Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 104
Filtrar
1.
J Immunother Cancer ; 9(1)2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33431630

RESUMO

Upper tract urothelial carcinoma (UTUC) is often diagnosed late and exhibits poor prognosis. Only limited data are available concerning therapeutic regimes and potential biomarkers for disease monitoring. Standard therapies often provide only insufficient treatment options. Hence, immunotherapies and complementary approaches, such as personalized neoepitope-derived multipeptide vaccine (PNMV), come into focus. In this context, genetic analysis of tumor tissue by whole exome sequencing represents an essential diagnostic step in order to calculate tumor mutational burden (TMB) and to reveal tumor-specific neoantigens. Furthermore, disease progression is essential to be monitored. Longitudinal screening of individually known mutations in plasma circulating tumor DNA (ctDNA) by the use of next-generation sequencing and digital droplet PCR (ddPCR) might be a promising method to fill this gap.Here, we present the case of a 55-year-old man who was diagnosed with high-risk metastatic UTUC in 2015. After initial surgery and palliative chemotherapy, he developed recurrence of the tumor. Genetic analysis revealed a high TMB of 41.2 mutations per megabase suggesting a potential success of immunotherapy. Therefore, in 2016, off-label treatment with the checkpoint-inhibitor pembrolizumab was started leading to strong regression of the disease. This therapy was then discontinued due to side effects and treatment with a previously produced PNMV was started that induced strong T cell responses. During both treatments, plasma Liquid Biopsies (pLBs) were performed to measure the number of mutated molecules per mL plasma (MM/mL) of a known tumor-specific variant in the MLH1 gene by ddPCR for longitudinal monitoring. Under treatment, MM/mL was constantly zero. A few months after all therapies had been discontinued, an increase of MM/mL was detected that persisted in the following pLBs. When MRI scans proved tumor recurrence, treatment with pembrolizumab was started again leading to a rapid decrease of MM/mL in the pLB to again zero. Treatment response was then also confirmed by MRI.This case shows that use of immunotherapy and PNMV might be a promising treatment option for patients with high-risk metastatic UTUC. Furthermore, measurement of individually known tumor mutations in plasma ctDNA by the use of pLB could be a very sensitive biomarker to longitudinally monitor disease.

3.
BMC Ophthalmol ; 21(1): 28, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33430815

RESUMO

BACKGROUND: Severe congenital ophthalmological malformations and glaucoma might be an important occasional feature in patients with Coffin-Siris syndrome (CSS), especially Coffin-Siris syndrome 9 (CSS9, OMIM #615866) caused by SOX11 mutation. Recently, primary (open-angle) glaucoma was described in two children with the most common form of Coffin-Siris syndrome, CSS1 (OMIM #135900) by ARID1B (AT-rich interaction domain-containing protein 1B) gene mutation. In this article, we present the first report of glaucoma with Coffin-Siris syndrome 9 as well as the first report of secondary glaucoma with any form of Coffin-Siris syndrome. These findings indicate that secondary glaucoma is an occasional finding in patients with Coffin-Siris syndrome. CASE PRESENTATION: A child with secondary childhood glaucoma and additional ocular manifestations was evaluated and treated at the childhood glaucoma centre in Mainz, Germany. Examination under general anaesthesia revealed ocular anterior segment dysgenesis (ASD) (Peters type iridocorneal dysgenesis) in combination with congenital limbal stem cell deficiency (LSCD), aniridia, and cataract. The patient also had multiple other congenital anomalies and severe developmental delay. To explain his combination of anomalies, molecular genetic analysis from peripheral blood was performed in late 2018 and early 2019. Following normal findings with a panel diagnostic of 18 genes associated with congenital glaucoma, whole exome sequencing was performed and revealed a novel likely pathogenic heterozygous variant c.251G>T, p.(Gly84Val) in the SOX11 gene (SRY-related HMG-box gene 11). The variant had occurred de novo. Thus, the multiple congenital anomalies and developmental delay of the patient represented Coffin-Siris syndrome 9 (CSS9, OMIM #615866). CONCLUSIONS: When eye diseases occur in combination with other systemic features, genetic analysis can be seminal. Results indicate that glaucoma is an occasional feature of patients with Coffin-Siris syndrome. As early treatment may improve the visual outcome of patients with glaucoma, we suggest that patients with Coffin-Siris syndrome should receive specific ophthalmological screening.

