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1.
Am J Hum Genet ; 105(2): 403-412, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31303265

RESUMO

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

2.
Value Health ; 22(3): 340-347, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30832972

RESUMO

INTRODUCTION: Diary-derived symptom score and rescue medication use endpoints, such as symptom-free days (SFDs) and rescue medication-free days (RFD), are frequently used as clinical trial endpoints. Estimates of meaningful change for SFDs and RFDs have not been generated in pediatric populations. This research aimed to generate evidence supporting estimates of the individual within-patient changes that constitute an important or meaningful change in SFDs, RFDs, and updated estimates on the Childhood Asthma Control Test (C-ACT) in pediatric asthma populations aged 5-11 years. METHODS: Semistructured, qualitative interviews were conducted with children (ages 8-11 years) who had asthma and parents/caregivers of children (4-11 years) with asthma. Before the interview (4-9 days) participants were asked to complete a morning and evening diary. RESULTS: On average, parent/caregiver estimates of the difference in SFDs between a "very bad" and a "little bad" week for their children's asthma were largely concordant with the values reported by their children (differences of 1.8 and 1.4 SFDs, respectively). Both parents/caregivers and children were able to articulate what a meaningful level of change would be on the C-ACT at the item level. This qualitative study generated C-ACT item-level meaningful change estimates in the region of 1-3 category change, which potentially suggests that, if scaled up to represent C-ACT total score, this would lead to change estimates of 7-15 points. CONCLUSIONS: Our findings suggest that both children with asthma and parents/caregivers can quantitatively estimate and to some extent qualitatively articulate meaningful change in SFDs and RFDs.


Assuntos
Antiasmáticos/uso terapêutico , Asma/diagnóstico , Asma/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto/normas , Ensaios Clínicos Fase IV como Assunto/normas , Uso Significativo/normas , Asma/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Uso Significativo/tendências , Registros Médicos/normas
3.
Am J Hum Genet ; 102(3): 468-479, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29429572

RESUMO

Variants affecting the function of different subunits of the BAF chromatin-remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2). Affected individuals share common clinical features described in individuals with Coffin-Siris syndrome, including coarse facial features, global developmental delay, intellectual disability, speech impairment, and hypoplasia of fingernails and toenails. All variants occur within the highly conserved PHD1 and PHD2 motifs. Moreover, missense variants are situated close to zinc binding sites and are predicted to disrupt these sites. Pull-down assays of recombinant proteins and histone peptides revealed that a subset of the identified missense variants abolish or impaire DPF2 binding to unmodified and modified H3 histone tails. These results suggest an impairment of PHD finger structural integrity and cohesion and most likely an aberrant recognition of histone modifications. Furthermore, the overexpression of these variants in HEK293 and COS7 cell lines was associated with the formation of nuclear aggregates and the recruitment of both wild-type DPF2 and BRG1 to these aggregates. Expression analysis of truncating variants found in the affected individuals indicated that the aberrant transcripts escape nonsense-mediated decay. Altogether, we provide compelling evidence that de novo variants in DPF2 cause Coffin-Siris syndrome and propose a dominant-negative mechanism of pathogenicity.

4.
J Med Genet ; 55(6): 384-394, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29386252

RESUMO

BACKGROUND: Germline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype-phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers. METHODS: A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses. RESULTS: Tumour risks analysis provided novel penetrance estimates and genotype-phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%). CONCLUSIONS: Overall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype-tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/SDHD mutation carriers.

