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2.
Eur J Hum Genet ; 27(8): 1197-1214, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31019283

RESUMO

With exome/genome sequencing (ES/GS) integrated into the practice of medicine, there is some potential for reporting incidental/secondary findings (IFs/SFs). The issue of IFs/SFs has been studied extensively over the last 4 years. In order to evaluate their implications in care organisation, we retrospectively evaluated, in a cohort of 700 consecutive probands, the frequency and burden of introducing the search for variants in a maximum list of 244 medically actionable genes (genes that predispose carriers to a preventable or treatable disease in childhood/adulthood and genes for genetic counselling issues). We also focused on the 59 PharmGKB class IA/IB pharmacogenetic variants. We also compared the results in different gene lists. We identified variants (likely) affecting protein function in genes for care in 26 cases (3.7%) and heterozygous variants in genes for genetic counselling in 29 cases (3.8%). Mean time for the 700 patients was about 6.3 min/patient for medically actionable genes and 1.3 min/patient for genes for genetic counselling, and a mean time of 37 min/patients for the reinterpreted variants. These results would lead to all 700 pre-test counselling sessions being longer, to 55 post-test genetic consultations and to 27 secondary specialised medical evaluations. ES also detected 42/59 pharmacogenetic variants or combinations of variants in the majority of cases. An extremely low metabolizer status in genes relevant for neurodevelopmental disorders (CYP2C9 and CYP2C19) was found in 57/700 cases. This study provides information regarding the need to anticipate the implementation of genomic medicine, notably the work overload at various steps of the process.

3.
Genet Med ; 21(7): 1657-1661, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30563986

RESUMO

PURPOSE: Exome sequencing (ES) powerfully identifies the molecular bases of heterogeneous conditions such as intellectual disability and/or multiple congenital anomalies (ID/MCA). Current ES analysis, combining diagnosis analysis restricted to disease-causing genes reported in OMIM database and subsequent research investigation extended to other genes, indicated causal and candidate genes around 40% and 10%. Nonconclusive results are frequent in such ultrarare conditions that recurrence and genotype-phenotype correlations are limited. International data-sharing permits the gathering of additional patients carrying variants in the same gene to draw definitive conclusions on their implication as disease causing. Several web-based tools have been developed and grouped in Matchmaker Exchange. In this study, we report our current experience as a regional center that has implemented ES as a first-line diagnostic test since 2013, working with a research laboratory devoted to disease gene identification. METHODS: We used GeneMatcher over 2.5 years to share 71 novel candidate genes identified by ES. RESULTS: Matches occurred in 60/71 candidate genes allowing to confirm the implication of 39% of matched genes as causal and to rule out 6% of them. CONCLUSION: The introduction of user-friendly gene-matching tools, such as GeneMatcher, appeared to be an essential step for the rapid identification of novel disease genes responsible for ID/MCA.

4.
J Med Genet ; 2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30287593

RESUMO

BACKGROUND: The clinical significance of 16p13.11 duplications remains controversial while frequently detected in patients with developmental delay (DD), intellectual deficiency (ID) or autism spectrum disorder (ASD). Previously reported patients were not or poorly characterised. The absence of consensual recommendations leads to interpretation discrepancy and makes genetic counselling challenging. This study aims to decipher the genotype-phenotype correlations to improve genetic counselling and patients' medical care. METHODS: We retrospectively analysed data from 16 013 patients referred to 12 genetic centers for DD, ID or ASD, and who had a chromosomal microarray analysis. The referring geneticists of patients for whom a 16p13.11 duplication was detected were asked to complete a questionnaire for detailed clinical and genetic data for the patients and their parents. RESULTS: Clinical features are mainly speech delay and learning disabilities followed by ASD. A significant risk of cardiovascular disease was noted. About 90% of the patients inherited the duplication from a parent. At least one out of four parents carrying the duplication displayed a similar phenotype to the propositus. Genotype-phenotype correlations show no impact of the size of the duplicated segment on the severity of the phenotype. However, NDE1 and miR-484 seem to have an essential role in the neurocognitive phenotype. CONCLUSION: Our study shows that 16p13.11 microduplications are likely pathogenic when detected in the context of DD/ID/ASD and supports an essential role of NDE1 and miR-484 in the neurocognitive phenotype. Moreover, it suggests the need for cardiac evaluation and follow-up and a large study to evaluate the aortic disease risk.

