Múltiplas/genética , Alelos , Sequência de Aminoácidos , Criança , Pré-Escolar , Estudos de Coortes , Exoma , Feminino , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Mutação/genética , Estrutura Terciária de Proteína/genética , Splicing de RNA/genética , Spliceossomos/genéticaRESUMO
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.