4.
J Immunol ; 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33298615

RESUMO

Gaining detailed insights into the role of host immune responses in viral clearance is critical for understanding COVID-19 pathogenesis and future treatment strategies. Although studies analyzing humoral immune responses against SARS-CoV-2 were available rather early during the pandemic, cellular immunity came into focus of investigations just recently. For the present work, we have adapted a protocol designed for the detection of rare neoantigen-specific memory T cells in cancer patients for studying cellular immune responses against SARS-CoV-2. Both CD4+ and CD8+ T cells were detected after 6 d of in vitro expansion using overlapping peptide libraries representing the whole viral protein. The assay readout was an intracellular cytokine staining and flow cytometric analysis detecting four functional markers simultaneously (CD154, TNF, IL-2, and IFN-γ). We were able to detect SARS-CoV-2-specific T cells in 10 of 10 COVID-19 patients with mild symptoms. All patients had reactive T cells against at least 1 of 12 analyzed viral Ags, and all patients had Spike-specific T cells. Although some Ags were detected by CD4+ and CD8+ T cells, VME1 was mainly recognized by CD4+ T cells. Strikingly, we were not able to detect SARS-CoV-2-specific T cells in 18 unexposed healthy individuals. When we stimulated the same samples overnight, we measured significant numbers of cytokine-producing cells even in unexposed individuals. Our comparison showed that the stimulation conditions can profoundly impact the activation readout in unexposed individuals. We are presenting a highly specific diagnostic tool for the detection of SARS-CoV-2-reactive T cells.

5.
Am J Med Genet A ; 182(9): 2068-2076, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32592542

RESUMO

Hand hyperphalangism leading to shortened index fingers with ulnar deviation, hallux valgus, mild facial dysmorphism and respiratory compromise requiring assisted ventilation are the key features of Chitayat syndrome. This condition results from the recurrent heterozygous missense variant NM_006494.2:c.266A>G; p.(Tyr89Cys) in ERF on chromosome 19q13.2, encoding the ETS2 repressor factor (ERF) protein. The pathomechanism of Chitayat syndrome is unknown. To date, seven individuals with Chitayat syndrome and the recurrent pathogenic ERF variant have been reported in the literature. Here, we describe six additional individuals, among them only one presenting with a history of assisted ventilation, and the remaining presenting with variable pulmonary phenotypes, including one individual without any obvious pulmonary manifestations. Our findings widen the phenotype spectrum caused by the recurrent pathogenic variant in ERF, underline Chitayat syndrome as a cause of isolated skeletal malformations and therefore contribute to the improvement of diagnostic strategies in individuals with hand hyperphalangism.

6.
J Allergy Clin Immunol ; 146(4): 901-911, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32278790

RESUMO

BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. OBJECTIVE: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. METHODS: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. CONCLUSIONS: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32073219

RESUMO

There are two forms of diabetes insipidus, central (neurohypophyseal), and nephrogenic, caused by pathogenic variants in the AVP gene and the AVPR2 or AQP2 genes, respectively. We report on a four-generation family, seven individuals had central diabetes insipidus (CDI) and the female index patient seen from age 16 to 26 years had (mild) nephrogenic diabetes insipidus. In her father with CDI, a known pathogenic heterozygous AVP variant c.232_234del p.(Glu78del) was identified, confirming the diagnosis of CDI in him and the other affected family members. In the proband, molecular analysis disclosed a novel heterozygous AVPR2 gene variant, c.962A > T p.(Asn321Ile) and an extremely skewed X-inactivation, confirming X-linked nephrogenic diabetes insipidus (XL-NDI). Whole exome sequencing showed no further causative mutation. This is the first report on the co-existence of CDI and NDI in one family. Our review of symptomatic female AVPR2 heterozygotes includes 23 families with at least one affected female (including this study). There were 21 different causative mutations. Mutation types in females did not differ from those in males. Both severe XL-NDI and mild forms were reported in females. All six females with severe XL-NDI had complete loss-of-function (null) mutations. The remaining 17 female probands had milder XL-NDI caused by 14 missense variants and three null variants of the AVPR2 gene. X-inactivation was studied in nine of these females; all showed extreme or slight skewing. The review underlines that XL-NDI in female AVPR2 heterozygotes is always accompanied by skewed X-inactivation, emphasizing a need for X-inactivation studies in these females.