6.
Genet Med ; 2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-30190612

RESUMO

PURPOSE: To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants. METHODS: We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants. RESULTS: The number of rare likely deleterious variants in functionally intolerant genes ("other hits") correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. CONCLUSION: Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.

7.
Am J Med Genet B Neuropsychiatr Genet ; 177(4): 397-405, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29603867

RESUMO

Recurrent deletions and duplications at the 2q13 locus have been associated with developmental delay (DD) and dysmorphisms. We aimed to undertake detailed clinical characterization of individuals with 2q13 copy number variations (CNVs), with a focus on behavioral and psychiatric phenotypes. Participants were recruited via the Unique chromosomal disorder support group, U.K. National Health Service Regional Genetics Centres, and the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) database. A review of published 2q13 patient case reports was undertaken to enable combined phenotypic analysis. We present a new case series of 2q13 CNV carriers (21 deletion, 4 duplication) and the largest ever combined analysis with data from published studies, making a total of 54 deletion and 23 duplication carriers. DD/intellectual disabilities was identified in the majority of carriers (79% deletion, 70% duplication), although in the new cases 52% had an IQ in the borderline or normal range. Despite the median age of the new cases being only 9 years, 64% had a clinical psychiatric diagnosis. Combined analysis found attention deficit hyperactivity disorder (ADHD) to be the most frequent diagnosis (48% deletion, 60% duplication), followed by autism spectrum disorders (33% deletion, 17% duplication). Aggressive (33%) and self-injurious behaviors (33%) were also identified in the new cases. CNVs at 2q13 are typically associated with DD with mildly impaired intelligence, and a high rate of childhood psychiatric diagnoses-particularly ADHD. We have further characterized the clinical phenotype related to imbalances of the 2q13 region and identified it as a region of interest for the neurobiological investigation of ADHD.

8.
Genet Med ; 20(6): 645-654, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29095811

RESUMO

PurposeCongenital anomalies and intellectual disability (CA/ID) are a major diagnostic challenge in medical genetics-50% of patients still have no molecular diagnosis after a long and stressful diagnostic "odyssey." Solo clinical whole-exome sequencing (WES) was applied in our genetics center to improve diagnosis in patients with CA/ID.MethodsThis retrospective study examined 416 consecutive tests performed over 3 years to demonstrate the effectiveness of periodically reanalyzing WES data. The raw data from each nonpositive test was reanalyzed at 12 months with the most recent pipeline and in the light of new data in the literature. The results of the reanalysis for patients enrolled in the third year are not yet available.ResultsOf the 416 patients included, data for 156 without a diagnosis were reanalyzed. We obtained 24 (15.4%) additional diagnoses: 12 through the usual diagnostic process (7 new publications, 4 initially misclassified, and 1 copy-number variant), and 12 through translational research by international data sharing. The final yield of positive results was 27.9% through a strict diagnostic approach, and 2.9% through an additional research strategy.ConclusionThis article highlights the effectiveness of periodically combining diagnostic reinterpretation of clinical WES data with translational research involving data sharing for candidate genes.


Assuntos
Anormalidades Congênitas/genética , Deficiência Intelectual/genética , Sequenciamento Completo do Exoma/métodos , Bases de Dados Genéticas , Exoma , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Doenças Raras/genética , Estudos Retrospectivos , Análise de Sequência de DNA/métodos
9.
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.

10.
J Clin Invest ; 127(11): 4090-4103, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28972538

RESUMO

Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired. The level of SRP54 mRNA in the bone marrow was 3.6-fold lower in patients with SRP54-mutations than in healthy controls. Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype. In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond-like phenotype.


Assuntos
Doenças da Medula Óssea/genética , Insuficiência Pancreática Exócrina/genética , Lipomatose/genética , Neutropenia/congênito , Partícula de Reconhecimento de Sinal/genética , Animais , Criança , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Modelos Moleculares , Neutropenia/genética , Pâncreas Exócrino/metabolismo , Fenótipo , Domínios Proteicos , Partícula de Reconhecimento de Sinal/química , Peixe-Zebra
11.
Eur J Med Genet ; 60(11): 595-604, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28807864

RESUMO

BACKGROUND AND OBJECTIVE: Whole-exome sequencing (WES) has now entered medical practice with powerful applications in the diagnosis of rare Mendelian disorders. Although the usefulness and cost-effectiveness of WES have been widely demonstrated, it is essential to reduce the diagnostic turnaround time to make WES a first-line procedure. Since 2011, the automation of laboratory procedures and advances in sequencing chemistry have made it possible to carry out diagnostic whole genome sequencing from the blood sample to molecular diagnosis of suspected genetic disorders within 50 h. Taking advantage of these advances, the main objective of the study was to improve turnaround times for sequencing results. METHODS: WES was proposed to 29 patients with severe undiagnosed disorders with developmental abnormalities and faced with medical situations requiring rapid diagnosis. Each family gave consent. The extracted DNA was sequenced on a NextSeq500 (Illumina) instrument. Data were analyzed following standard procedures. Variants were interpreted using in-house software. Each rare variant affecting protein sequences with clinical relevance was tested for familial segregation. RESULTS: The diagnostic rate was 45% (13/29), with a mean turnaround time of 40 days from reception of the specimen to delivery of results to the referring physician. Besides permitting genetic counseling, the rapid diagnosis for positive families led to two pre-natal diagnoses and two inclusions in clinical trials. CONCLUSIONS: This pilot study demonstrated the feasibility of rapid diagnostic WES in our primary genetics center. It reduced the diagnostic odyssey and helped provide support to families.


Assuntos
Exoma , Testes Genéticos/normas , Análise de Sequência de DNA/normas , Adolescente , Adulto , Criança , Pré-Escolar , Diagnóstico Precoce , Feminino , Testes Genéticos/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Sensibilidade e Especificidade , Análise de Sequência de DNA/métodos , Fatores de Tempo
12.
Nat Genet ; 49(4): 527-536, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28288114

RESUMO

Gain-of-function mutations in some genes underlie neurodegenerative conditions, whereas loss-of-function mutations in the same genes have distinct phenotypes. This appears to be the case with the protein ataxin 1 (ATXN1), which forms a transcriptional repressor complex with capicua (CIC). Gain of function of the complex leads to neurodegeneration, but ATXN1-CIC is also essential for survival. We set out to understand the functions of the ATXN1-CIC complex in the developing forebrain and found that losing this complex results in hyperactivity, impaired learning and memory, and abnormal maturation and maintenance of upper-layer cortical neurons. We also found that CIC activity in the hypothalamus and medial amygdala modulates social interactions. Informed by these neurobehavioral features in mouse mutants, we identified five individuals with de novo heterozygous truncating mutations in CIC who share similar clinical features, including intellectual disability, attention deficit/hyperactivity disorder (ADHD), and autism spectrum disorder. Our study demonstrates that loss of ATXN1-CIC complexes causes a spectrum of neurobehavioral phenotypes.


Assuntos
Ataxina-1/genética , Transtorno do Espectro Autista/genética , Doenças Neurodegenerativas/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Animais , Cerebelo/patologia , Feminino , Humanos , Deficiência Intelectual/genética , Relações Interpessoais , Masculino , Camundongos , Proteínas do Tecido Nervoso/genética , Fenótipo
13.
Eur J Hum Genet ; 25(4): 423-431, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28176767

RESUMO

Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5'-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G>A (family 2) and a maternally inherited c.420-8A>G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores=15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up.


Assuntos
Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Mutação , Feminino , Síndrome do Cromossomo X Frágil/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Processamento de RNA , Irmãos
14.
J Med Genet ; 54(7): 479-488, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28119487

RESUMO

BACKGROUND: Cohesinopathies are rare neurodevelopmental disorders arising from a dysfunction in the cohesin pathway, which enables chromosome segregation and regulates gene transcription. So far, eight genes from this pathway have been reported in human disease. STAG1 belongs to the STAG subunit of the core cohesin complex, along with five other subunits. This work aimed to identify the phenotype ascribed to STAG1 mutations. METHODS: Among patients referred for intellectual disability (ID) in genetics departments worldwide, array-comparative genomic hybridisation (CGH), gene panel, whole-exome sequencing or whole-genome sequencing were performed following the local diagnostic standards. RESULTS: A mutation in STAG1 was identified in 17 individuals from 16 families, 9 males and 8 females aged 2-33 years. Four individuals harboured a small microdeletion encompassing STAG1; three individuals from two families had an intragenic STAG1 deletion. Six deletions were identified by array-CGH, one by whole-exome sequencing. Whole-exome sequencing found de novo heterozygous missense or frameshift STAG1 variants in eight patients, a panel of genes involved in ID identified a missense and a frameshift variant in two individuals. The 17 patients shared common facial features, with wide mouth and deep-set eyes. Four individuals had mild microcephaly, seven had epilepsy. CONCLUSIONS: We report an international series of 17 individuals from 16 families presenting with syndromic unspecific ID that could be attributed to a STAG1 deletion or point mutation. This first series reporting the phenotype ascribed to mutation in STAG1 highlights the importance of data sharing in the field of rare disorders.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Deficiência Intelectual/genética , Mutação/genética , Proteínas Nucleares/genética , Adulto , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Humanos , Lactente , Masculino , Linhagem , Fenótipo , Síndrome , Sequenciamento Completo do Exoma
15.
Am J Med Genet A ; 170A(1): 116-29, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26420639

RESUMO

Xq28 duplications encompassing MECP2 have been described in male patients with a severe neurodevelopmental disorder associated with hypotonia and spasticity, severe learning disability, stereotyped movements, and recurrent pulmonary infections. We report on standardized brain magnetic resonance imaging (MRI) data of 30 affected patients carrying an Xq28 duplication involving MECP2 of various sizes (228 kb to 11.7 Mb). The aim of this study was to seek recurrent malformations and attempt to determine whether variations in imaging features could be explained by differences in the size of the duplications. We showed that 93% of patients had brain MRI abnormalities such as corpus callosum abnormalities (n = 20), reduced volume of the white matter (WM) (n = 12), ventricular dilatation (n = 9), abnormal increased hyperintensities on T2-weighted images involving posterior periventricular WM (n = 6), and vermis hypoplasia (n = 5). The occipitofrontal circumference varied considerably between >+2SD in five patients and <-2SD in four patients. Among the nine patients with dilatation of the lateral ventricles, six had a duplication involving L1CAM. The only patient harboring bilateral posterior subependymal nodular heterotopia also carried an FLNA gene duplication. We could not demonstrate a correlation between periventricular WM hyperintensities/delayed myelination and duplication of the IKBKG gene. We thus conclude that patients with an Xq28 duplication involving MECP2 share some similar but non-specific brain abnormalities. These imaging features, therefore, could not constitute a diagnostic clue. The genotype-phenotype correlation failed to demonstrate a relationship between the presence of nodular heterotopia, ventricular dilatation, WM abnormalities, and the presence of FLNA, L1CAM, or IKBKG, respectively, in the duplicated segment.


Assuntos
Encefalopatias/genética , Cromossomos Humanos X/genética , Duplicação Gênica , Imagem por Ressonância Magnética/métodos , Retardo Mental Ligado ao Cromossomo X/genética , Proteína 2 de Ligação a Metil-CpG/genética , Adolescente , Adulto , Encefalopatias/patologia , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Retardo Mental Ligado ao Cromossomo X/patologia , Pessoa de Meia-Idade , Linhagem , Fenótipo , Prognóstico , Adulto Jovem
16.
Eur J Hum Genet ; 24(6): 830-7, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26395556

RESUMO

The increasing use of array-CGH in malformation syndromes with intellectual disability could lead to the description of new contiguous gene syndrome by the analysis of the gene content of the microdeletion and reverse phenotyping. Thanks to a national and international call for collaboration by Achropuce and Decipher, we recruited four patients carrying de novo overlapping deletions of chromosome 9q33.3q34.11, including the STXBP1, the LMX1B and the ENG genes. We restrained the selection to these three genes because the effects of their haploinsufficency are well described in the literature and easily recognizable clinically. All deletions were detected by array-CGH and confirmed by FISH. The patients display common clinical features, including intellectual disability with epilepsy, owing to the presence of STXBP1 within the deletion, nail dysplasia and bone malformations, in particular patellar abnormalities attributed to LMX1B deletion, epistaxis and cutaneous-mucous telangiectasias explained by ENG haploinsufficiency and common facial dysmorphism. This systematic analysis of the genes comprised in the deletion allowed us to identify genes whose haploinsufficiency is expected to lead to disease manifestations and complications that require personalized follow-up, in particular for renal, eye, ear, vascular and neurological manifestations.


Assuntos
Deleção Cromossômica , Anormalidades Craniofaciais/genética , Endoglina/genética , Epilepsia/genética , Deficiência Intelectual/genética , Proteínas com Homeodomínio LIM/genética , Proteínas Munc18/genética , Fatores de Transcrição/genética , Adolescente , Criança , Cromossomos Humanos Par 9/genética , Anormalidades Craniofaciais/diagnóstico , Epilepsia/diagnóstico , Feminino , Haploinsuficiência , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Fenótipo , Síndrome
17.
Eur J Hum Genet ; 24(6): 838-43, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26395558

RESUMO

Semaphorins are a large family of secreted and membrane-associated proteins necessary for wiring of the brain. Semaphorin 5A (SEMA5A) acts as a bifunctional guidance cue, exerting both attractive and inhibitory effects on developing axons. Previous studies have suggested that SEMA5A could be a susceptibility gene for autism spectrum disorders (ASDs). We first identified a de novo translocation t(5;22)(p15.3;q11.21) in a patient with ASD and intellectual disability (ID). At the translocation breakpoint on chromosome 5, we observed a 861-kb deletion encompassing the end of the SEMA5A gene. We delineated the breakpoint by NGS and observed that no gene was disrupted on chromosome 22. We then used Sanger sequencing to search for deleterious variants affecting SEMA5A in 142 patients with ASD. We also identified two independent heterozygous variants located in a conserved functional domain of the protein. Both variants were maternally inherited and predicted as deleterious. Our genetic screens identified the first case of a de novo SEMA5A microdeletion in a patient with ASD and ID. Although our study alone cannot formally associate SEMA5A with susceptibility to ASD, it provides additional evidence that Semaphorin dysfunction could lead to ASD and ID. Further studies on Semaphorins are warranted to better understand the role of this family of genes in susceptibility to neurodevelopmental disorders.


Assuntos
Transtorno do Espectro Autista/genética , Deleção Cromossômica , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/diagnóstico , Criança , Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 5/genética , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico , Masculino , Herança Paterna , Translocação Genética
18.
Eur J Hum Genet ; 24(6): 911-8, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26486473

RESUMO

Learning disabilities (LDs) are a clinically and genetically heterogeneous group of diseases. Array-CGH and high-throughput sequencing have dramatically expanded the number of genes implicated in isolated intellectual disabilities and LDs, highlighting the implication of neuron-specific post-mitotic transcription factors and synaptic proteins as candidate genes. We report a unique family diagnosed with autosomal dominant learning disability and a 6p21 microdeletion segregating in three patients. The 870 kb microdeletion encompassed the brain-expressed gene LRFN2, which encodes for a synaptic cell adhesion molecule. Neuropsychological assessment identified selective working memory deficits, with borderline intellectual functioning. Further investigations identified a defect in executive function, and auditory-verbal processes. These data were consistent with brain MRI and FDG-PET functional brain imaging, which, when compared with controls, revealed abnormal brain volume and hypometabolism of gray matter structures implicated in working memory. We performed electron microscopy immunogold labeling demonstrating the localization of LRFN2 at synapses of cerebellar and hippocampal rat neurons, often associated with the NR1 subunit of N-methyl-D-aspartate receptors (NMDARs). Altogether, the combined approaches imply a role for LRFN2 in LD, specifically for working memory processes and executive function. In conclusion, the identification of familial cases of clinically homogeneous endophenotypes of LD might help in both the management of patients and genetic counseling for families.


