Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 64
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Genet Genomic Med ; 7(9): e839, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31393079

RESUMO

BACKGROUND: The most common inherited peripheral neuropathy is Charcot-Marie-Tooth disease (CMT), with a prevalence of 1/2500. Other symptoms can be associated to the condition, such as hearing loss. Currently, no global hearing impairment assessment has been determined, and the physiopathology is not well known. METHODS: The aim of the study was to analyze among a French series of 3,412 patients with inherited peripheral neuropathy (IPN), the ones who also suffer from hearing loss, to establish phenotype-genotype correlations. An NGS strategy for IPN one side and nonsyndromic hearing loss (NSHL) on the other side, were performed. RESULTS: Hearing loss (HL) was present in only 44 patients (1.30%). The clinical data of 27 patients were usable. Demyelinating neuropathy was diagnosed in 15 cases and axonal neuropathy in 12 cases. HL varied from mild to profound. Five cases of auditory neuropathy were noticed. Diagnosis was made for 60% of these patients. Seven novel pathogenic variants were discovered in five different genes: PRPS1; MPZ; SH3TC2; NEFL; and ABHD12. Two patients with PMP22 variant, had also an additional variant in COCH and MYH14 respectively. No pathogenic variant was found at the DFNB1 locus. Genotype-phenotype correlations do exist, especially with SH3TC2, PRPS1, ABHD12, NEFL, and TRPV4. CONCLUSION: Involvement of PMP22 is not enough to explain hearing loss in patients suffering from IPN. HL can be due to cochlear impairment and/or auditory nerve dysfunction. HL is certainly underdiagnosed, and should be evaluated in every patient suffering from IPN.

2.
Mol Genet Genomic Med ; 7(9): e875, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31338985

RESUMO

BACKGROUND: CMTX5 is characterized by peripheral neuropathy, early-onset sensorineural hearing impairment, and optic neuropathy. Only seven variants have been reported and no genotype-phenotype correlations have yet been established. PRPS1 has a crystallographic structure, as it is composed of three dimers that constitute a hexamer. METHODS: Next-generation sequencing (NGS) was performed using a custom 92-gene panel designed for the diagnosis of Charcot-Marie-Tooth (CMT) and associated neuropathies. RESULTS: We report the case of a 35-year-old male, who had presented CMT and hearing loss since childhood associated to bilateral optic neuropathy without any sign of retinitis pigmentosa. A new hemizygous variant on chromosomic position X:106,882,604, in the PRPS1 gene, c.202A > T, p.(Met68Leu) was found. This change is predicted to lead to an altered affinity between the different subunits in the dimer, thereby may prevent the hexamer formation. CONCLUSION: CMTX5 is probably under-diagnosed, as an overlap among the different features due to PRPS1 exists. Patients who developed polyneuropathy associated to sensorineural deafness and optic atrophy during childhood should be assessed for PRPS1.

3.
Circulation ; 140(4): 293-302, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31155932

RESUMO

BACKGROUND: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. METHODS: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator-treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. RESULTS: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959), and the calibration slope was 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. CONCLUSIONS: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03058185.

5.
Am J Hum Genet ; 104(2): 213-228, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639323

RESUMO

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

6.
Neuromuscul Disord ; 29(2): 114-126, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30598237

RESUMO

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder characterized by progressive motor and respiratory decline during the first year of life. Early and late-onset cases have recently been reported, although not meeting the established diagnostic criteria, these cases have been genotyped. We thus conducted a national multicenter observational retrospective study to determine the prognosis of children with SMARD1 according to their phenotype. We recorded all known French pediatric cases with mutations identified on the immunoglobulin µ-binding protein 2 gene and the presence of respiratory symptoms. Thirty centers provided 22 observations. A diaphragmatic palsy was diagnosed 1.5 months (p = 0.02) after first respiratory symptoms, and hypotonia preceded areflexia by 4 months (p = 0.02). Early onset of symptoms leading to specialist consultation before the age of 3 months was associated with a significantly worse prognosis (p < 0.01). Among the 6 patients who were still alive, all were tracheostomized. Only one case survived beyond 2 years without artificial ventilation. The remaining patients died at a median age of 7 months. Our results may help pediatricians to provide medical information to parents and improve the decision-making process of setting up life support.