5.
J Clin Endocrinol Metab ; 102(11): 4013-4022, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973655

RESUMO

Context: The co-occurrence of pheochromocytoma (PC) and renal tumors was linked to the inherited familial cancer syndrome von Hippel-Lindau (VHL) disease more than six decades ago. Subsequently, other shared genetic causes of predisposition to renal tumors and to PC, paraganglioma (PGL), or head and neck paraganglioma (HNPGL) have been described, but case series of non-VHL-related cases of renal tumor and pheochromocytoma/paraganglioma tumor association syndrome (RAPTAS) are rare. Objective: To determine the clinical and molecular features of non-VHL RAPTAS by literature review and characterization of a case series. Design: A review of the literature was performed and a retrospective study of referrals for investigation of genetic causes of RAPTAS. Results: Literature review revealed evidence of an association, in addition to VHL disease, between germline mutations in SDHB, SDHC, SDHD, TMEM127, and MAX genes and RAPTAS [defined here as the co-occurrence of tumors from both classes (PC/PGL/HNPGL and renal tumors) in the same individual or in first-degree relatives]. In both the literature review and our case series of 22 probands with non-VHL RAPTAS, SDHB mutations were the most frequent cause of non-VHL RAPTAS. A genetic cause was identified in 36.3% (8/22) of kindreds. Conclusion: Renal tumors and PC/PGL/HNPGL tumors share common molecular features and their co-occurrence in an individual or family should prompt genetic investigations. We report a case of MAX-associated renal cell carcinoma and confirm the role of TMEM127 mutations with renal cell carcinoma predisposition.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Neoplasias Renais/genética , Paraganglioma/genética , Feocromocitoma/genética , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Criança , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Paraganglioma/patologia , Feocromocitoma/patologia , Estudos Retrospectivos , Síndrome , Adulto Jovem , Doença de von Hippel-Lindau/genética , Doença de von Hippel-Lindau/patologia
6.
Genome Res ; 27(10): 1704-1714, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28855261

RESUMO

Structural mosaic abnormalities are large post-zygotic mutations present in a subset of cells and have been implicated in developmental disorders and cancer. Such mutations have been conventionally assessed in clinical diagnostics using cytogenetic or microarray testing. Modern disease studies rely heavily on exome sequencing, yet an adequate method for the detection of structural mosaicism using targeted sequencing data is lacking. Here, we present a method, called MrMosaic, to detect structural mosaic abnormalities using deviations in allele fraction and read coverage from next-generation sequencing data. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) simulations were used to calculate detection performance across a range of mosaic event sizes, types, clonalities, and sequencing depths. The tool was applied to 4911 patients with undiagnosed developmental disorders, and 11 events among nine patients were detected. For eight of these 11 events, mosaicism was observed in saliva but not blood, suggesting that assaying blood alone would miss a large fraction, possibly >50%, of mosaic diagnostic chromosomal rearrangements.


Assuntos
Exoma , Genoma Humano , Mosaicismo , Análise de Sequência de DNA/métodos , Feminino , Humanos , Masculino , Análise de Sequência de DNA/instrumentação
8.
Clin Ther ; 39(6): 1191-1199, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28545804

RESUMO

PURPOSE: A dry powder inhaler formulation of the inhaled corticosteroid fluticasone furoate (FF) is being evaluated for use in children. An important potential risk associated with the use of inhaled corticosteroids in children is growth suppression. Therefore, the aim of this study was to assess the short-term lower leg growth in children with asthma treated for 2 weeks with inhaled FF versus placebo from the ELLIPTA inhaler. METHODS: Prepubertal children with persistent asthma (n = 60; aged 5 to <12 years) were recruited into a randomized, double-blind, placebo-controlled, 2-way crossover, noninferiority study. The study consisted of four 2-week periods: run-in, 2 treatment periods, 1 washout period, and a 1-week follow-up period. Interventions were FF 50 µg and placebo once daily in the evening. Lower leg length was measured by using knemometry. FINDINGS: The randomized ITT population comprised 36 boys and 24 girls with a mean age of 8.7 (standard deviation, 1.5; range, 5-11) years; 58% had a duration of asthma ≥5 years. Fifty-eight subjects completed both treatment periods. The least squares mean growth rate was 0.31 mm/week during treatment with FF and 0.36 mm/week during the placebo period. The difference in adjusted least squares mean growth rates between FF and placebo was -0.052 mm/week with a 95% CI of -0.122 to 0.018. This finding was greater than the prespecified noninferiority margin of -0.20 mm/week. The overall incidence of adverse events was 35% with placebo and 22% with FF. IMPLICATIONS: Inhaled FF 50 µg provided once daily for 2 weeks was noninferior to placebo in terms of effects on short-term lower leg growth in children with asthma. To further quantify the risk of growth suppression in children, intermediate-term growth studies should be conducted. Inhaled FF 50 µg was well tolerated in this study population. ClinicalTrials.gov identifier: NCT02502734.