8.
Eur J Med Genet ; 63(1): 103613, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30677517

RESUMO

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN-IV), is a rare and severe autosomal recessive disorder. We report on an adult female patient whose clinical findings during childhood were not recognized as CIPA. There was neither complete anhidrosis nor a recognizable sensitivity to heat. Tumorlike swellings of many joints and skeletal signs of Charcot neuropathy developed in adolescence which, together with a history of self-mutilation, led to a clinical suspicion of CIPA confirmed by identification of a novel homozygous variant c.1795G > T in the NTRK1 gene in blood lymphocytes. Both parents were heterozygous for the mutation. The variant predicts a premature stop codon (p.Gly599Ter) and thus represents a pathogenic variant; the first reported in the Southeastern European population.


Assuntos
Artropatia Neurogênica/genética , Predisposição Genética para Doença , Ossificação Heterotópica/genética , Receptor trkA/genética , Adulto , Artropatia Neurogênica/fisiopatologia , Feminino , Humanos , Hipo-Hidrose/genética , Hipo-Hidrose/fisiopatologia , Ossificação Heterotópica/fisiopatologia , Dor/genética , Dor/fisiopatologia , Adulto Jovem
9.
Z Geburtshilfe Neonatol ; 224(3): 153-159, 2020 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-31853915

RESUMO

Within 4 years (2014-2017), we genetically diagnosed 2 newborns with Kagami-Ogata syndrome (OMIM #608149). As fetuses they exhibited prenatal polyhydramnios and in 1 case hepatomegaly. After birth, the newborns suffered from respiratory distress. Typical phenotypic features, such as muscular hypotonia, a protruding philtrum, full cheeks and a depressed nasal bridge, were present. Chest X-rays revealed coat-hanger ribs and a bell-shaped thorax, suggestive of the entity. Kagami-Ogata syndrome is caused by an aberrant gene expression of chromosome 14 and was first described in 1991. Possible causes are paternal uniparental disomy of chromosome 14, epimutations and microdeletions. Approximately 70 cases have been reported in the literature, with 34 comprising the original cohort of M. Kagami and T. Ogata. The incidence of the disease is unknown. Patients often manifest a developmental delay and an intellectual disability, although in the meantime cases with milder clinical courses have been described. In the cohort of Kagami and Ogata 3 patients developed hepatoblastoma, which is a common feature in another imprinting disorder, namely the Beckwith-Wiedemann syndrome. Therefore, hepatoblastoma should be considered in follow-up examinations.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 14/genética , Deficiência Intelectual/genética , Costelas/anormalidades , Tórax/anormalidades , Dissomia Uniparental/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Transtornos Cromossômicos/diagnóstico , Feminino , Impressão Genômica , Humanos , Recém-Nascido , Poli-Hidrâmnios , Gravidez , Costelas/diagnóstico por imagem , Tórax/diagnóstico por imagem
11.
Clin Dysmorphol ; 28(3): 137-141, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30789376

RESUMO

Rubinstein-Taybi syndrome (RSTS) is a rare dominant disorder with intellectual disability, postnatal growth deficiency, and multiple congenital anomalies. Approximately 50-70% of the patients have a mutation in the CREBBP gene (RSTS1) and 5-10% display an EP300 gene mutation (RSTS2). Craniospinal abnormalities such as microcranium, scoliosis, and lordosis are frequent findings in RSTS1, but malformations of the brain or spinal cord are seen only occasionally. Here, we report on a 3-year-old boy with facial abnormalities of RSTS, broad thumbs and halluces, developmental delay, autistic features, cerebellar underdevelopment, and a neural tube defect. Molecular diagnostic of the CREBBP and EP300 genes showed a heterozygous 17-bp deletion (c.5698_5714del AAGGCAGCAGGCCAGGT) in exon 31 of the EP300 gene. Findings underline that small (hypoplastic) cerebellum and neural tube defects belong to the phenotypic spectrum not only of RSTS1 but also of RSTS2. Based on the literature and this observation, we recommend that each individual with RSTS2 should be closely evaluated for neural axis and craniovertebral junction anomalies, and where appropriate, neuroimaging studies should be considered. Our frequency estimate of ~ 6% occult or overt neural tube defects in RSTS2 could represent an underestimate.


Assuntos
Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/fisiopatologia , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Cerebelo/anormalidades , Pré-Escolar , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/metabolismo , Éxons , Mutação da Fase de Leitura , Estudos de Associação Genética , Testes Genéticos , Genoma Humano , Genótipo , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Defeitos do Tubo Neural/genética , Deleção de Sequência/genética
12.
Hum Mol Genet ; 27(8): 1343-1352, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29432577

RESUMO

CHARGE syndrome is an autosomal dominant malformation disorder caused by heterozygous loss of function mutations in the chromatin remodeler CHD7. Chd7 regulates the expression of Sema3a, which also contributes to the pathogenesis of Kallmann syndrome, a heterogeneous condition with the typical features hypogonadotropic hypogonadism and an impaired sense of smell. Both features are common in CHARGE syndrome suggesting that SEMA3A may provide a genetic link between these syndromes. Indeed, we find evidence that SEMA3A plays a role in the pathogenesis of CHARGE syndrome. First, Chd7 is enriched at the Sema3a promotor in neural crest cells and loss of function of Chd7 inhibits Sema3a expression. Second, using a Xenopus CHARGE model, we show that human SEMA3A rescues Chd7 loss of function. Third, to elucidate if SEMA3A mutations in addition to CHD7 mutations also contribute to the severity of the CHARGE phenotype, we screened 31 CHD7-positive patients and identified one patient with a heterozygous non-synonymous SEMA3A variant, c.2002A>G (p.I668V). By analyzing protein expression and processing, we did not observe any differences of the p.I668V variant compared with wild-type SEMA3A, while a pathogenic SEMA3A variant p.R66W recently described in a patient with Kallmann syndrome did affect protein secretion. Furthermore, the p.I668V variant, but not the pathogenic p.R66W variant, rescues Chd7 loss of function in Xenopus, indicating that the p.I668V variant is likely benign. Thus, SEMA3A is part of an epigenetic loop that plays a role in the pathogenesis of CHARGE syndrome, however, it seems not to act as a common direct modifier.


Assuntos
Síndrome CHARGE/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Epigênese Genética , Crista Neural/metabolismo , Semaforina-3A/genética , Animais , Síndrome CHARGE/metabolismo , Síndrome CHARGE/patologia , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Embrião não Mamífero , Teste de Complementação Genética , Células HEK293 , Proteína Homeobox Nkx-2.5/genética , Proteína Homeobox Nkx-2.5/metabolismo , Humanos , Síndrome de Kallmann/genética , Síndrome de Kallmann/metabolismo , Síndrome de Kallmann/patologia , Mutação , Crista Neural/patologia , Regiões Promotoras Genéticas , Semaforina-3A/metabolismo , Índice de Gravidade de Doença , Xenopus laevis
14.
Am J Med Genet A ; 176(3): 668-675, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29341480

RESUMO

The cutis laxa syndromes are multisystem disorders that share loose redundant inelastic and wrinkled skin as a common hallmark clinical feature. The underlying molecular defects are heterogeneous and 13 different genes have been involved until now, all of them being implicated in elastic fiber assembly. We provide here molecular and clinical characterization of three unrelated patients with a very rare phenotype associating cutis laxa, facial dysmorphism, severe growth retardation, hyperostotic skeletal dysplasia, and intellectual disability. This disorder called Lenz-Majewski syndrome (LMS) is associated with gain of function mutations in PTDSS1, encoding an enzyme involved in phospholipid biosynthesis. This report illustrates that LMS is an unequivocal cutis laxa syndrome and expands the clinical and molecular spectrum of this group of disorders. In the neonatal period, brachydactyly and facial dysmorphism are two early distinctive signs, later followed by intellectual disability and hyperostotic skeletal dysplasia with severe dwarfism allowing differentiation of this condition from other cutis laxa phenotypes. Further studies are needed to understand the link between PTDSS1 and extra cellular matrix assembly.


Assuntos
Cútis Laxa/diagnóstico , Cútis Laxa/genética , Hiperostose/diagnóstico , Hiperostose/genética , Mutação , Transferases de Grupos Nitrogenados/genética , Fenótipo , Adulto , Alelos , Criança , Pré-Escolar , Éxons , Facies , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Radiografia
15.
Orphanet J Rare Dis ; 13(1): 23, 2018 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-29373990

RESUMO

BACKGROUND: Many of the genetic childhood disorders leading to death in the pre- or neonatal period or during early childhood follow autosomal recessive modes of inheritance and bear specific challenges for genetic counseling and prenatal diagnostics. Parents are carriers but clinically unaffected, and diseases are rare but have recurrence risks of 25% in the same family. Often, affected children (or fetuses) die before a genetic diagnosis can be established, post-mortem analysis and phenotypic descriptions are insufficient and DNA from affected fetuses or children is not available for later analysis. A genetic diagnosis showing biallelic causative mutations is, however, the requirement for targeted carrier testing in parents and prenatal and preimplantation genetic diagnosis in further pregnancies. METHODS: We undertook targeted next-generation sequencing (NGS) for carrier screening of autosomal recessive lethal disorders in 8 consanguineous and 5 non-consanguineous couples with one or more affected children. We searched for heterozygous variants (non-synonymous coding or splice variants) in parents' DNA, using a set of 430 genes known to be causative for rare autosomal recessive diseases with poor prognosis, and then filtering for variants present in genes overlapping in both partners. Putative pathogenic variants were tested for cosegregation in affected fetuses or children where material was available. RESULTS: The diagnosis for the premature death in children was established in 5 of the 13 couples. Out of the 8 couples in which no causative diagnosis could be established 4 consented to undergo further analysis, in two of those a potentially causative variant in a novel candidate gene was identified. CONCLUSIONS: For the families in whom causative variants could be identified, these may now be used for prenatal and preimplantation genetic diagnostics. Our data show that NGS based gene panel sequencing of selected genes involved in lethal autosomal recessive disorders is an effective tool for carrier screening in parents and for the identification of recessive gene defects and offers the possibility of prenatal and preimplantation genetic diagnosis in further pregnancies in families that have experienced deaths in early childhood and /or multiple abortions.


Assuntos
Genes Recessivos/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Feminino , Humanos , Masculino , Análise em Microsséries/métodos , Linhagem
16.
Hum Genet ; 137(2): 111-127, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29305691

RESUMO

Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients.


Assuntos
Ataxia Cerebelar/genética , Deformidades Congênitas do Pé/genética , Perda Auditiva Central/genética , Perda Auditiva Neurossensorial/genética , Atrofia Óptica/genética , Reflexo Anormal/genética , ATPase Trocadora de Sódio-Potássio/genética , Adolescente , Adulto , Ataxia Cerebelar/epidemiologia , Ataxia Cerebelar/fisiopatologia , Criança , Pré-Escolar , Dinamarca/epidemiologia , Feminino , Deformidades Congênitas do Pé/epidemiologia , Deformidades Congênitas do Pé/fisiopatologia , Alemanha/epidemiologia , Perda Auditiva Central/epidemiologia , Perda Auditiva Central/fisiopatologia , Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Masculino , Simulação de Dinâmica Molecular , Mutação de Sentido Incorreto/genética , Atrofia Óptica/epidemiologia , Atrofia Óptica/fisiopatologia , Fenótipo , Estudos Retrospectivos , ATPase Trocadora de Sódio-Potássio/química , Suécia/epidemiologia , Adulto Jovem
17.
Mol Syndromol ; 8(4): 172-178, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28690482

RESUMO

Barber-Say syndrome (BSS) and ablepharon-macrostomia syndrome (AMS) are infrequently reported congenital malformation disorders caused by mutations in the TWIST2 gene. Both are characterized by abnormalities in ectoderm-derived structures and cause a very unusual morphology of mainly the face in individuals with otherwise normal cognition and normal physical functioning. We studied the impact that the presence of BSS and AMS has on psychosocial functioning of affected individuals and their families, using their point of view to start with. We tabulated frequently asked questions from affected individuals and families, and a parent of an affected child and an affected adult woman offered personal testimonies. We focused on perception of illness, body satisfaction, and the consequences for an otherwise normal individual who has a disorder that interferes with body image. The importance of paying particular attention to the management of both the physical appearance and the consequences of these entities on the quality of life is stressed by the affected individuals themselves.

20.
Am J Med Genet A ; 170(12): 3069-3082, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27648933

RESUMO

Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype-phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia. © 2016 Wiley Periodicals, Inc.


Assuntos
Proteína de Ligação a CREB/genética , Proteína p300 Associada a E1A/genética , Pré-Eclâmpsia/genética , Síndrome de Rubinstein-Taybi/genética , Adulto , Montagem e Desmontagem da Cromatina/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Pré-Eclâmpsia/fisiopatologia , Gravidez , Síndrome de Rubinstein-Taybi/patologia , Deleção de Sequência
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA