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1.
Clin Genet ; 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-33277917

RESUMO

INTRODUCTION: White-Sutton syndrome is a rare developmental disorder characterized by global developmental delay, intellectual disabilities (ID), and neurobehavioral abnormalities secondary to pathogenic POGZ variants. The purpose of our study was to describe the neurocognitive phenotype of an unbiased national cohort of patients with identified POGZ pathogenic variants. MATERIALS AND METHODS: This study is based on a French collaboration through the AnDDI-Rares network, and includes 19 patients from 18 families with POGZ pathogenic variants. All clinical data and neuropsychological tests were collected from medical files. RESULTS: Among the 19 patients, 14 patients exhibited ID (6 mild, 5 moderate and 3 severe). The 5 remaining patients had learning disabilities and shared a similar neurocognitive profile, including language difficulties, dysexecutive syndrome, attention disorders, slowness and social difficulties. One patient evaluated for autism was found to have moderate autism spectrum disorder. CONCLUSION: This study reveals that the cognitive phenotype of patients with POGZ pathogenic variants can range from learning disabilities to severe ID. It highlights that pathogenic variations in the same genes can be reported in a large spectrum of neurocognitive profiles, and that children with learning disabilities could benefit from next generation sequencing techniques.

2.
Clin Genet ; 2020 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-33368193

RESUMO

Smith-Magenis syndrome (SMS), characterized by dysmorphic features, neurodevelopmental disorder, and sleep disturbance, is due to an interstitial deletion of chromosome 17p11.2 (90%) or to point mutations in the RAI1 gene. In this retrospective cohort, we studied the clinical, cognitive, and behavioral profile of 47 European patients with SMS caused by a 17p11.2 deletion. We update the clinical and neurobehavioral profile of SMS. Intrauterine growth was normal in most patients. Prenatal anomalies were reported in 15%. 60% of our patients older than 10 years were overweight. Prevalence of heart defects (6.5% tetralogy of Fallot, 6.5% pulmonary stenosis), ophthalmological problems (89%), scoliosis (43%), or deafness (32%) were consistent with previous reports. Epilepsy was uncommon (2%). We identified a high prevalence of obstipation (45%). All patients had learning difficulties and developmental delay, but ID range was wide and 10% of patients had IQ in the normal range. Behavioral problems included temper tantrums and other difficult behaviors (84%) and night-time awakenings (86%). Optimal care of SMS children is multidisciplinary and requires important parental involvement. In our series, half of patients were able to follow adapted schooling, but 70% of parents had to adapt their working time, illustrating the medical, social, educative, and familial impact of having a child with SMS.

3.
Genet Med ; 22(11): 1838-1850, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32694869

RESUMO

PURPOSE: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown. METHODS: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes. RESULTS: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification. CONCLUSION: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.

4.
Eur J Med Genet ; 63(10): 104004, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32688057

RESUMO

De novo pathogenic variants in the GATAD2B gene have been associated with a syndromic neurodevelopmental disorder (GAND) characterized by severe intellectual disability (ID), impaired speech, childhood hypotonia, and dysmorphic features. Since its first description in 2013, nine patients have been reported in case reports and a series of 50 patients was recently published, which is consistent with the relative frequency of GATAD2B pathogenic variants in public databases. We report the detailed phenotype of 19 patients from various ethnic backgrounds with confirmed pathogenic GATAD2B variants including intragenic deletions. All individuals presented developmental delay with a median age of 2.5 years for independent walking and of 3 years for first spoken words. GATAD2B variant carriers showed very little subsequent speech progress, two patients over 30 years of age remaining non-verbal. ID was mostly moderate to severe, with one profound and one mild case, which shows a wider spectrum of disease severity than previously reported. We confirm macrocephaly as a major feature in GAND (53%). Most common dysmorphic features included broad forehead, deeply set eyes, hypertelorism, wide nasal base, and pointed chin. Conversely, prenatal abnormalities, non-cerebral malformations, epilepsy, and autistic behavior were uncommon. Other features included feeding difficulties, behavioral abnormalities, and unspecific abnormalities on brain MRI. Improving our knowledge of the clinical phenotype is essential for correct interpretation of the molecular results and accurate patient management.

5.
J Occup Environ Med ; 62(6): e260-e266, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32510909

RESUMO

OBJECTIVE: To assess the effect and transferability of a workplace food labeling intervention. METHODS: Employees' purchase of food items in cafeterias of an international company was monitored in six intervention sites (one in France and five in the United States [US]) where green-labels were displayed in healthy food items. One cafeteria in France represented the control site. Descriptive statistics were performed inter- and intra-site. RESULTS: One year after the intervention, purchase of labeled items was higher in the French intervention site compared with the control (P < 0.001). This consumption was increasing 2 years after the intervention (P < 0.001). The percentage (+8.0% from T0 to T1) of sales of labeled items from the US sites confirmed the transferability of this intervention. CONCLUSIONS: Workplace food labeling using positive nudge can contribute to healthy eating habits among employees. This can be replicated in other worksite cafeterias.

6.
EMBO J ; 39(13): e104163, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32484994

RESUMO

The relationships between impaired cortical development and consequent malformations in neurodevelopmental disorders, as well as the genes implicated in these processes, are not fully elucidated to date. In this study, we report six novel cases of patients affected by BBSOAS (Boonstra-Bosch-Schaff optic atrophy syndrome), a newly emerging rare neurodevelopmental disorder, caused by loss-of-function mutations of the transcriptional regulator NR2F1. Young patients with NR2F1 haploinsufficiency display mild to moderate intellectual disability and show reproducible polymicrogyria-like brain malformations in the parietal and occipital cortex. Using a recently established BBSOAS mouse model, we found that Nr2f1 regionally controls long-term self-renewal of neural progenitor cells via modulation of cell cycle genes and key cortical development master genes, such as Pax6. In the human fetal cortex, distinct NR2F1 expression levels encompass gyri and sulci and correlate with local degrees of neurogenic activity. In addition, reduced NR2F1 levels in cerebral organoids affect neurogenesis and PAX6 expression. We propose NR2F1 as an area-specific regulator of mouse and human brain morphology and a novel causative gene of abnormal gyrification.

7.
J Med Genet ; 57(7): 466-474, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32277047

RESUMO

PURPOSE: Marfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan-Fryns syndrome explain no more than 20% of subjects. METHODS: To further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic. RESULTS: We identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2). Using simulation models, we showed that five genes (DLG4, NFIX, EHMT1, ZEB2 and ATP1A1) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including NSD1 and NFIX, which are known to be mutated in overgrowth syndromes. CONCLUSION: We demonstrated that DNVs were enriched in chromatin remodelling (p=2×10-4) and genes regulated by the fragile X mental retardation protein (p=3×10-8), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.

8.
Genet Med ; 22(6): 1061-1068, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32099069

RESUMO

PURPOSE: TNR, encoding Tenascin-R, is an extracellular matrix glycoprotein involved in neurite outgrowth and neural cell adhesion, proliferation and migration, axonal guidance, myelination, and synaptic plasticity. Tenascin-R is exclusively expressed in the central nervous system with highest expression after birth. The protein is crucial in the formation of perineuronal nets that ensheath interneurons. However, the role of Tenascin-R in human pathology is largely unknown. We aimed to establish TNR as a human disease gene and unravel the associated clinical spectrum. METHODS: Exome sequencing and an online matchmaking tool were used to identify patients with biallelic variants in TNR. RESULTS: We identified 13 individuals from 8 unrelated families with biallelic variants in TNR sharing a phenotype consisting of spastic para- or tetraparesis, axial muscular hypotonia, developmental delay, and transient opisthotonus. Four homozygous loss-of-function and four different missense variants were identified. CONCLUSION: We establish TNR as a disease gene for an autosomal recessive nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus and highlight the role of central nervous system extracellular matrix proteins in the pathogenicity of spastic disorders.

9.
Genet Med ; 22(1): 181-188, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31363182

RESUMO

PURPOSE: Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype-phenotype correlations in KS individuals from a registry. METHODS: Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis. RESULTS: Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027). CONCLUSION: The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.


Assuntos
Doenças Autoimunes/epidemiologia , Proteínas de Ligação a DNA/genética , Face/anormalidades , Doenças Hematológicas/complicações , Histona Desmetilases/genética , Proteínas de Neoplasias/genética , Doenças da Imunodeficiência Primária/epidemiologia , Doenças Vestibulares/complicações , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/imunologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Doenças Hematológicas/genética , Doenças Hematológicas/imunologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação , Prevalência , Sistema de Registros , Índice de Gravidade de Doença , Doenças Vestibulares/genética , Doenças Vestibulares/imunologia , Adulto Jovem
10.
Genet Med ; 22(3): 524-537, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31578471

RESUMO

PURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated. RESULTS: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. CONCLUSIONS: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.

11.
J Med Genet ; 57(3): 160-168, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31586944

RESUMO

BACKGROUND: The type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying an IGF1R defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified IGF1R defects, as no external validation was available. Furthermore, we aimed to develop a functional test to allow the classification of variants of unknown significance (VUS) in vitro. METHODS: DNA was tested for either deletions or single nucleotide variant (SNV) and the phosphorylation of downstream pathways studied after stimulation with IGF-I by western blot analysis of fibroblast of nine patients. RESULTS: We detected 21 IGF1R defects in 35 patients, including 8 deletions and 10 heterozygous, 1 homozygous and 1 compound-heterozygous SNVs. The main clinical characteristics of these patients were being born small for gestational age (90.9%), short stature (88.2%) and microcephaly (74.1%). Feeding difficulties and varying degrees of developmental delay were highly prevalent (54.5%). There were no differences in phenotypes between patients with deletions and SNVs of IGF1R. Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation. CONCLUSION: We report eight new pathogenic variants of IGF1R and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of IGF1R defects with a sensitivity of 95.2%. We developed an efficient functional test to assess the pathogenicity of SNVs, which is useful, especially for VUS.

13.
BMC Med Genomics ; 12(1): 105, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288860

RESUMO

BACKGROUND: Nicolaides-Baraitser syndrome (NCBRS) is a neurodevelopmental disorder caused by pathogenic sequence variants in SMARCA2 which encodes the catalytic component of the chromatin remodeling BAF complex. Pathogenic variants in genes that encode epigenetic regulators have been associated with genome-wide changes in DNA methylation (DNAm) in affected individuals termed DNAm signatures. METHODS: Genome-wide DNAm was assessed in whole-blood samples from the individuals with pathogenic SMARCA2 variants and NCBRS diagnosis (n = 8) compared to neurotypical controls (n = 23) using the Illumina MethylationEPIC array. Differential methylated CpGs between groups (DNAm signature) were identified and used to generate a model enabling classification variants of uncertain significance (VUS; n = 9) in SMARCA2 as "pathogenic" or "benign". A validation cohort of NCBRS cases (n = 8) and controls (n = 96) demonstrated 100% model sensitivity and specificity. RESULTS: We identified a DNAm signature of 429 differentially methylated CpG sites in individuals with NCBRS. The genes to which these CpG sites map are involved in cell differentiation, calcium signaling, and neuronal function consistent with NCBRS pathophysiology. DNAm model classifications of VUS were concordant with the clinical phenotype; those within the SMARCA2 ATPase/helicase domain classified as "pathogenic". A patient with a mild neurodevelopmental NCBRS phenotype and a VUS distal to the ATPase/helicase domain did not score as pathogenic, clustering away from cases and controls. She demonstrated an intermediate DNAm profile consisting of one subset of signature CpGs with methylation levels characteristic of controls and another characteristic of NCBRS cases; each mapped to genes with ontologies consistent with the patient's unique clinical presentation. CONCLUSIONS: Here we find that a DNAm signature of SMARCA2 pathogenic variants in NCBRS maps to CpGs relevant to disorder pathophysiology, classifies VUS, and is sensitive to the position of the variant in SMARCA2. The patient with an intermediate model score demonstrating a unique genotype-epigenotype-phenotype correlation underscores the potential utility of this signature as a functionally relevant VUS classification system scalable beyond binary "benign" versus "pathogenic" scoring. This is a novel feature of DNAm signatures that could enable phenotypic predictions from genotype data. Our findings also demonstrate that DNAm signatures can be domain-specific, highlighting the precision with which they can reflect genotypic variation.


Assuntos
Metilação de DNA , Deformidades Congênitas do Pé/genética , Variação Genética , Hipotricose/genética , Deficiência Intelectual/genética , Fatores de Transcrição/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Ilhas de CpG/genética , Facies , Feminino , Humanos , Masculino , Fenótipo
14.
Am J Hum Genet ; 104(4): 758-766, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30929739

RESUMO

By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.


Assuntos
Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Nanismo/genética , Variação Genética , Deficiência Intelectual/genética , Histona Desmetilases com o Domínio Jumonji/genética , Anormalidades Musculoesqueléticas/genética , Estatura , Criança , Exoma , Face , Feminino , Estudos de Associação Genética , Mutação em Linhagem Germinativa , Haploinsuficiência , Histonas/química , Humanos , Masculino , Mutação de Sentido Incorreto , Fenótipo
15.
J Allergy Clin Immunol ; 143(1): 325-334.e2, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29906526

RESUMO

BACKGROUND: V(D)J recombination ensures the diversity of the adaptive immune system. Although its complete defect causes severe combined immunodeficiency (ie, T-B- severe combined immunodeficiency), its suboptimal activity is associated with a broad spectrum of immune manifestations, such as late-onset combined immunodeficiency and autoimmunity. The earliest molecular diagnosis of these patients is required to adopt the best therapy strategy, particularly when it involves a myeloablative conditioning regimen for hematopoietic stem cell transplantation. OBJECTIVE: We aimed at developing biomarkers based on analysis of the T-cell receptor (TCR) α repertoire to assist in the diagnosis of patients with primary immunodeficiencies with V(D)J recombination and DNA repair deficiencies. METHODS: We used flow cytometric (fluorescence-activated cell sorting) analysis to quantify TCR-Vα7.2-expressing T lymphocytes in peripheral blood and developed PROMIDISα, a multiplex RT-PCR/next-generation sequencing assay, to evaluate a subset of the TCRα repertoire in T lymphocytes. RESULTS: The combined fluorescence-activated cell sorting and PROMIDISα analyses revealed specific signatures in patients with V(D)J recombination-defective primary immunodeficiencies or ataxia telangiectasia/Nijmegen breakage syndromes. CONCLUSION: Analysis of the TCRα repertoire is particularly appropriate in a prospective way to identify patients with partial immune defects caused by suboptimal V(D)J recombination activity, a DNA repair defect, or both. It also constitutes a valuable tool for the retrospective in vivo functional validation of variants identified through exome or panel sequencing. Its broader implementation might be of interest to assist early diagnosis of patients presenting with hypomorphic DNA repair defects inclined to experience acute toxicity during prehematopoietic stem cell transplantation conditioning.


Assuntos
Síndromes de Imunodeficiência , Receptores de Antígenos de Linfócitos T alfa-beta , Recombinação V(D)J/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Estudos Retrospectivos
16.
Eur J Hum Genet ; 26(7): 996-1006, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29695756

RESUMO

High-throughput sequencing (HTS) of human genome coding regions allows the simultaneous screen of a large number of genes, significantly improving the diagnosis of non-syndromic intellectual disabilities (ID). HTS studies permit the redefinition of the phenotypical spectrum of known disease-causing genes, escaping the clinical inclusion bias of gene-by-gene Sanger sequencing. We studied a cohort of 903 patients with ID not reminiscent of a well-known syndrome, using an ID-targeted HTS of several hundred genes and found de novo heterozygous variants in TCF4 (transcription factor 4) in eight novel patients. Piecing together the patients from this study and those from previous large-scale unbiased HTS studies, we estimated the rate of individuals with ID carrying a disease-causing TCF4 mutation to 0.7%. So far, TCF4 molecular abnormalities were known to cause a syndromic form of ID, Pitt-Hopkins syndrome (PTHS), which combines severe ID, developmental delay, absence of speech, behavioral and ventilation disorders, and a distinctive facial gestalt. Therefore, we reevaluated ten patients carrying a pathogenic or likely pathogenic variant in TCF4 (eight patients included in this study and two from our previous ID-HTS study) for PTHS criteria defined by Whalen and Marangi. A posteriori, five patients had a score highly evocative of PTHS, three were possibly consistent with this diagnosis, and two had a score below the defined PTHS threshold. In conclusion, these results highlight TCF4 as a frequent cause of moderate to profound ID and broaden the clinical spectrum associated to TCF4 mutations to nonspecific ID.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Hiperventilação/genética , Deficiência Intelectual/genética , Fator de Transcrição 4/genética , Adolescente , Adulto , Criança , Pré-Escolar , Facies , Feminino , Humanos , Hiperventilação/diagnóstico , Hiperventilação/patologia , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Masculino , Mutação , Fenótipo , Adulto Jovem
17.
J Med Genet ; 55(6): 359-371, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29618507

RESUMO

The Xq28 duplication involving the MECP2 gene (MECP2 duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial MECP2 duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of MECP2 duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.


Assuntos
Exotropia/genética , Hipertensão Pulmonar/genética , Deficiência Intelectual/genética , Retardo Mental Ligado ao Cromossomo X/genética , Proteína 2 de Ligação a Metil-CpG/genética , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos Humanos X/genética , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Epilepsia/complicações , Epilepsia/genética , Epilepsia/fisiopatologia , Exotropia/complicações , Exotropia/fisiopatologia , França/epidemiologia , Humanos , Hiperopia/complicações , Hiperopia/genética , Hiperopia/fisiopatologia , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/fisiopatologia , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/fisiopatologia , Masculino , Retardo Mental Ligado ao Cromossomo X/complicações , Retardo Mental Ligado ao Cromossomo X/fisiopatologia , Linhagem , Fenótipo , Distúrbios Somatossensoriais/genética , Distúrbios Somatossensoriais/fisiopatologia , Transtorno de Movimento Estereotipado/complicações , Transtorno de Movimento Estereotipado/genética , Transtorno de Movimento Estereotipado/fisiopatologia , Adulto Jovem
18.
Kidney Int ; 93(2): 526, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29389400
19.
NPJ Genom Med ; 2: 32, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29263841

RESUMO

Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inherited SHANK3 deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.

20.
Brain ; 140(5): 1316-1336, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28379373

RESUMO

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.


Assuntos
Epilepsia/tratamento farmacológico , Epilepsia/genética , Epilepsia/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Canal de Sódio Disparado por Voltagem NAV1.2/fisiologia , Transtornos do Neurodesenvolvimento/genética , Bloqueadores dos Canais de Sódio/uso terapêutico , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Dinamarca/epidemiologia , Epilepsia/epidemiologia , Feminino , Humanos , Lactente , Masculino , Mutação , Fenótipo , Adulto Jovem
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