Assuntos
Androstadienos/uso terapêutico , Asma/tratamento farmacológico , Desenvolvimento Infantil/efeitos dos fármacos , Glucocorticoides/uso terapêutico , Perna (Membro)/crescimento & desenvolvimento , Administração por Inalação , Criança , Pré-Escolar , Estudos Cross-Over , Método Duplo-Cego , Inaladores de Pó Seco , Feminino , Humanos , Masculino , Resultado do Tratamento
9.
BMC Pulm Med ; 17(1): 75, 2017 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-28454528

RESUMO

BACKGROUND: To analyse the efficacy of fluticasone propionate (FP) alone and combined with salmeterol (SAL) in achieving guideline-defined asthma control in Asian patients. METHODS: A post hoc analysis of the GOAL study in which patients were stratified by prior-medication use into inhaled corticosteroid (ICS)-naïve (Stratum [S] 1), low-dose ICS (S2), and medium-dose ICS (S3), and randomised to receive FP/SAL or FP. Doses were stepped-up every 12 weeks until Totally Controlled asthma or maximum dose was reached (PhI) and then maintained until study end (PhII). The primary endpoint was the proportion of patients achieving Well-Controlled asthma during PhI. Additional endpoints included Total Control and adverse events. Asian and non-Asian patients were analysed separately. RESULTS: In Asian patients in PhI, 74% (n = 87/118) in S1 achieved Well-Controlled asthma with FP/SAL versus 74% (n = 89/121) with FP alone (p = 0.839); corresponding values were 76% (n = 81/107) versus 60% (n = 62/104; p = 0.005) in S2, and 58% (n = 59/102) versus 43% (n = 41/95; p = 0.015) in S3. More patients in all three strata achieved Totally Controlled asthma with FP/SAL versus FP alone. Control was achieved more rapidly and with lower ICS doses with FP/SAL versus FP. A high proportion of patients who achieved control during PhI maintained control during PhII. Similar trends were found in non-Asian patients. No new safety concerns were identified. CONCLUSIONS: A greater proportion of Asian patients (S2 and S3, for Well-Controlled; all strata, for Totally Controlled) achieved guideline-defined asthma control with FP/SAL versus FP alone. High proportions of Asian patients in S1 achieved Well-Controlled asthma in both treatment groups.


Assuntos
Asma/tratamento farmacológico , Broncodilatadores/administração & dosagem , Fluticasona/administração & dosagem , Xinafoato de Salmeterol/administração & dosagem , Corticosteroides/administração & dosagem , Adulto , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Internacionalidade , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Testes de Função Respiratória , Índice de Gravidade de Doença , Resultado do Tratamento
10.
J Pediatr ; 186: 213-214, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28302327
11.
Fam Cancer ; 16(3): 433-440, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28091804

RESUMO

In the United Kingdom, current screening guidelines for TP53 germline mutation carriers solely recommends annual breast MRI, despite the wide spectrum of malignancies typically seen in this group. This study sought to investigate the role of one-off non-contrast whole-body MRI (WB MRI) in the screening of asymptomatic TP53 mutation carriers. 44 TP53 mutation carriers and 44 population controls were recruited. Scans were read by radiologists blinded to participant carrier status. The incidence of malignancies diagnosed in TP53 mutation carriers against general population controls was calculated. The incidences of non-malignant relevant disease and irrelevant disease were measured, as well as the number of investigations required to determine relevance of findings. In TP53 mutation carriers, 6 of 44 (13.6, 95% CI 5.2-27.4%) participants were diagnosed with cancer during the study, all of which would be considered life threatening if untreated. Two were found to have two primary cancers. Two participants with cancer had abnormalities on the MRI which were initially thought to be benign (a pericardial cyst and a uterine fibroid) but transpired to be sarcomas. No controls were diagnosed with cancer. Fifteen carriers (34.1, 95% CI 20.5-49.9%) and seven controls (15.9, 95% CI 6.7-30.1%) underwent further investigations following the WB MRI for abnormalities that transpired to be benign (p = 0.049). The cancer detection rate in this group justifies a minimum baseline non-contrast WB MRI in germline TP53 mutation carriers. This should be adopted into national guidelines for management of adult TP53 mutation carriers in addition to the current practice of contrast enhanced breast MRI imaging.


Assuntos
Detecção Precoce de Câncer/métodos , Neoplasias/diagnóstico , Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Adulto , Feminino , Predisposição Genética para Doença/genética , Heterozigoto , Humanos , Incidência , Imagem por Ressonância Magnética , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Mutação , Neoplasias/epidemiologia , Reino Unido , Imagem Corporal Total/métodos , Adulto Jovem
12.
Eur J Med Genet ; 60(2): 130-135, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27915094

RESUMO

Loss of function mutations in CTNNB1 have been reported in individuals with intellectual disability [MIM #615075] associated with peripheral spasticity, microcephaly and central hypotonia, suggesting a recognisable phenotype associated with haploinsufficiency for this gene. Trio based whole exome sequencing via the Deciphering Developmental Disorders (DDD) study has identified eleven further individuals with de novo loss of function mutations in CTNNB1. Here we report detailed phenotypic information on ten of these. We confirm the features that have been previously described and further delineate the skin and hair findings, including fair skin and fair and sparse hair with unusual patterning.


Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Microcefalia/genética , beta Catenina/genética , Adolescente , Adulto , Criança , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Exoma/genética , Feminino , Haploinsuficiência/genética , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Microcefalia/fisiopatologia , Mutação , Fenótipo , Análise de Sequência de DNA
13.
J Pediatr ; 178: 246-253.e2, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27622699

RESUMO

OBJECTIVE: To evaluate the dose-response, efficacy, and safety of fluticasone furoate (FF; 25 µg, 50 µg, and 100 µg), administered once daily in the evening during a 12-week treatment period to children with inadequately controlled asthma. STUDY DESIGN: This was a Phase IIb, multicenter, stratified, randomized, double-blind, double-dummy, parallel-group, placebo- and active-controlled study in children aged 5-11 years with inadequately controlled asthma. The study comprised a 4-week run-in period, 12-week treatment period, and 1-week follow-up period. Children were randomized to receive either placebo once daily, fluticasone propionate (FP) 100 µg twice daily, FF 25 µg, FF 50 µg, or FF 100 µg each once daily in the evening. Primary endpoint was the mean change from baseline in daily morning peak expiratory flow (PEF) averaged over weeks 1-12. Adverse events (AEs) also were investigated. RESULTS: In total, 593 children were included in the intent-to-treat population. The difference vs placebo in change from baseline daily morning PEF averaged over weeks 1-12 was statistically significant for the FF 25, FF 50, FF 100, and FP 100 groups (18.6 L/min, 19.5 L/min, 12.5 L/min, and 14.0 L/min, respectively; P < .001 for all). The incidence of AEs was greater in the FF groups (32%-36%) than in the placebo group (29%); the most frequent AE was cough. CONCLUSION: FF and FP resulted in significant improvements in morning PEF compared with placebo, suggesting that they are effective treatments for children with inadequately controlled asthma. All treatments were well tolerated; no new safety concerns were identified. TRIAL REGISTRATION: ClinicalTrials.gov:NCT01563029.


Assuntos
Androstadienos/administração & dosagem , Asma/tratamento farmacológico , Broncodilatadores/administração & dosagem , Administração por Inalação , Androstadienos/efeitos adversos , Broncodilatadores/efeitos adversos , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Resultado do Tratamento
14.
Respir Res ; 17: 37, 2016 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-27044326

