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1.
Eat Weight Disord ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664672

RESUMO

PURPOSE: Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. Up to now, four genome-wide association studies of AN have been conducted to date and identified only few significant loci. However, both previous studies focused on common variation and on rare exonic variants. Currently, de novo variants are one of the most significant risk factors for neurodevelopmental disorders and psychiatric disorders. METHODS: We analyzed by whole exome sequencing a cohort of nine female AN individuals and their parents (mother and father), and focused our analysis on de novo variants. RESULTS: Here, we found seven de novo missense variants in potential genes in nine studied AN patients. Four of these genes (CSMD1, CREB3, PTPRD and GAB1) belong to a same signaling pathway involving neuron differentiation and dopamine pathway. CONCLUSIONS: This study provides a list of interesting genes such as CSDM1 and CREB3 that are candidates to be involved in the etiology of anorexia nervosa. LEVEL OF EVIDENCE: basic research.

2.
J Neural Transm (Vienna) ; 126(11): 1505-1511, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31388831

RESUMO

Anorexia nervosa (AN) is a severe debilitating eating disorder. To date, only very few genes that predispose to AN have been identified. An alternative to association studies is to characterize ultra-rare variants in familial forms of AN. Here, we have implemented this approach to identify pathways that contribute to the development of AN through the analysis of a family with three members suffering from AN by exome analysis. We identified three ultra-rare deleterious variants in three genes (DRD4, CCKAR, NMS), already connected to the reward pathway, that co-segregate with AN, suggesting that this pathway might be playing a predisposing role in AN at least in familial forms.

3.
Hum Mutat ; 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31350925

RESUMO

Whole-exome/genome sequencing analyses lead to detect disease-causing variants that are unrelated to the initial clinical question. Irrespective of any actionable gene list, only pathogenic variants should be considered. The pathogenicity of 55 cystic fibrosis transmembrane conductance regulator (CFTR) variants of known various impacts was assessed by a group of experts by comparing data from specialized databases CFTR-France and CFTR2 with those of general clinical databases ClinVar and Human Gene Mutation Database (HGMD®) Professional and data aggregators VarSome and InterVar. The assessment of cystic fibrosis (CF) variants was correct with ClinVar and HGMD® Professional while less reliable with VarSome and InterVar. Conversely, the risk of overclassifying variants as CF-causing was up to 82% with HGMD® Professional. The concordance between data aggregators was only 50%. The use of general databases and aggregators is thus associated with a substantial risk of misclassifying variants. This evaluation may be extrapolated to other disease conditions and incites to remain cautious in interpreting and disclosing incidental findings.

4.
Lancet ; 393(10185): 2035-2036, 2019 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-31106745
5.
Psychiatr Genet ; 29(4): 103-110, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30933048

RESUMO

BACKGROUND: Anorexia nervosa is a complex neuropsychiatric disorder presenting with life-threatening low body weight, and a persistent fear of gaining weight. To date, no whole exome sequencing was performed in male individuals with anorexia nervosa. AIM AND METHODS: Here, we performed an exome analysis in two independent families with male individuals with anorexia nervosa and found variants in the Neuronatin (NNAT) gene in both probands. To confirm our data, we carried out the screening of the NNAT gene in a cohort of 8 male and 144 female individuals with anorexia nervosa. RESULTS: Exome sequencing revealed a nonsense variant p.Trp33* in NNAT in one patient and a rare variant in the 5'UTR region of NNAT in the other patient. Screening of the NNAT gene in a cohort of 8 male and 144 female individuals with anorexia nervosa allowed to identify 11 other NNAT variants showing that 40.00% and 6.25% of male and female anorexia nervosa individuals carried a NNAT variant, respectively. Moreover, two novel missense variants were identified in female anorexia nervosa patients. CONCLUSION: Our data suggest that NNAT variants and NNAT expression changes may be associated with susceptibility to eating disorders such as anorexia nervosa.

6.
Epilepsy Behav ; 94: 308-311, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30898514

RESUMO

Eight patients, seven girls and one boy, had CDKL5 gene mutation, duplication, or deletion. Epileptic spasms started at a mean age of 3.5 months (range = 4 weeks-8 months). In five cases, tonic seizures preceded spasms at a median age of 6 weeks. In one patient who started at 8 months, spasms had a component of terror on awakening, reminding sleep terror. In two patients, electroencephalogram polygraphy of a so-called tonic seizure revealed that the tonic phase was followed by an overlooked clonic phase and then by a cluster of spasms during which each spasm was preceded by a brief clonic jerk revealed by electromyography. This sequence is rather particular and can be an early diagnostic clue. Progressive transition from this seizure type to epileptic spasms in clusters seems to result from increasing expression of the CDKL5 gene, as the child grows older. Five patients responded to the combination of vigabatrin and zonisamide.

7.
Dev Med Child Neurol ; 61(8): 891-898, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30680721

RESUMO

The aim of this study was to disentangle mechanisms of epileptogenesis in monogenic epilepsies in children. We reviewed paediatric monogenic epilepsies excluding brain malformation or an inborn error of metabolism, but including the gene function whether there is loss-of-function or gain-of-function, age at gene expression when available, and associated epilepsy syndrome. Genes for which at least five patients with similar epilepsy phenotype had been reported were selected. Three mechanisms are shared by most monogenic epilepsies: (1) excess of N-methyl-d-aspartate (NMDA) transmission activation (NMDA-pathies); (2) abnormal gamma-aminobutyric acid (GABA) transmission with reduced inhibition (phasic GABA-pathies); and (3) tonic activation of extrasynaptic GABAA receptors by extracellular GABA (tonic GABA-pathies). NMDA-pathies comprise early epileptic encephalopathy with suppression-burst, neonatal/infantile benign seizures, West and Lennox-Gastaut syndromes, and encephalopathy with continuous spike waves in slow sleep, thus brief seizures with major interictal spiking. Phasic GABA-pathies comprise mostly generalized epilepsy with febrile seizures plus and Dravet syndrome, thus long-lasting seizures with mild interictal spiking. Tonic GABA-pathies cause epilepsy with myoclonic-atonic seizures and Angelman syndrome, thus major high-amplitude slow-wave activity. This pathophysiological approach to monogenic epilepsies provides diagnostic clues and helps to guide treatment strategy. WHAT THIS PAPER ADDS: In paediatric monogenic epilepsies, electroclinical patterns point to three main mechanisms: NMDA-pathies, and phasic and tonic GABA-pathies. Antiepileptic treatment choice could be guided by each of these mechanisms.

9.
Gene ; 679: 305-313, 2018 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-30217758

RESUMO

Histone lysine methylation influences processes such as gene expression and DNA repair. Thirty Jumonji C (JmjC) domain-containing proteins have been identified and phylogenetically clustered into seven subfamilies. Most JmjC domain-containing proteins have been shown to possess histone demethylase activity toward specific histone methylation marks. One of these subfamilies, the KDM5 family, is characterized by five conserved domains and includes four members. Interestingly, de novo loss-of-function and missense variants in KDM5B were identified in patients with intellectual disability (ID) and autism spectrum disorder (ASD) but also in unaffected individuals. Here, we report two novel de novo splice variants in the KDM5B gene in three patients with ID and ASD. The c.808 + 1G > A variant was identified in a boy with mild ID and autism traits and is associated with a significant reduced KDM5B mRNA expression without alteration of its H3K4me3 pattern. In contrast, the c.576 + 2T > C variant was found in twins with global delay in developmental milestones, poor language and ASD. This variant causes the production of an abnormal transcript which may produce an altered protein with the loss of the ARID1B domain with an increase in global gene H3K4me3. Our data reinforces the recent observation that the KDM5B haploinsufficiency is not a mechanism involved in intellectual disability and that KDM5B disorder associated with LOF variants is a recessive disorder. However, some variants may also cause gain of function, and need to be interpreted with caution, and functional studies should be performed to identify the molecular consequences of these different rare variants.


Assuntos
Processamento Alternativo , Transtorno do Espectro Autista/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Histona Desmetilases com o Domínio Jumonji/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Adolescente , Transtorno do Espectro Autista/metabolismo , Linhagem Celular , Criança , Deficiências do Desenvolvimento/metabolismo , Regulação para Baixo , Feminino , Predisposição Genética para Doença , Haploinsuficiência , Humanos , Deficiência Intelectual/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Masculino , Proteínas Nucleares/metabolismo , Linhagem , Proteínas Repressoras/metabolismo
10.
Genet Med ; 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30206421

RESUMO

PURPOSE: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences. METHODS: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms. RESULTS: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments. CONCLUSION: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.

11.
Neuromolecular Med ; 20(3): 409-417, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30014449

RESUMO

A growing number of histone modifiers are involved in human neurodevelopmental disorders, suggesting that proper regulation of chromatin state is essential for the development of the central nervous system. Among them, heterozygous de novo variants in KMT2A, a gene coding for histone methyltransferase, have been associated with Wiedemann-Steiner syndrome (WSS), a rare developmental disorder mainly characterized by intellectual disability (ID) and hypertrichosis. As KMT2A is known to regulate the expression of multiple target genes through methylation of lysine 4 of histone 3 (H3K4me), we sought to investigate the transcriptomic consequences of KMT2A variants involved in WSS. Using fibroblasts from four WSS patients harboring loss-of-function KMT2A variants, we performed RNA sequencing and identified a number of genes for which transcription was altered in KMT2A-mutated cells compared to the control ones. Strikingly, analysis of the pathways and biological functions significantly deregulated between patients with WSS and healthy individuals revealed a number of processes predicted to be altered that are relevant for hypertrichosis and intellectual disability, the cardinal signs of this disease.

12.
Fetal Diagn Ther ; : 1-5, 2018 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-29920495

RESUMO

BACKGROUND: Cystic fibrosis (CF) can be revealed during fetal life by diverse ultrasound digestive abnormalities (USDA) such as fetal echogenic bowel or fetal intestinal loop dilatation, nonvisualization of the fetal gallbladder (NVFGB) being rarely observed in isolation. Only 6 cases of CF revealed by isolated NVFGB have been reported so far in the literature. Furthermore, recent studies suggested that this sign is of poor predictive value for CF. METHODS: We report on the results of a 6-year French tricenter study on 1,124 cases of fetal USDA for whom a comprehensive molecular study was performed for CF. RESULTS: Among the 37 CF fetuses, 5 (13.5%) presented with isolated NVFGB at ultrasound (US) examination at 24-31 weeks of gestation. This sign was more frequently observed in CF fetuses than in non-CF fetuses, with a likelihood ratio of 2.7. The genotypes included three c.1521_1523del (F508del) homozygous cases and two compound heterozygous cases for a frequent and a rare CF-causing variant. DISCUSSION: These observations highlight the importance to report on the presence and aspect of the fetal gallbladder at the second trimester US scan and to consider prenatal CFTR molecular analysis in cases of isolated NVFGB.

13.
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.

14.
Clin Chem Lab Med ; 56(5): 728-738, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29613853

RESUMO

BACKGROUND: To limit risks of miscarriages associated with invasive procedures of current prenatal diagnosis practice, we aim to develop a personalized medicine-based protocol for non-invasive prenatal diagnosis (NIPD) of monogenic disorders relying on the detection of paternally inherited mutations in maternal blood using droplet digital PCR (ddPCR). METHODS: This study included four couples at risk of transmitting paternal neurofibromatosis type 1 (NF1) mutations and four couples at risk of transmitting compound heterozygous CFTR mutations. NIPD was performed between 8 and 15 weeks of gestation, in parallel to conventional invasive diagnosis. We designed specific hydrolysis probes to detect the paternal mutation and to assess the presence of cell-free fetal DNA by ddPCR. Analytical performances of each assay were determined from paternal sample, an then fetal genotype was inferred from maternal plasma sample. RESULTS: Presence or absence of the paternal mutant allele was correctly determined in all the studied plasma DNA samples. CONCLUSIONS: We report an NIPD protocol suitable for implementation in an experienced laboratory of molecular genetics. Our proof-of-principle results point out a high accuracy for early detection of paternal NF1 and CFTR mutations in cell-free DNA, and open new perspectives for extending the technology to NIPD of many other monogenic diseases.

15.
Eur J Hum Genet ; 26(1): 107-116, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29203834

RESUMO

Variants in KMT2A, encoding the histone methyltransferase KMT2A, are a growing cause of intellectual disability (ID). Up to now, the majority of KMT2A variants are non-sense and frameshift variants causing a typical form of Wiedemann-Steiner syndrome. We studied KMT2A gene in a cohort of 200 patients with unexplained syndromic and non-syndromic ID and identified four novel variants, one splice and three missense variants, possibly deleterious. We used primary cells from the patients and molecular approaches to determine the deleterious effects of those variants on KMT2A expression and function. For the putative splice variant c.11322-1G>A, we showed that it led to only one nucleotide deletion and loss of the C-terminal part of the protein. For two studied KMT2A missense variants, c.3460C>T (p.(Arg1154Trp)) and c.8558T>G (p.(Met2853Arg)), located at the cysteine-rich CXXC domain and the transactivation domain of the protein, respectively, we found altered KMT2A target genes expression in patient's fibroblasts compared to controls. Furthermore, we found a disturbed subcellular distribution of KMT2A for the c.3460C>T mutant. Taken together, our results demonstrated the deleterious impact of the splice variant and of the missense variants located at two different functional domains and suggested reduction of KMT2A function as the disease-causing mechanism.

16.
Neuromuscul Disord ; 27(10): 911-913, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28802771

RESUMO

Duchenne Muscular Dystrophy (DMD) is the most frequent muscular dystrophy in childhood, with a worldwide incidence of one in 5000 live male births. It is due to mutations in the dystrophin gene leading to absence of full-length dystrophin protein. Central nervous system involvement is well-known in Duchenne Muscular Dystrophy. The multiple dystrophin isoforms expressed in brain have important roles in cerebral development and functioning. The association of Duchenne Muscular Dystrophy with seizures has been reported, and there is a higher prevalence of epilepsy in Duchenne Muscular Dystrophy patients (between 6.3% and 12.3%) than in the general pediatric population (0.5-1%). Duchenne Muscular Dystrophy patients may present with focal seizures, generalized tonic-clonic seizures or absences. We report on two boys in whom Duchenne Muscular Dystrophy is associated with epileptic spasms and hypsarrhythmia that fulfil the criteria for West syndrome, thus extending the spectrum of seizure types described in Duchenne Muscular Dystrophy patients.


Assuntos
Distrofina/genética , Distrofia Muscular de Duchenne/genética , Mutação/genética , Sistema Nervoso Central/metabolismo , Pré-Escolar , Epilepsia/complicações , Epilepsia/etiologia , Epilepsia/genética , Humanos , Lactente , Masculino , Distrofia Muscular de Duchenne/complicações , Isoformas de Proteínas/genética , Convulsões/etiologia , Convulsões/genética , Espasmos Infantis/complicações , Espasmos Infantis/genética
17.
Hum Mutat ; 38(8): 932-941, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28585349

RESUMO

De novo mutations are a frequent cause of disorders related to brain development. We report the results from the screening of two patients diagnosed with intellectual disability (ID) using exome sequencing to identify new causative de novo mutations. Exome sequencing was conducted in two patient-parent trios to identify de novo variants. In silico and expression studies were also performed to evaluate the functional consequences of these variants. The two patients presented developmental delay with minor facial dysmorphy. One of them presented pharmacoresistant myoclonic epilepsy. We identified two de novo splice variants (c.175+2T>G; c.367+2T>C) in the CSNK2B gene encoding the ß subunit of the Caseine kinase 2 (CK2). CK2 is a ubiquitously expressed kinase that is present in high levels in brain and it appears to be constitutively active. The mRNA transcripts were abnormal and significantly reduced in affected fibroblasts and most likely produced truncated proteins. Taking into account that mutations in CSNK2A1, encoding the α subunit of CK2, were previously identified in patients with neurodevelopmental disorders and dysmorphic features, our study confirmed that the protein kinase CK2 plays a major role in brain, and showed that CSNK2, encoding the ß subunit, is a novel ID gene. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy, and highlights CSNK2B as a new gene for neurodevelopmental disorders.


Assuntos
Caseína Quinase II/genética , Deficiências do Desenvolvimento/genética , Epilepsias Mioclônicas/genética , Deficiência Intelectual/genética , Caseína Quinase II/metabolismo , Pré-Escolar , Hibridização Genômica Comparativa , Exoma/genética , Feminino , Humanos , Lactente , Masculino , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Sequenciamento Completo do Exoma/métodos
18.
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
19.
Eur J Hum Genet ; 25(5): 560-564, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28145425

RESUMO

p.(Arg320His) mutation in the KCNC1 gene in human 11p15.1 has recently been identified in patients with progressive myoclonus epilepsies, a group of rare inherited disorders manifesting with action myoclonus, myoclonic epilepsy, and ataxia. This KCNC1 variant causes a dominant-negative effect. Here we describe three patients from the same family with intellectual disability and dysmorphic features. The three affected individuals carry a c.1015C>T (p.(Arg339*)) nonsense variant in KCNC1 gene. As previously observed in the mutant mouse carrying a disrupted KCNC1 gene, these findings reveal that individuals with a KCNC1 loss-of-function variant can present intellectual disability without seizure and epilepsy.


Assuntos
Códon sem Sentido , Anormalidades Craniofaciais/genética , Deficiência Intelectual/genética , Convulsões/genética , Canais de Potássio Shaw/genética , Adulto , Criança , Anormalidades Craniofaciais/diagnóstico , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Linhagem , Convulsões/diagnóstico , Síndrome
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