7.
Fetal Diagn Ther ; : 1-10, 2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30121677

RESUMO

BACKGROUND: Analysis of cell-free fetal DNA in maternal plasma is very promising for early diagnosis of monogenic diseases. However, it has been limited by the need to set up patient- or disease-specific custom-made approaches. Here we propose a universal test based on fluorescent multiplex PCR and size fragment analysis for an indirect diagnosis of cystic fibrosis (CF). METHODS: The test, based on haplotyping, includes nine intra- and extragenic short tandem repeats of the CFTR locus, the coamplification of p.Phe508del (the most frequent mutation in CF patients worldwide), and a specific SRY sequence. The assay is able to determine the inherited paternal allele. RESULTS: Our simple approach was successfully applied to 30 couples and provided clear results from the maternal plasma. The mean rate of informative markers was sufficient to propose it for use in indirect diagnosis. CONCLUSIONS: This noninvasive prenatal diagnosis test, focused on indirect diagnosis of CF, offers many advantages over current methods: it is simple, rapid, and cost-effective. It allows for the testing of a large number of couples with high risk of CF, whatever the familial mutation of the CFTR gene. It provides an alternative method to reduce the number of invasive tests.

8.
J Mol Diagn ; 20(4): 533-549, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29792937

RESUMO

Myopathies and muscular dystrophies (M-MDs) are genetically heterogeneous diseases, with >100 identified genes, including the giant and complex titin (TTN) and nebulin (NEB) genes. Next-generation sequencing technology revolutionized M-MD diagnosis and revealed high frequency of TTN and NEB variants. We developed a next-generation sequencing diagnostic strategy targeted to the coding sequences of 135 M-MD genes. Comparison of two targeted capture technologies (SeqCap EZ Choice library capture kit and Nextera Rapid Capture Custom Enrichment kit) and of two whole-exome sequencing kits (SureSelect V5 and TruSeq RapidExome capture) revealed best coverage with the SeqCap EZ Choice protocol. A marked decrease in coverage was observed with the other kits, affecting mostly the first exons of genes and the repeated regions of TTN and NEB. Bioinformatics analysis strategy was fine-tuned to achieve optimal detection of variants, including small insertions/deletions (INDELs) and copy number variants (CNVs). Analysis of a cohort of 128 patients allowed the detection of 52 substitutions, 13 INDELs (including a trinucleotide repeat expansion), and 3 CNVs. Two INDELs were localized in the repeated regions of NEB, suggesting that these mutations may be frequent but underestimated. A large deletion was also identified in TTN that is, to our knowledge, the first published CNV in this gene.

9.
JAMA Neurol ; 75(4): 495-502, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29356829

RESUMO

Importance: Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia due to mutations in the aprataxin gene (APTX) that is characterized by early-onset cerebellar ataxia, oculomotor apraxia, axonal motor neuropathy, and eventual decrease of albumin serum levels. Objectives: To improve the clinical, biomarker, and molecular delineation of AOA1 and provide genotype-phenotype correlations. Design, Setting, and Participants: This retrospective analysis included the clinical, biological (especially regarding biomarkers of the disease), electrophysiologic, imaging, and molecular data of all patients consecutively diagnosed with AOA1 in a single genetics laboratory from January 1, 2002, through December 31, 2014. Data were analyzed from January 1, 2015, through January 31, 2016. Main Outcomes and Measures: The clinical, biological, and molecular spectrum of AOA1 and genotype-phenotype correlations. Results: The diagnosis of AOA1 was confirmed in 80 patients (46 men [58%] and 34 women [42%]; mean [SD] age at onset, 7.7 [7.4] years) from 51 families, including 57 new (with 8 new mutations) and 23 previously described patients. Elevated levels of α-fetoprotein (AFP) were found in 33 patients (41%); hypoalbuminemia, in 50 (63%). Median AFP level was higher in patients with AOA1 (6.0 ng/mL; range, 1.1-17.0 ng/mL) than in patients without ataxia (3.4 ng/mL; range, 0.8-17.2 ng/mL; P < .01). Decreased albumin levels (ρ = -0.532) and elevated AFP levels (ρ = 0.637) were correlated with disease duration. The p.Trp279* mutation, initially reported as restricted to the Portuguese founder haplotype, was discovered in 53 patients with AOA1 (66%) with broad white racial origins. Oculomotor apraxia was found in 49 patients (61%); polyneuropathy, in 74 (93%); and cerebellar atrophy, in 78 (98%). Oculomotor apraxia correlated with the severity of ataxia and mutation type, being more frequent with deletion or truncating mutations (83%) than with presence of at least 1 missense variant (17%; P < .01). Mean (SD) age at onset was higher for patients with at least 1 missense mutation (17.7 [11.4] vs 5.2 [2.6] years; P < .001). Conclusions and Relevance: The AFP level, slightly elevated in a substantial fraction of patients, may constitute a new biomarker for AOA1. Oculomotor apraxia may be an optional finding in AOA1 and correlates with more severe disease. The p.Trp279* mutation is the most frequent APTX mutation in the white population. APTX missense mutations may be associated with a milder phenotype.