Assuntos
Deleção de Genes , Transtornos de Aprendizagem/genética , Proteínas de Membrana/genética , Transtornos da Memória/genética , Memória de Curto Prazo , Adulto , Animais , Encéfalo/diagnóstico por imagem , Células Cultivadas , Criança , Feminino , Fluordesoxiglucose F18 , Heterozigoto , Humanos , Transtornos de Aprendizagem/complicações , Transtornos de Aprendizagem/diagnóstico , Imagem por Ressonância Magnética , Masculino , Proteínas de Membrana/metabolismo , Transtornos da Memória/complicações , Transtornos da Memória/diagnóstico , Linhagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo , Sinapses/ultraestrutura
19.
Mol Cytogenet ; 8: 42, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26110021

RESUMO

BACKGROUND: Prader-Willi syndrome (PWS) is characterized by hypotonia, delayed neuropsychomotor development, overeating, obesity and mental deficiency. This phenotype is encountered in other conditions, defining Prader-Willi-like syndrome (PWLS). CASE PRESENTATION: We report a 14-year-old boy with a complex small supernumerary marker chromosome (sSMC) associated with PWLS. The propositus presents clinical features commonly found in patients with PWLS, including growth hormone deficit. Banding karyotype analysis and fluorescence in situ hybridization (FISH) revealed a marker derived from chromosome 6 and a neocentromere as suspected, but array-CGH enabled us to characterize this marker as a der(10)t(6;10)(6qter → 6q23.3::10p11.1 → 10p11.21)dn. As far as we know, this is the first diagnosed case of PWLS associated with a complex sSMC, involving a 30.9 Mb gain in the 6q16.3q23.3 region and a 3.5 Mb gain in the 10p11.21p11.1 region. Several genes have been mapped to the 6q region including the TCBA1 gene, which is associated with developmental delay and recurrent infections, the ENPP1 gene, associated with insulin resistance and susceptibility to obesity and the BMIQ3 gene, associated with body mass index (BMI). No OMIM gene was found in the smallest 10p11.21p11.1 region. CONCLUSIONS: We suggest that the duplicated chromosome segment 6q16.3q23.3 may be responsible for the phenotype of our case and may also be a candidate locus of PWLS.

20.
Am J Med Genet A ; 164A(12): 3027-34, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25258245

RESUMO

Distal limb contractures (DLC) represent a heterogeneous clinical and genetic condition. Overall, 20-25% of the DLC are caused by mutations in genes encoding the muscle contractile apparatus. Large interstitial deletions of the 3p have already been diagnosed by standard chromosomal analysis, but not associated with a specific phenotype. We report on four patients with syndromic DLC presenting with a de novo 3p14.1p13 microdeletion. The clinical features associated multiple contractures, feeding problems, developmental delay, and intellectual disability. Facial dysmorphism was constant with low-set posteriorly rotated ears and blepharophimosis. Review of previously reported cases with a precise mapping of the deletions, documented a 250 kb smallest region of overlap (SRO) necessary for DLC. This region contained one gene, EIF4E3, the first three exons of the FOXP1 gene, and an intronic enhancer of FOXP1 named hs1149. Sanger sequencing and locus quantification of hs1149, EIF4E3, and FOXP1 in a cohort of 11 French patients affected by DLC appeared normal. In conclusion, we delineate a new microdeletion syndrome involving the 3p14.1p13 locus and associated with DLC and severe developmental delay.


Assuntos
Artrogripose/epidemiologia , Aberrações Cromossômicas , Cromossomos Humanos Par 3/genética , Contratura/epidemiologia , Contratura/genética , Extremidades/patologia , Animais , Proteínas de Transporte/genética , Hibridização Genômica Comparativa , Contratura/patologia , Feminino , Fatores de Transcrição Forkhead/genética , França/epidemiologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Proteínas Repressoras/genética , Síndrome
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