RESUMO

BACKGROUND: Inhaled corticosteroids (ICS) are effective maintenance treatments for childhood asthma; however, many children remain uncontrolled. Vilanterol (VI) is an inhaled long-acting beta-2 agonist which, in combination with the ICS fluticasone furoate, is being explored as a once-daily treatment for asthma in children. We evaluated the dose-response, efficacy, and safety of once-daily VI (6.25 µg, 12.5 µg and 25 µg) administered in the evening over 4 weeks, on background fluticasone propionate (FP) in children with asthma inadequately controlled on ICS. METHODS: This was a Phase IIb, multicentre, randomised, double-blind, parallel-group, placebo-controlled study in children ages 5-11 years with persistent asthma on ICS and as-needed short-acting beta-agonist. The study comprised a 4-week run-in, 4-week treatment period, and 1-week follow-up. From study start, children replaced their current ICS with open-label FP 100 µg twice daily. Children were randomised to receive placebo, VI 6.25 µg, VI 12.5 µg or VI 25 µg once daily. Primary endpoint was treatment difference between VI 25 and placebo groups in mean change from baseline in evening peak expiratory flow averaged over the 4-week treatment. Secondary endpoints included change from baseline in trough forced expiratory volume in one second (FEV1) at Week 4 and change from baseline in percentage of rescue-free and symptom-free 24-h periods. Safety assessments included incidence of adverse events (AEs) and asthma exacerbations. RESULTS: In total, 456 children comprised the intention-to-treat population. The adjusted treatment difference between VI 25 and placebo groups for the primary endpoint was not statistically significant (p = 0.227) so no statistical inference was made for other VI dose comparisons or other endpoints. No difference in change from baseline in trough FEV1 was observed for any VI treatments versus placebo; however, VI 25 resulted in an additional 0.6 rescue-free days and 0.7 symptom-free days per week versus placebo. The incidence of AEs was slightly higher in the VI groups (28-33 %) versus placebo (22 %). Nine children experienced asthma exacerbations during the treatment period. CONCLUSION: VI plus FP did not result in significant improvements in lung function versus placebo plus FP, but was well tolerated at all doses assessed. TRIAL REGISTRATION: NCT01573767 (ClinicalTrials.gov).


Assuntos
Corticosteroides/administração & dosagem , Asma/diagnóstico , Asma/tratamento farmacológico , Álcoois Benzílicos/administração & dosagem , Clorobenzenos/administração & dosagem , Fluticasona/administração & dosagem , Administração por Inalação , Corticosteroides/efeitos adversos , Antiasmáticos/administração & dosagem , Álcoois Benzílicos/efeitos adversos , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Criança , Pré-Escolar , Clorobenzenos/efeitos adversos , Terapia Combinada/métodos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Fluticasona/efeitos adversos , Humanos , Masculino , Efeito Placebo , Resultado do Tratamento
15.
Brain ; 137(Pt 4): 1030-8, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24566669

RESUMO

Congenital disorders of glycosylation comprise a group of genetic defects with a high frequency of intellectual disability, caused by deficient glycosylation of proteins and lipids. The molecular basis of the majority of the congenital disorders of glycosylation type I subtypes, localized in the cytosol and endoplasmic reticulum, has been solved. However, elucidation of causative genes for defective Golgi glycosylation (congenital disorders of glycosylation type II) remains challenging because of a lack of sufficiently specific diagnostic serum methods. In a single patient with intellectual disability, whole-exome sequencing revealed MAN1B1 as congenital disorder of glycosylation type II candidate gene. A novel mass spectrometry method was applied for high-resolution glycoprofiling of intact plasma transferrin. A highly characteristic glycosylation signature was observed with hybrid type N-glycans, in agreement with deficient mannosidase activity. The speed and robustness of the method allowed subsequent screening in a cohort of 100 patients with congenital disorder of glycosylation type II, which revealed the characteristic glycosylation profile of MAN1B1-congenital disorder of glycosylation in 11 additional patients. Abnormal hybrid type N-glycans were also observed in the glycoprofiles of total serum proteins, of enriched immunoglobulins and of alpha1-antitrypsin in variable amounts. Sanger sequencing revealed MAN1B1 mutations in all patients, including severe truncating mutations and amino acid substitutions in the alpha-mannosidase catalytic site. Clinically, this group of patients was characterized by intellectual disability and delayed motor and speech development. In addition, variable dysmorphic features were noted, with truncal obesity and macrocephaly in ∼65% of patients. In summary, MAN1B1 deficiency appeared to be a frequent cause in our cohort of patients with unsolved congenital disorder of glycosylation type II. Our method for analysis of intact transferrin provides a rapid test to detect MAN1B1-deficient patients within congenital disorder of glycosylation type II cohorts and can be used as efficient diagnostic method to identify MAN1B1-deficient patients in intellectual disability cohorts. In addition, it provides a functional confirmation of MAN1B1 mutations as identified by next-generation sequencing in individuals with intellectual disability.


Assuntos
Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Adolescente , Adulto , Pré-Escolar , Análise Mutacional de DNA/métodos , Feminino , Glicosilação , Humanos , Lactente , Deficiência Intelectual/sangue , Masculino , Proteínas de Membrana/sangue , Mutação , Proteínas Nucleares/sangue , Adulto Jovem
16.
Nat Genet ; 45(3): 304-7, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23354436

RESUMO

Craniosynostosis, the premature fusion of the cranial sutures, is a heterogeneous disorder with a prevalence of ∼1 in 2,200 (refs. 1,2). A specific genetic etiology can be identified in ∼21% of cases, including mutations of TWIST1, which encodes a class II basic helix-loop-helix (bHLH) transcription factor, and causes Saethre-Chotzen syndrome, typically associated with coronal synostosis. Using exome sequencing, we identified 38 heterozygous TCF12 mutations in 347 samples from unrelated individuals with craniosynostosis. The mutations predominantly occurred in individuals with coronal synostosis and accounted for 32% and 10% of subjects with bilateral and unilateral pathology, respectively. TCF12 encodes one of three class I E proteins that heterodimerize with class II bHLH proteins such as TWIST1. We show that TCF12 and TWIST1 act synergistically in a transactivation assay and that mice doubly heterozygous for loss-of-function mutations in Tcf12 and Twist1 have severe coronal synostosis. Hence, the dosage of TCF12-TWIST1 heterodimers is critical for normal coronal suture development.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Craniossinostoses , Proteínas Nucleares/genética , Proteína 1 Relacionada a Twist/genética , Acrocefalossindactilia/complicações , Acrocefalossindactilia/genética , Acrocefalossindactilia/patologia , Animais , Suturas Cranianas/crescimento & desenvolvimento , Suturas Cranianas/patologia , Craniossinostoses/complicações , Craniossinostoses/genética , Craniossinostoses/patologia , Dimerização , Exoma , Regulação da Expressão Gênica no Desenvolvimento , Heterozigoto , Humanos , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Mutação , Análise de Sequência de DNA , Ativação Transcricional
17.
Clin Endocrinol (Oxf) ; 78(6): 898-906, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23072324

RESUMO

OBJECTIVES: Research studies have reported that about a third of individuals with phaeochromocytoma/paraganglioma (PPGL) have an inherited predisposition, although the frequency of specific mutations can vary between populations. We evaluated VHL, SDHB and SDHD mutation testing in cohorts of patients with non-syndromic PPGL and head and neck paraganglioma (HNPGL). DESIGN: Prospective, observational evaluation of NHS practice. PATIENTS: Individuals with PPGL/HNPGL referred to a supraregional genetics testing service over a 10-year period. MEASUREMENTS: Clinical (age, tumour site, malignancy, etc.), mutation frequencies and characteristics. RESULTS: A total of 501 probands with PPGL (n = 413) or HNPGL (n = 88) were studied. Thirty-one percent of patients with PPGL presented had a pathogenic mutation in SDHB, SDHD or VHL. Mutation detection rates were highest in those with a positive family history (62%), malignancy (53%), multiple tumours (33%) or PGL (44%). Twenty-eight percent of individuals with a single sporadic phaeochromocytoma had a mutation. Overall, 63% of patients with HNPGL had a mutation (92% of those with a family history, 89% of those with multicentric tumours and 34% of those with a single sporadic HNPGL). Penetrance was calculated in 121 SDHB mutation-positive probands and 187 of their mutation-positive relatives. Most relatives were asymptomatic and lifetime penetrance in non-proband SDHB mutation carriers was <50%. CONCLUSIONS: Practice-based evaluations of genetic testing in PPGL reveal high mutation detection rates. Although clinical criteria can be used to prioritize mutation testing, mutations were detected in 'low risk groups' indicating a need for comprehensive and inexpensive genetic testing strategies for PPGL and HNPGL.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Predisposição Genética para Doença/genética , Neoplasias de Cabeça e Pescoço/genética , Paraganglioma/genética , Feocromocitoma/genética , Succinato Desidrogenase/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Testes Genéticos , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos
18.
Neuropediatrics ; 43(5): 283-8, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22932948

RESUMO

BACKGROUND: Mutations in COL4A1 are responsible for a spectrum of clinical phenotypes characterized by neurological, ocular, and renal involvement. Neurological features are the most prominent but as such are rather nonspecific. CASE PRESENTATION: Here, we report three new cases that, like five patients we previously described, show the novel common finding of raised creatine kinase (CK) concentration. CONCLUSION: Raised CK concentration, in addition to intracranial calcification, is to be considered another useful pointer to a final diagnosis of COL4A1-related disease.


Assuntos
Encefalopatias/genética , Encefalopatias/metabolismo , Calcinose/etiologia , Colágeno Tipo IV/genética , Creatina Quinase/metabolismo , Mutação/genética , Adolescente , Adulto , Encefalopatias/patologia , Calcinose/genética , Córtex Cerebral/patologia , Criança , Pré-Escolar , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fibras Nervosas Mielinizadas/patologia
19.
Hum Mutat ; 31(10): 1142-54, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20672375

RESUMO

A range of phenotypes including Greig cephalopolysyndactyly and Pallister-Hall syndromes (GCPS, PHS) are caused by pathogenic mutation of the GLI3 gene. To characterize the clinical variability of GLI3 mutations, we present a subset of a cohort of 174 probands referred for GLI3 analysis. Eighty-one probands with typical GCPS or PHS were previously reported, and we report the remaining 93 probands here. This includes 19 probands (12 mutations) who fulfilled clinical criteria for GCPS or PHS, 48 probands (16 mutations) with features of GCPS or PHS but who did not meet the clinical criteria (sub-GCPS and sub-PHS), 21 probands (6 mutations) with features of PHS or GCPS and oral-facial-digital syndrome, and 5 probands (1 mutation) with nonsyndromic polydactyly. These data support previously identified genotype-phenotype correlations and demonstrate a more variable degree of severity than previously recognized. The finding of GLI3 mutations in patients with features of oral-facial-digital syndrome supports the observation that GLI3 interacts with cilia. We conclude that the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the genotype-phenotype correlation persists. Individuals with features of either GCPS or PHS should be screened for mutations in GLI3 even if they do not fulfill clinical criteria.


Assuntos
Anormalidades Múltiplas/genética , Fatores de Transcrição Kruppel-Like/genética , Mutação , Proteínas do Tecido Nervoso/genética , Síndrome de Pallister-Hall/patologia , Polidactilia/patologia , Sindactilia/patologia , Anormalidades Craniofaciais/genética , Genótipo , Humanos , Anormalidades da Boca/genética , Síndrome de Pallister-Hall/genética , Fenótipo , Polidactilia/genética , Sindactilia/genética , Proteína Gli3 com Dedos de Zinco
20.
Am J Med Genet A ; 152A(8): 1951-9, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20635359

RESUMO

Monosomy 1p36 is the most common terminal deletion syndrome seen in humans, occurring in approximately 1 in 5,000 live births. Common features include mental retardation, characteristic dysmorphic features, hypotonia, seizures, hearing loss, heart defects, cardiomyopathy, and behavior abnormalities. Similar phenotypes are seen among patients with a variety of deletion sizes, including terminal and interstitial deletions, complex rearrangements, and unbalanced translocations. Consequently, critical regions harboring causative genes for each of these features have been difficult to identify. Here we report on five individuals with 200-823 kb overlapping deletions of proximal 1p36.33, four of which are apparently de novo. They present with features of monosomy 1p36, including developmental delay and mental retardation, dysmorphic features, hypotonia, behavioral abnormalities including hyperphagia, and seizures. The smallest region of deletion overlap is 174 kb and contains five genes; these genes are likely candidates for some of the phenotypic features in monosomy 1p36. Other genes deleted in a subset of the patients likely play a contributory role in the phenotypes, including GABRD and seizures, PRKCZ and neurologic features, and SKI and dysmorphic and neurologic features. Characterization of small deletions is important for narrowing critical intervals and for the identification of causative or candidate genes for features of monosomy 1p36 syndrome.


Assuntos
Anormalidades Múltiplas , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Monossomia , Adolescente , Adulto , Pré-Escolar , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Doenças do Sistema Nervoso/genética , Fenótipo , Proteína Quinase C/genética , Proteínas Proto-Oncogênicas/genética , Receptores de GABA-A/genética , Convulsões/genética , Síndrome , Adulto Jovem
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