10.
Orphanet J Rare Dis ; 12(1): 118, 2017 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-28659150

RESUMO

BACKGROUND: PWS is a severe neurodevelopmental genetic disorder now usually diagnosed in the neonatal period from hypotonia and feeding difficulties. Our study analyzed the birth incidence and care of infants with early diagnosis. METHODS: Data were collected on 61 infants with a molecular diagnosis of PWS born in 2012 and 2013 in France. RESULTS: Thirty-eight infants with PWS were born in 2013. The median age at diagnosis was 18 days. Birth incidence calculated for 2013 was 1/21,000 births. No case was diagnosed prenatally, despite 9 amniocenteses, including 4 for polyhydramnios. Five infants had delayed diagnosis, after 3 months of life. For 2 of them, the diagnosis was not suspected at birth and for 3, FISH analysis in the neonatal period was normal, with no further molecular studies. Ninety-three percent of the neonates were hospitalized, and 84% needed nasogastric tube feeding for a median of 38 days. Swallowing assessment was performed for 45%, at a median age of 10 days. Physiotherapy was started for 76% during hospitalization. Eighty percent of those diagnosed within the first 3 months were seen by a pediatric endocrinologist within the first week of life. CONCLUSION: Our study is the first to assess the birth incidence of PWS in France, at 1/21,000 births. Some prenatal or neonatal cases remain undiagnosed because of unrecognized clinical signs and the inappropriate choice of the initial molecular test. We also underscore the need to optimize neonatal care of infants with PWS.


Assuntos
Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/terapia , Diagnóstico Tardio , Diagnóstico Precoce , Feminino , Genótipo , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Síndrome de Prader-Willi/genética , Gravidez , Diagnóstico Pré-Natal
11.
Hum Mutat ; 38(10): 1297-1315, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28603918

RESUMO

Most of the 2,000 variants identified in the CFTR (cystic fibrosis transmembrane regulator) gene are rare or private. Their interpretation is hampered by the lack of available data and resources, making patient care and genetic counseling challenging. We developed a patient-based database dedicated to the annotations of rare CFTR variants in the context of their cis- and trans-allelic combinations. Based on almost 30 years of experience of CFTR testing, CFTR-France (https://cftr.iurc.montp.inserm.fr/cftr) currently compiles 16,819 variant records from 4,615 individuals with cystic fibrosis (CF) or CFTR-RD (related disorders), fetuses with ultrasound bowel anomalies, newborns awaiting clinical diagnosis, and asymptomatic compound heterozygotes. For each of the 736 different variants reported in the database, patient characteristics and genetic information (other variations in cis or in trans) have been thoroughly checked by a dedicated curator. Combining updated clinical, epidemiological, in silico, or in vitro functional data helps to the interpretation of unclassified and the reassessment of misclassified variants. This comprehensive CFTR database is now an invaluable tool for diagnostic laboratories gathering information on rare variants, especially in the context of genetic counseling, prenatal and preimplantation genetic diagnosis. CFTR-France is thus highly complementary to the international database CFTR2 focused so far on the most common CF-causing alleles.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Bases de Dados Genéticas , Mutação/genética , Alelos , Fibrose Cística/diagnóstico , França , Aconselhamento Genético , Humanos , Recém-Nascido , Fenótipo
12.
Europace ; 19(4): 651-659, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28431061

RESUMO

Aims: Mutations in PRKAG2, the gene encoding for the γ2 subunit of 5'-AMP-activated protein kinase (AMPK), are responsible for an autosomal dominant glycogenosis with a cardiac presentation, associating hypertrophic cardiomyopathy (HCM), ventricular pre-excitation (VPE), and progressive heart block. The aim of this study was to perform a retrospective time-to-event study of the clinical manifestations associated with PRKAG2 mutations. Methods and Results: A cohort of 34 patients from 9 families was recruited between 2001 and 2010. DNA were sequenced on all exons and flanking sequences of the PRKAG2 gene using Sanger sequencing. Overall, four families carried the recurrent p.Arg302Gln mutation, and the five others carried private mutations among which three had never been reported. In the total cohort, at 40 years of age, the risk of developing HCM was 61%, VPE 70%, conduction block 22%, and sudden cardiac death (SCD) 20%. The global survival at 60 years of age was 66%. Thirty-two per cent of patients (N = 10) required a device implantation (5 pacemakers and 5 defibrillators) at a median age of 66 years, and two patients required heart transplant. Only one patient presented with significant skeletal muscle symptoms. No significant differences regarding the occurrence of VPE, ablation complications, or death incidence were observed between different mutations. Conclusion: This study of patients with PRKAG2 mutations provides a more comprehensive view of the natural history of this disease and demonstrates a high risk of cardiac complications. Early recognition of this disease appears important to allow an appropriate management.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/genética , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/mortalidade , Doença de Depósito de Glicogênio/genética , Doença de Depósito de Glicogênio/mortalidade , Adulto , Comorbidade , Feminino , França/epidemiologia , Marcadores Genéticos/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Prevalência , Fatores de Risco , Taxa de Sobrevida
14.
Am J Hum Genet ; 100(2): 352-363, 2017 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-28132691

RESUMO

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.


Assuntos
Transtornos do Neurodesenvolvimento/genética , Complexo de Endopeptidases do Proteassoma/genética , Adolescente , Animais , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Deleção de Genes , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Polimorfismo de Nucleotídeo Único , Peixe-Zebra/genética
15.
J Nephrol ; 30(2): 211-218, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26946416

RESUMO

BACKGROUND: While reproductive technologies are increasingly used worldwide, epidemiologic, clinical and genetic data regarding infertile men with combined genital tract and renal abnormalities remain scarce, preventing adequate genetic counseling. METHODS: In a cohort-based study, we assessed the prevalence (1995-2014) and the clinical characteristics of renal disorders in infertile males with genital tract malformation. In a subset of 34 patients, we performed a detailed phenotype analysis of renal and genital tract disorders. RESULTS: Among the 180 patients with congenital uni- or bilateral absence of vas deferens (CU/BAVD), 45 (25 %) had a renal malformation. We also identified 14 infertile men with combined seminal vesicle (SV) and renal malformation but no CU/BAVD. Among the 34 patients with detailed clinical description, renal disease was unknown before the assessment of the infertility in 27 (79.4 %), and 7 (20.6 %) had chronic renal failure. Four main renal phenotypes were observed: solitary kidney (47 %); autosomal-dominant polycystic kidney disease (ADPKD, 0.6 %); uni- or bilateral hypoplastic kidneys (20.6 %); and a complex renal phenotype associated with a mutation of the HNF1B gene (5.8 %). Absence of SV and azoospermia were significantly associated with the presence of a solitary kidney, while dilatation of SV and necroasthenozoospermia were suggestive of ADPKD. CONCLUSION: A dominantly inherited renal disease (ADPKD or HNF1B-related nephropathy) is frequent in males with infertility and combined renal and genital tract abnormalities (26 %). A systematic renal screening should be proposed in infertile males with CU/BAVD or SV disorders.


Assuntos
Fertilidade/genética , Aconselhamento Genético , Fator 1-beta Nuclear de Hepatócito/genética , Infertilidade Masculina , Rim/anormalidades , Doenças Urogenitais Masculinas/genética , Mutação , Rim Policístico Autossômico Dominante/genética , Ducto Deferente/anormalidades , Adulto , Feminino , França/epidemiologia , Predisposição Genética para Doença , Humanos , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/epidemiologia , Infertilidade Masculina/genética , Infertilidade Masculina/fisiopatologia , Rim/fisiopatologia , Nascimento Vivo , Masculino , Doenças Urogenitais Masculinas/epidemiologia , Doenças Urogenitais Masculinas/fisiopatologia , Doenças Urogenitais Masculinas/terapia , Pessoa de Meia-Idade , Fenótipo , Rim Policístico Autossômico Dominante/epidemiologia , Rim Policístico Autossômico Dominante/fisiopatologia , Rim Policístico Autossômico Dominante/terapia , Gravidez , Taxa de Gravidez , Prevalência , Técnicas de Reprodução Assistida , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Ducto Deferente/fisiopatologia
17.
J Clin Endocrinol Metab ; 101(12): 4895-4903, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27662437

RESUMO

CONTEXT: Adults with Prader-Willi syndrome (PWS) have an increased proportion of sc fat mass compared with body mass index (BMI)-matched controls, but whether the genotype influences body composition and metabolic profile remains controversial. OBJECTIVE: To assess body composition and metabolic features in adults with PWS, according to genetic subtype. In addition, the effect of previous GH treatment was assessed. Main Outcomes and Measures: Body composition (Dual Energy X-ray Absorptiometry) and metabolic parameters were compared in PWS adults (mean age, 25.5 ± 8.9 y) with deletion (n = 47) or uniparental disomy (UPD) (n = 26), taking into account GH treatment in childhood and/or adolescence. In subgroups, adipocyte size, fasting total ghrelin levels, and resting energy expenditure were measured, and hyperphagia was assessed by the Dykens Hyperphagia Questionnaire. MAIN OUTCOMES AND MEASURES: Body composition (Dual Energy X-ray Absorptiometry) and metabolic parameters were compared in PWS adults (mean age, 25.5 ± 8.9 y) with deletion (n = 47) or uniparental disomy (UPD) (n = 26), taking into account GH treatment in childhood and/or adolescence. In subgroups, adipocyte size, fasting total ghrelin levels, and resting energy expenditure were measured, and hyperphagia was assessed by the Dykens Hyperphagia Questionnaire. RESULTS: In the whole sample, the deletion group had a higher BMI compared with UPD (40.9 ± 11.5 vs 34.6 ± 9.6 kg/m2, P = .02), but there was no difference between groups in percent body fat, metabolic profile, adipocyte size, resting energy expenditure, hyperphagia score, or ghrelin levels. In subjects previously treated with GH, BMI was not different between UPD and deletion groups (33.0 ± 9.7 vs 33.5 ± 11.1 kg/m2). In addition, previous GH treatment was associated with decreased percent body fat and adipocyte volume only in the deletion group. CONCLUSION: A deletion genotype in adults with PWS is associated with increased BMI. GH treatment in childhood and/or adolescence limits this deleterious phenotypic effect with improved adiposity markers. This study suggests relationships between the molecular phenotype of PWS and adipose tissue development as well as sensitivity to GH.


Assuntos
Adipócitos , Adiposidade , Índice de Massa Corporal , Hormônio do Crescimento/uso terapêutico , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/metabolismo , Absorciometria de Fóton , Adolescente , Adulto , Deleção Cromossômica , Cromossomos Humanos Par 15 , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Síndrome de Prader-Willi/classificação , Dissomia Uniparental , Adulto Jovem
18.
Am J Hum Genet ; 99(2): 437-42, 2016 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-27476656

RESUMO

In 80% of infertile men with obstructive azoospermia caused by a congenital bilateral absence of the vas deferens (CBAVD), mutations are identified in the cystic fibrosis transmembrane conductance regulator gene (CFTR). For the remaining 20%, the origin of the CBAVD is unknown. A large cohort of azoospermic men with CBAVD was retrospectively reassessed with more stringent selection criteria based on consistent clinical data, complete description of semen and reproductive excurrent ducts, extensive CFTR testing, and kidney ultrasound examination. To maximize the phenotypic prioritization, men with CBAVD and with unilateral renal agenesis were considered ineligible for the present study. We performed whole-exome sequencing on 12 CFTR-negative men with CBAVD and targeted sequencing on 14 additional individuals. We identified three protein-truncating hemizygous mutations, c.1545dupT (p.Glu516Ter), c.2845delT (p.Cys949AlafsTer81), and c.2002_2006delinsAGA (p.Leu668ArgfsTer21), in ADGRG2, encoding the epididymal- and efferent-ducts-specific adhesion G protein-coupled receptor G2, in four subjects, including two related individuals with X-linked transmission of their infertility. Previous studies have demonstrated that Adgrg2-knockout male mice develop obstructive infertility. Our study confirms the crucial role of ADGRG2 in human male fertility and brings new insight into congenital obstructive azoospermia pathogenesis. In men with CBAVD who are CFTR-negative, ADGRG2 testing could allow for appropriate genetic counseling with regard to the X-linked transmission of the molecular defect.


Assuntos
Deleção de Genes , Genes Ligados ao Cromossomo X/genética , Doenças Urogenitais Masculinas/genética , Receptores Acoplados a Proteínas-G/genética , Ducto Deferente/anormalidades , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Análise Mutacional de DNA , Exoma/genética , Feminino , Humanos , Masculino , Linhagem
19.
J Med Genet ; 53(11): 743-751, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27317772

RESUMO

BACKGROUND: Heterozygous NSD1 mutations were identified in 60%-90% of patients with Sotos syndrome. Recently, mutations of the SETD2 and DNMT3A genes were identified in patients exhibiting only some Sotos syndrome features. Both NSD1 and SETD2 genes encode epigenetic 'writer' proteins that catalyse methylation of histone 3 lysine 36 (H3K36me). The DNMT3A gene encodes an epigenetic 'reader' protein of the H3K36me chromatin mark. METHODS: We aimed at confirming the implication of DNMT3A and SETD2 mutations in an overgrowth phenotype, through a comprehensive targeted-next generation sequencing (NGS) screening in 210 well-phenotyped index cases with a Sotos-like phenotype and no NSD1 mutation, from a French cohort. RESULTS: Six unreported heterozygous likely pathogenic variants in DNMT3A were identified in seven patients: two nonsense variants and four de novo missense variants. One de novo unreported heterozygous frameshift variant was identified in SETD2 in one patient. All the four DNMT3A missense variants affected DNMT3A functional domains, suggesting a potential deleterious impact. DNMT3A-mutated index cases shared similar clinical features including overgrowth phenotype characterised by postnatal tall stature (≥+2SD), macrocephaly (≥+2SD), overweight or obesity at older age, intellectual deficiency and minor facial features. The phenotype associated with SETD2 mutations remains to be described more precisely. The p.Arg882Cys missense de novo constitutional DNMT3A variant found in two patients is the most frequent DNMT3A somatic mutation in acute leukaemia. CONCLUSIONS: Our results illustrate the power of targeted NGS to identify rare disease-causing variants. These observations provided evidence for a unifying mechanism (disruption of apposition and reading of the epigenetic chromatin mark H3K36me) that causes an overgrowth syndrome phenotype. Further studies are needed in order to assess the role of SETD2 and DNMT3A in intellectual deficiency without overgrowth.

20.
PLoS One ; 11(2): e0149717, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26918704

RESUMO

BACKGROUND: Intellectual Disability (ID) is characterized by deficits in intellectual functions such as reasoning, problem-solving, planning, abstract thinking, judgment, and learning. As new avenues are emerging for treatment of genetically determined ID (such as Down's syndrome or Fragile X syndrome), it is necessary to identify objective reliable and sensitive outcome measures for use in clinical trials. OBJECTIVE: We developed a novel visual analogical reasoning paradigm, inspired by the Progressive Raven's Matrices, but appropriate for Intellectually Disabled patients. This new paradigm assesses reasoning and inhibition abilities in ID patients. METHODS: We performed behavioural analyses for this task (with a reaction time and error rate analysis, Study 1) in 96 healthy controls (adults and typically developed children older than 4) and 41 genetically determined ID patients (Fragile X syndrome, Down syndrome and ARX mutated patients). In order to establish and quantify the cognitive strategies used to solve the task, we also performed an eye-tracking analysis (Study 2). RESULTS: Down syndrome, ARX and Fragile X patients were significantly slower and made significantly more errors than chronological age-matched healthy controls. The effect of inhibition on error rate was greater than the matrix complexity effect in ID patients, opposite to findings in adult healthy controls. Interestingly, ID patients were more impaired by inhibition than mental age-matched healthy controls, but not by the matrix complexity. Eye-tracking analysis made it possible to identify the strategy used by the participants to solve the task. Adult healthy controls used a matrix-based strategy, whereas ID patients used a response-based strategy. Furthermore, etiologic-specific reasoning differences were evidenced between ID patients groups. CONCLUSION: We suggest that this paradigm, appropriate for ID patients and developmental populations as well as adult healthy controls, provides an objective and quantitative assessment of visual analogical reasoning and cognitive inhibition, enabling testing for the effect of pharmacological or behavioural intervention in these specific populations.


Assuntos
Deficiência Intelectual/psicologia , Pensamento , Adolescente , Adulto , Estudos de Casos e Controles , Cognição , Síndrome de Down/fisiopatologia , Síndrome de Down/psicologia , Feminino , Síndrome do Cromossomo X Frágil/fisiopatologia , Síndrome do Cromossomo X Frágil/psicologia , Proteínas de Homeodomínio/genética , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação , Fatores de Transcrição/genética , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA