Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 95
Filtrar
Filtros adicionais











País/Região como assunto
Intervalo de ano
1.
Am J Med Genet A ; 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31509347

RESUMO

Fetal micrognathia can be detected early in pregnancy. Prognosis of micrognathia depends on the risk of respiratory distress at birth and on the long-term risk of intellectual disability. The purpose of this study was to evaluate the long-term prognosis of fetuses with prenatal diagnosis of micrognathia by estimating the prevalence and the severity of confirmed genetic diagnosis in our cohort. Our retrospective study included 41 fetuses with prenatal diagnosis of micrognathia referred to the multidisciplinary centers for prenatal diagnosis in Nice and Marseille, France, between 2006 and 2016. Fetal micrognathia was associated with cleft palate in 27 cases. A genetic cause was confirmed in 21 cases (67%). A chromosomal abnormality was present in 12 cases, including three copy-number variations diagnosed by array CGH. Monogenic disorders were identified in nine cases, most often after birth. Fetuses with family history of micrognathia or Pierre Robin sequence had a favorable outcome. Prognosis was good for the fetuses without associated findings and normal chromosomal analysis, with the exception of one case with a postnatal diagnosis of mandibulofacial dysostosis with microcephaly. Prognostic was poor for the fetuses with additional ultrasound anomalies, as only 5 out of 28 children had a good outcome. Prenatal diagnosis of micrognathia is an indicator of a possible fetal pathology justifying multidisciplinary management. Our study confirms the necessity of performing prenatal array CGH. Use of high-throughput gene sequencing in prenatal period could improve diagnostic performance, prenatal counseling, and adequate postnatal care.

2.
Genet Med ; 2019 Jul 31.
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.

3.
Clin Dysmorphol ; 28(4): 205-210, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31425298

RESUMO

Gonadal mosaicism has been reported in a variety of dominant or X-linked conditions and should be considered in all cases of apparent de-novo variation. Recently, some cases of supposed parental germline mosaicism have been shown to result from low-level somatic mosaicism. In most of the cases, mosaicism has been reported for pathogenic single nucleotide variants with only a few cases of copy number variation mosaicism described so far. Herein, we present the first case of parental somatic and gonadal copy number variation mosaicism in the SATB2 gene. We report three brothers presenting with the SATB2-associated syndrome. They all carry the same 121-kb heterozygous intragenic deletion of SATB2. Parental somatic mosaicism was detected by array-comparative genomic hybridization on a maternal blood sample and confirmed by Fluorescence in situ hybridization analysis on blood and buccal cells. This clinical report highlights the importance of investigating for parental somatic mosaicism to estimate the proper recurrence risk for subsequent pregnancy.

6.
Am J Med Genet A ; 176(10): 2172-2181, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30289625

RESUMO

The 22q11.2 deletion syndrome is caused by non-allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C, and D. Most patients have a typical LCR22A-D (AD) deletion of 3 million base pairs (Mb). In this report, we evaluated IQ scores in 1,478 subjects with 22q11.2DS. The mean of full scale IQ, verbal IQ, and performance IQ scores in our cohort were 72.41 (standard deviation-SD of 13.72), 75.91(SD of 14.46), and 73.01(SD of 13.71), respectively. To investigate whether IQ scores are associated with deletion size, we examined individuals with the 3 Mb, AD (n = 1,353) and nested 1.5 Mb, AB (n = 74) deletions, since they comprised the largest subgroups. We found that full scale IQ was decreased by 6.25 points (p = .002), verbal IQ was decreased by 8.17 points (p = .0002) and performance IQ was decreased by 4.03 points (p = .028) in subjects with the AD versus AB deletion. Thus, individuals with the smaller, 1.5 Mb AB deletion have modestly higher IQ scores than those with the larger, 3 Mb AD deletion. Overall, the deletion of genes in the AB region largely explains the observed low IQ in the 22q11.2DS population. However, our results also indicate that haploinsufficiency of genes in the LCR22B-D region (BD) exert an additional negative impact on IQ. Furthermore, we did not find evidence of a confounding effect of severe congenital heart disease on IQ scores in our cohort.

7.
Hum Genet ; 137(9): 753-768, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30167850

RESUMO

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.


Assuntos
Proteínas de Transporte/genética , Canalopatias/genética , Deficiências do Desenvolvimento/genética , Marcadores Genéticos , Variação Genética , Proteínas de Membrana/genética , Canais de Sódio/genética , Adolescente , Adulto , Canalopatias/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Adulto Jovem
8.
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.

9.
J Clin Endocrinol Metab ; 103(7): 2436-2446, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29659920

RESUMO

Context: Silver-Russell syndrome (SRS) (mainly secondary to 11p15 molecular disruption) and Temple syndrome (TS) (secondary to 14q32.2 molecular disruption) are imprinting disorders with phenotypic (prenatal and postnatal growth retardation, early feeding difficulties) and molecular overlap. Objective: To describe the clinical overlap between SRS and TS and extensively study the molecular aspects of TS. Patients: We retrospectively collected data on 28 patients with disruption of the 14q32.2 imprinted region, identified in our center, and performed extensive molecular analysis. Results: Seventeen (60.7%) patients showed loss of methylation of the MEG3/DLK1 intergenic differentially methylated region by epimutation. Eight (28.6%) patients had maternal uniparental disomy of chromosome 14 and three (10.7%) had a paternal deletion in 14q32.2. Most patients (72.7%) had a Netchine-Harbison SRS clinical scoring system ≥4/6, and consistent with a clinical diagnosis of SRS. The mean age at puberty onset was 7.2 years in girls and 9.6 years in boys; 37.5% had premature pubarche. The body mass index of all patients increased before pubarche and/or the onset of puberty. Multilocus analysis identified multiple methylation defects in 58.8% of patients. We identified four potentially damaging genetic variants in genes encoding proteins involved in the establishment or maintenance of DNA methylation. Conclusions: Most patients with 14q32.2 disruption fulfill the criteria for a clinical diagnosis of SRS. These clinical data suggest similar management of patients with TS and SRS, with special attention to their young age at the onset of puberty and early increase of body mass index.

10.
J Med Case Rep ; 12(1): 79, 2018 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-29549886

RESUMO

BACKGROUND: Autism spectrum disorders are serious neurodevelopmental disorders that affect approximately 1% of the population. These disorders are substantially influenced by genetics. Several recent linkage analyses have examined copy number variations associated with autism risk. Microdeletion of the 2q13 region is considered a pathogenic copy number variation. This microdeletion is involved in developmental delays, congenital heart defects, dysmorphism, and various psychiatric disorders, including autism spectrum disorders. There are only 34 reported cases with this chromosomal deletion, and five cases of autism spectrum disorders have been identified among them. The autistic phenotype associated with this microdeletion has never been described. CASE PRESENTATION: We describe the case of a 44-month-old Caucasian girl with the 2q13 microdeletion and autism spectrum disorders with global development delay but no associated organ anomalies. We examined the autistic phenotype using different workups and observed an atypical phenotype defined by relatively preserved relational competency and imitation abilities. CONCLUSIONS: The main contribution of this case report is the precise description of the autistic phenotype in the case of this deletion. We observed some atypical clinical features that could be markers of this genetic anomaly. We have discussed the pathophysiology of autism associated with this microdeletion and its incomplete penetrance and variable expressivity.


Assuntos
Transtorno do Espectro Autista/genética , Deleção Cromossômica , Fenótipo , Pré-Escolar , Feminino , Humanos
11.
Eur J Hum Genet ; 26(1): 143-148, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29187737

RESUMO

INTRODUCTION: A large number of genes involved in autosomal recessive forms of intellectual disability (ID) were identified over the past few years through whole-exome sequencing (WES) or whole-genome sequencing in consanguineous families. Disease-associated variants in TRAPPC9 were reported in eight multiplex consanguineous sibships from different ethnic backgrounds, and led to the delineation of the phenotype. Affected patients have microcephaly, obesity, normal motor development, severe ID, and language impairment and brain anomalies. PATIENTS: We report six new patients recruited through a national collaborative network. RESULTS: In the two patients heterozygous for a copy-number variation (CNV), the phenotype was clinically relevant with regard to the literature, which prompted to sequence the second allele, leading to identification of disease-associated variants in both. The third patient was homozygote for an intragenic TRAPPC9 CNV. The phenotype of the patients reported was concordant with the literature. Recent reports emphasized the role of CNVs in the etiology of rare recessive disorders. CONCLUSION: This study demonstrates that CNVs significantly contribute to the mutational spectrum of TRAPPC9 gene, and also confirms the interest of combining WES with CNV analysis to provide a molecular diagnosis to patients with rare Mendelian disorders.

12.
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.

13.
Am J Med Genet C Semin Med Genet ; 175(4): 417-430, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29178447

RESUMO

CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype-phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad (). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory-bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square-shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent.


Assuntos
Síndrome CHARGE/diagnóstico , Síndrome CHARGE/genética , Estudos de Associação Genética , Genótipo , Fenótipo , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , Sistema Nervoso Central/anormalidades , Criança , Pré-Escolar , Estudos de Coortes , Nervos Cranianos/anormalidades , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Feminino , França , Testes Genéticos , Humanos , Lactente , Masculino , Técnicas de Diagnóstico Molecular , Adulto Jovem
14.
Circ Cardiovasc Genet ; 10(5)2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29025761

RESUMO

BACKGROUND: The 22q11.2 deletion syndrome (22q11.2DS; DiGeorge syndrome/velocardiofacial syndrome) occurs in 1 of 4000 live births, and 60% to 70% of affected individuals have congenital heart disease, ranging from mild to severe. In our cohort of 1472 subjects with 22q11.2DS, a total of 62% (n=906) have congenital heart disease and 36% (n=326) of these have tetralogy of Fallot (TOF), comprising the largest subset of severe congenital heart disease in the cohort. METHODS AND RESULTS: To identify common genetic variants associated with TOF in individuals with 22q11.2DS, we performed a genome-wide association study using Affymetrix 6.0 array and imputed genotype data. In our cohort, TOF was significantly associated with a genotyped single-nucleotide polymorphism (rs12519770, P=2.98×10-8) in an intron of the adhesion GPR98 (G-protein-coupled receptor V1) gene on chromosome 5q14.3. There was also suggestive evidence of association between TOF and several additional single-nucleotide polymorphisms in this region. Some genome-wide significant loci in introns or noncoding regions could affect regulation of genes nearby or at a distance. On the basis of this possibility, we examined existing Hi-C chromatin conformation data to identify genes that might be under shared transcriptional regulation within the region on 5q14.3. There are 6 genes in a topologically associated domain of chromatin with GPR98, including MEF2C (Myocyte-specific enhancer factor 2C). MEF2C is the only gene that is known to affect heart development in mammals and might be of interest with respect to 22q11.2DS. CONCLUSIONS: In conclusion, common variants may contribute to TOF in 22q11.2DS and may function in cardiac outflow tract development.


Assuntos
Síndrome de DiGeorge/genética , Estudo de Associação Genômica Ampla , Receptores Acoplados a Proteínas-G/genética , Tetralogia de Fallot/genética , Cromatina/metabolismo , Cromossomos Humanos Par 5 , Síndrome de DiGeorge/complicações , Loci Gênicos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Desequilíbrio de Ligação , Fatores de Transcrição MEF2/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas-G/metabolismo , Análise de Sequência de DNA , Tetralogia de Fallot/complicações
16.
Am J Med Genet A ; 173(11): 3114-3117, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28940926

RESUMO

CHAND syndrome is an autosomal recessive disorder characterized by curly hair, ankyloblepharon, and nail dysplasia. Only few patients were reported to date. A homozygous RIPK4 mutation was recently identified by homozygosity mapping and whole exome sequencing in three patients from an expanded consanguineous kindred with a clinical diagnosis of CHAND syndrome. RIPK4 was previously known to be implicated in Bartsocas-Papas syndrome, the autosomal recessive form of popliteal pterygium syndrome. We report here two cases of RIPK4 homozygous mutations in a fetus with severe Bartsocas-Papas syndrome and a patient with CHAND syndrome. The patient with CHAND syndrome harbored the same mutation as the one identified in the family previously reported. We thus confirm the implication of RIPK4 gene in CHAND syndrome in addition to Bartsocas-Papas syndrome and discuss genotype/phenotype correlations.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Anormalidades do Olho/genética , Doenças Palpebrais/genética , Doenças do Cabelo/genética , Joelho/anormalidades , Transtornos do Desenvolvimento da Linguagem/genética , Unhas Malformadas/genética , Proteínas Serina-Treonina Quinases/genética , Sindactilia/genética , Pré-Escolar , Fenda Labial/diagnóstico , Fenda Labial/fisiopatologia , Fissura Palatina/diagnóstico , Fissura Palatina/fisiopatologia , Consanguinidade , Exoma/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/fisiopatologia , Doenças Palpebrais/diagnóstico , Doenças Palpebrais/fisiopatologia , Feminino , Feto , Doenças do Cabelo/diagnóstico , Doenças do Cabelo/fisiopatologia , Homozigoto , Humanos , Recém-Nascido , Joelho/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Mutação , Unhas Malformadas/diagnóstico , Unhas Malformadas/fisiopatologia , Sindactilia/diagnóstico , Sindactilia/fisiopatologia
17.
Nat Med ; 23(10): 1226-1233, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28869610

RESUMO

Basal cell carcinoma (BCC), the most common human cancer, results from aberrant activation of the Hedgehog signaling pathway. Although most cases of BCC are sporadic, some forms are inherited, such as Bazex-Dupré-Christol syndrome (BDCS)-a cancer-prone genodermatosis with an X-linked, dominant inheritance pattern. We have identified mutations in the ACTRT1 gene, which encodes actin-related protein T1 (ARP-T1), in two of the six families with BDCS that were examined in this study. High-throughput sequencing in the four remaining families identified germline mutations in noncoding sequences surrounding ACTRT1. These mutations were located in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1 expression. ARP-T1 was found to directly bind to the GLI1 promoter, thus inhibiting GLI1 expression, and loss of ARP-T1 led to activation of the Hedgehog pathway in individuals with BDCS. Moreover, exogenous expression of ACTRT1 reduced the in vitro and in vivo proliferation rates of cell lines with aberrant activation of the Hedgehog signaling pathway. In summary, our study identifies a disease mechanism in BCC involving mutations in regulatory noncoding elements and uncovers the tumor-suppressor properties of ACTRT1.


Assuntos
Carcinoma Basocelular/genética , Hipotricose/genética , Proteínas dos Microfilamentos/genética , Neoplasias Cutâneas/genética , Animais , Sistemas CRISPR-Cas , Imunoprecipitação da Cromatina , Elementos Facilitadores Genéticos/genética , Feminino , Perfilação da Expressão Gênica , Proteínas Hedgehog/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Camundongos , Camundongos Nus , Mutação , Transplante de Neoplasias , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Transdução de Sinais
18.
Am J Psychiatry ; 174(11): 1054-1063, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28750581

RESUMO

OBJECTIVE: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression. METHOD: Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: a schizophrenia group and those with no psychotic disorder at age ≥25 years. The authors assessed whether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia. RESULTS: Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci. CONCLUSIONS: The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno Autístico/genética , Transtornos Cromossômicos/genética , Síndrome de DiGeorge/genética , Deficiência Intelectual/genética , Esquizofrenia/genética , Adulto , Transtorno do Espectro Autista/psicologia , Transtorno Autístico/psicologia , Deleção Cromossômica , Transtornos Cromossômicos/psicologia , Cromossomos Humanos Par 16/genética , Variações do Número de Cópias de DNA , Síndrome de DiGeorge/psicologia , Feminino , Humanos , Deficiência Intelectual/psicologia , Masculino , Pessoa de Meia-Idade
19.
Am J Med Genet A ; 173(9): 2489-2493, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28657660

RESUMO

6p25 deletion is a rare but well-known entity. The main clinical features include an abnormal facial appearance, developmental delay, and ocular anomalies. Cardiac anomalies are frequently seen but remain poorly delineated. We describe a 4-year-old girl with 6p25.3 deletion, which includes the FOXC1 gene, typical dysmorphic features associated with developmental delay and oculo-motor anomalies. Aortic valve dysplasia was diagnosed early in life. The cardiac lesion progressed very rapidly between the age of 3 and 4 years requiring aortic valve replacement. Genomic analysis of blood and excised valve tissue showed down-regulation of FOXC1 but also FOXC2 expression in the diseased aortic valve. This allows us to speculate on the potential role of FOXC1 in aortic valve anomalies.


Assuntos
Anormalidades Múltiplas/genética , Fatores de Transcrição Forkhead/genética , Cardiopatias Congênitas/genética , Doenças das Valvas Cardíacas/genética , Anormalidades Múltiplas/fisiopatologia , Valva Aórtica/fisiopatologia , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 6/genética , Anormalidades do Olho/genética , Anormalidades do Olho/fisiopatologia , Feminino , Regulação da Expressão Gênica , Haploinsuficiência/genética , Cardiopatias Congênitas/fisiopatologia , Doenças das Valvas Cardíacas/fisiopatologia , Humanos , Fenótipo
20.
Eur J Obstet Gynecol Reprod Biol ; 212: 166-170, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28391132

RESUMO

OBJECTIVE: The aim of this study was to identify antenatal prognostic factors of neonatal outcomes in cases of fetal echogenic bowel (FEB). STUDY DESIGN: A retrospective study in three tertiary referral centers including fetal echogenic bowel over a 10-year period (from January 2003 to December 2013). The echogenicity of the fetal bowel was graded from 1 to 3, according to Slotnick's definition. Associated echographic findings such as bowel dilations, gallbladder abnormalities, calcifications, extra-abdominal abnormalities, intrauterine growth restriction (IUGR) and a decrease in amniotic fluid volume, if present were also recorded. This was followed by the FEB's sonographic evolution. The sonographic evolution was considered favorable if it was stable or decreasing and unfavorable if the echogenicity of the bowel increased or if additional sonographic findings appeared. Neonates had a pediatric examination in the delivery room and upon discharge from the maternity hospital. An outcome was considered good in the case of on-term delivery of a newborn with normal clinical examination and meconium elimination. RESULTS: Complete pregnancy outcome data were available for 409 pregnancies. 338 newborns had uneventful outcomes (82.6%). Antenatal exploration diagnosed 4 cases of aneuploidy (1 case of trisomy 13, 1 case of trisomy 18 and 2 cases of triploidies), 16 cases of congenital infections, 9 cases of cystic fibrosis and 11 cases of bowel abnormalities. After a multivariate analysis, we discovered the sonographic grade of the echogenic bowel was not a prognostic factor of neonatal outcome. The isolated fetal echogenic bowel had a 6.6-fold increase chance of uneventful outcomes (adjusted odd ratio (aOR) 6.6, 95% CI 3-14.4). Notably, favorable sonographic evolution (aOR 8.1, 95% CI 4.1-16) and late gestational age at the time of the diagnosis (aOR 1.17, 95% CI 1.07-1.27) are independent, good prognostic factors of good neonatal outcomes. None of the 180 fetuses with isolated fetal echogenic bowel and favorable sonographic evolution had adverse outcomes. Among these, 4 cases (0.98%) of aneuploïdy, 17 cases (4.2%) of congenital infections and 9 cases (2.2%) of cystic fibroses were also diagnosed. No cases of Down syndrome (DS) were reported. CONCLUSION: Our study shows that the grade should not be considered a prognostic factor of neonatal outcomes. Our data suggests the need to reevaluate the concept of systematic amniocentesis. Sonographic evolution of fetal bowel is an independent, strong prognostic factor for good neonatal outcomes. It also better defines the FEB prognostic.


Assuntos
Intestino Ecogênico/diagnóstico por imagem , Ultrassonografia Pré-Natal , Adulto , Intestino Ecogênico/classificação , Intestino Ecogênico/mortalidade , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Fatores de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA