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1.
Genet Med ; 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31316167

RESUMO

PURPOSE: Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing. METHODS: In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2-positive (n = 44) and FBN2-negative group (n = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups. RESULTS: The total score was significantly different between the groups (P < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups. CONCLUSIONS: Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.

2.
Genet Med ; 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31164752

RESUMO

PURPOSE: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists. METHODS: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds. RESULTS: The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene. CONCLUSION: Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis.

3.
Genet Med ; 21(10): 2216-2223, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30976099

RESUMO

PURPOSE: To provide a detailed electroclinical description and expand the phenotype of PIGT-CDG, to perform genotype-phenotype correlation, and to investigate the onset and severity of the epilepsy associated with the different genetic subtypes of this rare disorder. Furthermore, to use computer-assisted facial gestalt analysis in PIGT-CDG and to the compare findings with other glycosylphosphatidylinositol (GPI) anchor deficiencies. METHODS: We evaluated 13 children from eight unrelated families with homozygous or compound heterozygous pathogenic variants in PIGT. RESULTS: All patients had hypotonia, severe developmental delay, and epilepsy. Epilepsy onset ranged from first day of life to two years of age. Severity of the seizure disorder varied from treatable seizures to severe neonatal onset epileptic encephalopathies. The facial gestalt of patients resembled that of previously published PIGT patients as they were closest to the center of the PIGT cluster in the clinical face phenotype space and were distinguishable from other gene-specific phenotypes. CONCLUSION: We expand our knowledge of PIGT. Our cases reaffirm that the use of genetic testing is essential for diagnosis in this group of disorders. Finally, we show that computer-assisted facial gestalt analysis accurately assigned PIGT cases to the multiple congenital anomalies-hypotonia-seizures syndrome phenotypic series advocating the additional use of next-generation phenotyping technology.

6.
Genet Med ; 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30349098

RESUMO

PURPOSE: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. METHODS: Clinicians entered clinical data in an extensive web-based survey. RESULTS: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. CONCLUSION: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.

7.
Am J Med Genet A ; 176(9): 1991-1995, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30088855

RESUMO

KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. After the advent of whole exome sequencing, the number of clinical reports with KBG diagnosis has increased, leading to a revision of the phenotypic spectrum associated with this syndrome. Here, we report a female child showing clinical features of the KBG syndrome in addition to a caudal appendage at the coccyx with prominent skin fold and a peculiar calcaneus malformation. Exons and exon-intron junctions targeted resequencing of SH3PXD2B and MASP1 genes, known to be associated with prominent coccyx, gave negative outcome, whereas sequencing of ANKRD11 whose mutations matched the KBG phenotype of the proband showed a de novo heterozygous frameshift variant c.4528_4529delCC in exon 9 of ANKRD11. This report contributes to expand the knowledge of the clinical features of KBG syndrome and highlights the need to search for vertebral anomalies and suspect this condition in the presence of a prominent, elongated coccyx.

9.
Eur J Med Genet ; 61(10): 627-630, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29660409

RESUMO

We report a novel patient with the phenotypic characteristics of Schaaf-Yang syndrome. In addition, the patient has a severe chronic digestive malfunction, rendering him dependent on intermittent enteral supplementation. To our knowledge, this is the first report of Schaaf-Yang syndrome associated with severe chronic digestive malfunction manifesting with both a malrotation and signs of a chronic intestinal pseudo-obstruction.

11.
Ugeskr Laeger ; 180(11)2018 Mar 12.
Artigo em Dinamarquês | MEDLINE | ID: mdl-29530238

RESUMO

KBG syndrome is a rare condition characterised by macrodontia of the upper central incisors, distinctive craniofacial findings, short stature, skeletal anomalies, and neurologic involvement including global developmental delay, seizures, and intellectual disability. This is a case report of a seven-year-old boy, who presented with symptoms fulfilling the diagnostic criteria of KBG syndrome, molecularly confirmed by detection of a heterozygous mutation in ANKRD11. To our knowledge, this is the first patient diagnosed with KBG syndrome in Denmark. The aim of this study is to raise awareness of this recognisable syndrome.

12.
Eur J Med Genet ; 2018 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-29601900

RESUMO

We report the clinical and neuroradiological findings in a young boy harboring the 9p deletion syndrome including the novel findings of thalamic infarction and germinal matrix haemorrhage and neonatal hyperinsulinemic hypoglycemia. Both the hypoglycemic events and the ventriculomegaly found in this patient have previously only been reported in two patients, while the thalamic infarction and germinal matrix haemorrhage are novel features.

13.
Genet Med ; 20(9): 965-975, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29300384

RESUMO

PURPOSE: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS. METHODS: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. RESULTS: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations. CONCLUSION: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.

14.
Genome Med ; 10(1): 3, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29310717

RESUMO

BACKGROUND: Glycosylphosphatidylinositol biosynthesis defects (GPIBDs) cause a group of phenotypically overlapping recessive syndromes with intellectual disability, for which pathogenic mutations have been described in 16 genes of the corresponding molecular pathway. An elevated serum activity of alkaline phosphatase (AP), a GPI-linked enzyme, has been used to assign GPIBDs to the phenotypic series of hyperphosphatasia with mental retardation syndrome (HPMRS) and to distinguish them from another subset of GPIBDs, termed multiple congenital anomalies hypotonia seizures syndrome (MCAHS). However, the increasing number of individuals with a GPIBD shows that hyperphosphatasia is a variable feature that is not ideal for a clinical classification. METHODS: We studied the discriminatory power of multiple GPI-linked substrates that were assessed by flow cytometry in blood cells and fibroblasts of 39 and 14 individuals with a GPIBD, respectively. On the phenotypic level, we evaluated the frequency of occurrence of clinical symptoms and analyzed the performance of computer-assisted image analysis of the facial gestalt in 91 individuals. RESULTS: We found that certain malformations such as Morbus Hirschsprung and diaphragmatic defects are more likely to be associated with particular gene defects (PIGV, PGAP3, PIGN). However, especially at the severe end of the clinical spectrum of HPMRS, there is a high phenotypic overlap with MCAHS. Elevation of AP has also been documented in some of the individuals with MCAHS, namely those with PIGA mutations. Although the impairment of GPI-linked substrates is supposed to play the key role in the pathophysiology of GPIBDs, we could not observe gene-specific profiles for flow cytometric markers or a correlation between their cell surface levels and the severity of the phenotype. In contrast, it was facial recognition software that achieved the highest accuracy in predicting the disease-causing gene in a GPIBD. CONCLUSIONS: Due to the overlapping clinical spectrum of both HPMRS and MCAHS in the majority of affected individuals, the elevation of AP and the reduced surface levels of GPI-linked markers in both groups, a common classification as GPIBDs is recommended. The effectiveness of computer-assisted gestalt analysis for the correct gene inference in a GPIBD and probably beyond is remarkable and illustrates how the information contained in human faces is pivotal in the delineation of genetic entities.


Assuntos
Citometria de Fluxo/métodos , Glicosilfosfatidilinositóis/biossíntese , Processamento de Imagem Assistida por Computador , Anormalidades Múltiplas/metabolismo , Automação , Biomarcadores/metabolismo , Humanos , Deficiência Intelectual/metabolismo , Fenótipo , Distúrbios do Metabolismo do Fósforo/metabolismo , Síndrome
15.
JAMA Neurol ; 74(10): 1228-1236, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28806457

RESUMO

Importance: Knowing the range of symptoms seen in patients with a missense or loss-of-function variant in KCNB1 and how these symptoms correlate with the type of variant will help clinicians with diagnosis and prognosis when treating new patients. Objectives: To investigate the clinical spectrum associated with KCNB1 variants and the genotype-phenotype correlations. Design, Setting, and Participants: This study summarized the clinical and genetic information of patients with a presumed pathogenic variant in KCNB1. Patients were identified in research projects or during clinical testing. Information on patients from previously published articles was collected and authors contacted if feasible. All patients were seen at a clinic at one of the participating institutes because of presumed genetic disorder. They were tested in a clinical setting or included in a research project. Main Outcomes and Measures: The genetic variant and its inheritance and information on the patient's symptoms and characteristics in a predefined format. All variants were identified with massive parallel sequencing and confirmed with Sanger sequencing in the patient. Absence of the variant in the parents could be confirmed with Sanger sequencing in all families except one. Results: Of 26 patients (10 female, 15 male, 1 unknown; mean age at inclusion, 9.8 years; age range, 2-32 years) with developmental delay, 20 (77%) carried a missense variant in the ion channel domain of KCNB1, with a concentration of variants in region S5 to S6. Three variants that led to premature stops were located in the C-terminal and 3 in the ion channel domain. Twenty-one of 25 patients (84%) had seizures, with 9 patients (36%) starting with epileptic spasms between 3 and 18 months of age. All patients had developmental delay, with 17 (65%) experiencing severe developmental delay; 14 (82%) with severe delay had behavioral problems. The developmental delay was milder in 4 of 6 patients with stop variants and in a patient with a variant in the S2 transmembrane element rather than the S4 to S6 region. Conclusions and Relevance: De novo KCNB1 missense variants in the ion channel domain and loss-of-function variants in this domain and the C-terminal likely cause neurodevelopmental disorders with or without seizures. Patients with presumed pathogenic variants in KCNB1 have a variable phenotype. However, the type and position of the variants in the protein are (imperfectly) correlated with the severity of the disorder.


Assuntos
Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Canais de Potássio Shab/genética , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Eletroencefalografia , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imagem por Ressonância Magnética , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Fenótipo , Adulto Jovem
18.
Genet Med ; 19(6): 691-700, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27831545

RESUMO

PURPOSE: Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined. METHODS: Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations. RESULTS: Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis. CONCLUSION: This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016.


Assuntos
Encéfalo/diagnóstico por imagem , Doença de Hirschsprung/diagnóstico por imagem , Deficiência Intelectual/diagnóstico por imagem , Imagem por Ressonância Magnética , Microcefalia/diagnóstico por imagem , Neuroimagem , Encéfalo/patologia , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia/patologia , Facies , Feminino , Genótipo , Haploinsuficiência , Doença de Hirschsprung/genética , Doença de Hirschsprung/patologia , Humanos , Lactente , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Estudos Longitudinais , Masculino , Microcefalia/genética , Microcefalia/patologia , Fenótipo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
19.
Am J Med Genet A ; 170(6): 1479-84, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26994744

RESUMO

Mutations in the NOG gene give rise to a wide range of clinical phenotypes. Noggin, the protein encoded by this gene is a secreted modulator of multiple pathways involved in both bone and joint development. Proximal symphalangism is commonly observed in patients bearing mutations in this gene, however secondary symptomes are often found including typical facies with hemicylindrical nose with bulbous tip, hyperopia, reduced mobility of multiple joints, hearing loss due to stapes fixation, and recurrent pain from affected joints. With large variation of the phenotype both within and between affected families careful delineation of the genotype-phenotype correlation is needed. In this work we describe a Danish family suffering from SYNS1 due to a novel NOG gene mutation (C230Y). We provide detailed clinical description of the family members presenting rare phenotype of the shoulders shared by affected individuals but no hearing loss, further adding to the phenotypic variability of the syndrome. With these findings we broaden the understanding of NOG-related-symphalangism spectrum disorder. © 2016 Wiley Periodicals, Inc.


Assuntos
Ossos do Carpo/anormalidades , Proteínas de Transporte/genética , Deformidades Congênitas do Pé/diagnóstico , Deformidades Congênitas do Pé/genética , Estudos de Associação Genética , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Perda Auditiva/genética , Mutação , Fenótipo , Estribo/anormalidades , Sinostose/diagnóstico , Sinostose/genética , Ossos do Tarso/anormalidades , Adulto , Alelos , Pré-Escolar , Facies , Família , Feminino , Genótipo , Humanos , Lactente , Masculino , Linhagem , Exame Físico , Radiografia , Análise de Sequência de DNA
20.
Epilepsia ; 56(4): e36-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25778844

RESUMO

Dravet syndrome is a severe infantile-onset epileptic encephalopathy associated with mutations in the sodium channel alpha-1 subunit gene SCN1A. We aimed to describe the incidence of Dravet syndrome in the Danish population. Based on a 6-year birth cohort from 2004 to 2009, we propose an incidence of 1:22,000, which is higher than what has been established earlier. We identified 17 cases with SCN1A mutation-positive Dravet syndrome. Fifteen patients were found, by conventional Sanger sequencing. Two additional patients with clinical Dravet syndrome, but without a detectable SCN1A mutation by Sanger sequencing, were diagnosed with a SCN1A mutation after using a targeted next-generation sequencing gene panel.


Assuntos
Epilepsias Mioclônicas/epidemiologia , Epilepsias Mioclônicas/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Vigilância da População , Criança , Pré-Escolar , Estudos de Coortes , Dinamarca/epidemiologia , Epilepsias Mioclônicas/diagnóstico , Feminino , Humanos , Incidência , Masculino , Mutação/genética , Vigilância da População/métodos , Estudos Retrospectivos
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