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1.
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.

2.
J Med Genet ; 55(6): 422-429, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29459493

RESUMO

BACKGROUND: Segmentation defects of the vertebrae (SDV) are non-specific features found in various syndromes. The molecular bases of SDV are not fully elucidated due to the wide range of phenotypes and classification issues. The genes involved are in the Notch signalling pathway, which is a key system in somitogenesis. Here we report on mutations identified in a diagnosis cohort of SDV. We focused on spondylocostal dysostosis (SCD) and the phenotype of these patients in order to establish a diagnostic strategy when confronted with SDV. PATIENTS AND METHODS: We used DNA samples from a cohort of 73 patients and performed targeted sequencing of the five known SCD-causing genes (DLL3, MESP2, LFNG, HES7 and TBX6) in the first 48 patients and whole-exome sequencing (WES) in 28 relevant patients. RESULTS: Ten diagnoses, including four biallelic variants in TBX6, two biallelic variants in LFNG and DLL3, and one in MESP2 and HES7, were made with the gene panel, and two diagnoses, including biallelic variants in FLNB and one variant in MEOX1, were made by WES. The diagnostic yield of the gene panel was 10/73 (13.7%) in the global cohort but 8/10 (80%) in the subgroup meeting the SCD criteria; the diagnostic yield of WES was 2/28 (8%). CONCLUSION: After negative array CGH, targeted sequencing of the five known SCD genes should only be performed in patients who meet the diagnostic criteria of SCD. The low proportion of candidate genes identified by WES in our cohort suggests the need to consider more complex genetic architectures in cases of SDV.

3.
Am J Med Genet A ; 173(11): 2923-2946, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28948695

RESUMO

Facial femoral syndrome (FFS) is a rare congenital abnormality, also known as femoral hypoplasia-unusual facies syndrome, characterized by variable degrees of femoral hypoplasia, associated with specific facial features. Other organ malformations are sometimes present. Most cases are sporadic, but rare family observations suggest genetic origin. However, no chromosomal or genetic abnormalities have ever been incriminated. We conducted a comprehensive literature review and added three new unreported observations. Through these 92 cases, authors aimed to determine sonographic signs that should direct towards diagnosis, and discuss potential genetic etiology. Diagnosis was suspected prenatally in 27.2% of cases, and maternal diabetes was found in 42.4% of patients. When fetal karyotype was available, it was normal in 97.1% of cases, but genomic variations of unknown significance were discovered in all three cases in which array comparative genomic hybridization (CGH) techniques were applied. Femoral affection defining FFS was hypoplasia in 78.3% of cases, agenesis in 12%, and both in 9.8%. Affection was bilateral in 84.8% of cases. Retrognathia was present in 65.2% of cases, cleft lip and/or palate in 63%, and other organ malformations in 53.3%. Intellectual development was normal in 79.2% of cases. Better prenatal recognition of this pathology, notably frequently associated malformations, should lead to a more precise estimation of functional prognosis. It seems likely that today's tendency to systematically employ array-CGH and exome/genome sequencing methods to investigate malformative sequences will allow the identification of a causal genetic abnormality in the near future.


Assuntos
Anormalidades Múltiplas/diagnóstico , Fêmur/anormalidades , Síndrome de Pierre Robin/diagnóstico , Diagnóstico Pré-Natal , Ultrassonografia Pré-Natal/métodos , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Adulto , Fenda Labial/diagnóstico , Fenda Labial/diagnóstico por imagem , Fenda Labial/genética , Fenda Labial/fisiopatologia , Hibridização Genômica Comparativa , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/diagnóstico por imagem , Diabetes Gestacional/fisiopatologia , Feminino , Fêmur/diagnóstico por imagem , Fêmur/fisiopatologia , Feto , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Síndrome de Pierre Robin/diagnóstico por imagem , Síndrome de Pierre Robin/genética , Síndrome de Pierre Robin/fisiopatologia , Gravidez
4.
Am J Med Genet A ; 173(2): 435-443, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27862890

RESUMO

Loss-of-function mutations and deletions of the SOX2 gene are known to cause uni- and bilateral anophthalmia and microphthalmia as well as related disorders such as anophthalmia-esophageal-genital syndrome. Thus, anophthalmia/microphthalmia is the primary indication for targeted, "phenotype first" analyses of SOX2. However, SOX2 mutations are also associated with a wide range of non-ocular abnormalities, such as postnatal growth retardation, structural brain anomalies, hypogenitalism, and developmental delay. The present report describes three patients without anophthalmia/microphthalmia and loss-of-function mutations or microdeletions of SOX2 who had been investigated in a "genotype first" manner due to intellectual disability/developmental delay using whole exome sequencing or chromosomal microarray analyses. This result prompted us to perform SOX2 Sanger sequencing in 192 developmental delay/intellectual disability patients without anophthalmia or microphthalmia. No additional SOX2 loss-of-function mutations were detected in this cohort, showing that SOX2 is clearly not a major cause of intellectual disability without anophthalmia/microphthalmia. In our three patients and four further, reported "genotype first" SOX2 microdeletion patients, anophthalmia/microphthalmia was present in less than half of the patients. Thus, SOX2 is another example of a gene whose clinical spectrum is broadened by the generation of "genotype first" findings using hypothesis-free, genome-wide methods. © 2016 Wiley Periodicals, Inc.


Assuntos
Estudos de Associação Genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Fenótipo , Mutação Puntual , Fatores de Transcrição SOXB1/genética , Deleção de Sequência , Encéfalo/anormalidades , Pré-Escolar , Hibridização Genômica Comparativa , Exoma , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Facies , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recém-Nascido , Imagem por Ressonância Magnética/métodos , Masculino , Polimorfismo de Nucleotídeo Único , Sistema de Registros
5.
PLoS Genet ; 12(3): e1005894, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26967905

RESUMO

Ciliopathies are a group of genetic multi-systemic disorders related to dysfunction of the primary cilium, a sensory organelle present at the cell surface that regulates key signaling pathways during development and tissue homeostasis. In order to identify novel genes whose mutations would cause severe developmental ciliopathies, >500 patients/fetuses were analyzed by a targeted high throughput sequencing approach allowing exome sequencing of >1200 ciliary genes. NEK8/NPHP9 mutations were identified in five cases with severe overlapping phenotypes including renal cystic dysplasia/hypodysplasia, situs inversus, cardiopathy with hypertrophic septum and bile duct paucity. These cases highlight a genotype-phenotype correlation, with missense and nonsense mutations associated with hypodysplasia and enlarged cystic organs, respectively. Functional analyses of NEK8 mutations in patient fibroblasts and mIMCD3 cells showed that these mutations differentially affect ciliogenesis, proliferation/apoptosis/DNA damage response, as well as epithelial morphogenesis. Notably, missense mutations exacerbated some of the defects due to NEK8 loss of function, highlighting their likely gain-of-function effect. We also showed that NEK8 missense and loss-of-function mutations differentially affect the regulation of the main Hippo signaling effector, YAP, as well as the expression of its target genes in patient fibroblasts and renal cells. YAP imbalance was also observed in enlarged spheroids of Nek8-invalidated renal epithelial cells grown in 3D culture, as well as in cystic kidneys of Jck mice. Moreover, co-injection of nek8 MO with WT or mutated NEK8-GFP RNA in zebrafish embryos led to shortened dorsally curved body axis, similar to embryos injected with human YAP RNA. Finally, treatment with Verteporfin, an inhibitor of YAP transcriptional activity, partially rescued the 3D spheroid defects of Nek8-invalidated cells and the abnormalities of NEK8-overexpressing zebrafish embryos. Altogether, our study demonstrates that NEK8 human mutations cause major organ developmental defects due to altered ciliogenesis and cell differentiation/proliferation through deregulation of the Hippo pathway.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Cílios/genética , Fosfoproteínas/genética , Doenças Renais Policísticas/genética , Proteínas Quinases/genética , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Animais , Diferenciação Celular/genética , Cílios/patologia , Feminino , Estudos de Associação Genética , Humanos , Rim/metabolismo , Rim/patologia , Camundongos , Morfogênese/genética , Mutação , Quinases Relacionadas a NIMA , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/biossíntese , Doenças Renais Policísticas/patologia , Porfirinas/administração & dosagem , Transdução de Sinais , Verteporfina , Peixe-Zebra
6.
Eur J Hum Genet ; 24(8): 1124-31, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26757980

RESUMO

Noonan syndrome is a heterogeneous autosomal dominant disorder caused by mutations in at least eight genes involved in the RAS/MAPK signaling pathway. Recently, RIT1 (Ras-like without CAAX 1) has been shown to be involved in the pathogenesis of some patients. We report a series of 44 patients from 30 pedigrees (including nine multiplex families) with mutations in RIT1. These patients display a typical Noonan gestalt and facial phenotype. Among the probands, 8.7% showed postnatal growth retardation, 90% had congenital heart defects, 36% had hypertrophic cardiomyopathy (a lower incidence compared with previous report), 50% displayed speech delay and 52% had learning difficulties, but only 22% required special education. None had major skin anomalies. One child died perinatally of juvenile myelomonocytic leukemia. Compared with the canonical Noonan phenotype linked to PTPN11 mutations, patients with RIT1 mutations appear to be less severely growth retarded and more frequently affected by cardiomyopathy. Based on our experience, we estimate that RIT1 could be the cause of 5% of Noonan syndrome patients. Because mutations found constitutionally in Noonan syndrome are also found in several tumors in adulthood, we evaluated the potential contribution of RIT1 to leukemogenesis in Noonan syndrome. We screened 192 pediatric cases of acute lymphoblastic leukemias (96 B-ALL and 96 T-ALL) and 110 cases of juvenile myelomonocytic leukemias (JMML), but detected no variation in these tumoral samples, suggesting that Noonan patients with germline RIT1 mutations are not at high risk to developing JMML or ALL, and that RIT1 has at most a marginal role in these sporadic malignancies.


Assuntos
Leucemia Mielomonocítica Juvenil/genética , Mutação , Síndrome de Noonan/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas ras/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Leucemia Mielomonocítica Juvenil/patologia , Masculino , Síndrome de Noonan/patologia , Linhagem , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
7.
Eur J Hum Genet ; 24(1): 44-50, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25898926

RESUMO

Nail-Patella Syndrome (NPS) is a rare autosomal dominant condition comprising nail and skeletal anomalies. Skeletal features include dysplastic patellae and iliac horns, as well as scapula and elbow dysplasia. Nephropathy and glaucoma or intra-ocular hypertension can sometimes be present. NPS is due to variants affecting function in LMX1B, which encodes a LIM-homeodomain protein critical for limb, kidney and eye development. We describe the phenotype and the molecular data of 55 index patients and their 39 relatives presenting with typical NPS. We identified 38 different LMX1B anomalies, 19 of which were not reported before. In our series, 9% of families are not carriers of a LMX1B genomic alteration after extensive study of the coding and non-coding regions of the gene. One of the families showed no linkage to the LMX1B locus, raising the hypothesis of a genetic heterogeneity.


Assuntos
Heterogeneidade Genética , Glaucoma/genética , Proteínas com Homeodomínio LIM/genética , Síndrome da Unha-Patela/genética , Nefrite Hereditária/genética , Hipertensão Ocular/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Criança , Pré-Escolar , Éxons , Feminino , Expressão Gênica , Genes Dominantes , Glaucoma/patologia , Humanos , Ílio/anormalidades , Ílio/metabolismo , Íntrons , Masculino , Pessoa de Meia-Idade , Síndrome da Unha-Patela/patologia , Unhas/metabolismo , Unhas/patologia , Nefrite Hereditária/patologia , Hipertensão Ocular/patologia , Patela/anormalidades , Patela/metabolismo , Fenótipo , Polimorfismo Genético , Escápula/anormalidades , Escápula/metabolismo , Análise de Sequência de DNA
8.
Genet Med ; 18(1): 49-56, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25790162

RESUMO

PURPOSE: Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C. METHODS: We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype-genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene. RESULTS: We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature. CONCLUSION: Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype-genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.


Assuntos
RNA Polimerases Dirigidas por DNA/genética , Disostose Mandibulofacial/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Feminino , Estudos de Associação Genética , Humanos , Masculino , Disostose Mandibulofacial/diagnóstico , Microcefalia/genética , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Fatores de Alongamento de Peptídeos/genética , Ribonucleoproteína Nuclear Pequena U5/genética , Deleção de Sequência , Adulto Jovem
10.
Eur J Hum Genet ; 23(1): 92-102, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24736735

RESUMO

The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype-phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype-phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues.


Assuntos
Estudos de Associação Genética , Fatores de Transcrição Kruppel-Like/genética , Mutação , Proteínas do Tecido Nervoso/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Acrocefalossindactilia/diagnóstico , Acrocefalossindactilia/genética , Estudos de Coortes , Análise Mutacional de DNA , Família , Expressão Gênica , Rearranjo Gênico , Haploinsuficiência , Humanos , Hibridização in Situ Fluorescente , Fenótipo , Proteína Gli3 com Dedos de Zinco
11.
Hum Mutat ; 35(9): 1092-100, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24924640

RESUMO

Marshall-Smith syndrome (MSS) is a very rare malformation syndrome characterized by typical craniofacial anomalies, abnormal osseous maturation, developmental delay, failure to thrive, and respiratory difficulties. Mutations in the nuclear factor 1/X gene (NFIX) were recently identified as the cause of MSS. In our study cohort of 17 patients with a clinical diagnosis of MSS, conventional sequencing of NFIX revealed frameshift and splice-site mutations in 10 individuals. Using multiplex ligation-dependent probe amplification analysis, we identified a recurrent deletion of NFIX exon 6 and 7 in five individuals. We demonstrate this recurrent deletion is the product of a recombination between AluY elements located in intron 5 and 7. Two other patients had smaller deletions affecting exon 6. These findings show that MSS is a genetically homogeneous Mendelian disorder. RT-PCR experiments with newly identified NFIX mutations including the recurrent exon 6 and 7 deletion confirmed previous findings indicating that MSS-associated mutant mRNAs are not cleared by nonsense-mediated mRNA decay. Predicted MSS-associated mutant NFIX proteins consistently have a preserved DNA binding and dimerization domain, whereas they grossly vary in their C-terminal portion. This is in line with the hypothesis that MSS-associated mutations encode dysfunctional proteins that act in a dominant negative manner.


Assuntos
Anormalidades Múltiplas/genética , Elementos Alu , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Éxons , Fatores de Transcrição NFI/genética , Displasia Septo-Óptica/genética , Deleção de Sequência , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/diagnóstico , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Anormalidades Craniofaciais/diagnóstico , Análise Mutacional de DNA , Facies , Feminino , Expressão Gênica , Loci Gênicos , Humanos , Lactente , Masculino , Mutação , Fenótipo , RNA Mensageiro/genética , Displasia Septo-Óptica/diagnóstico , Adulto Jovem
12.
J Med Genet ; 50(2): 91-8, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23339108

RESUMO

BACKGROUND: Asphyxiating Thoracic Dysplasia (ATD) belongs to the short rib polydactyly group and is characterized by a narrow thorax, short long bones and trident acetabular roof. Other reported features include polydactyly, renal, liver and retinal involvement. To date, mutations in IFT80, DYNC2H1, TTC21B and WDR19 have been reported in ATD. The clinical and molecular heterogeneity leads to difficulties in the evaluation of the long-term prognosis. METHODS: We investigated 53 ATD cases (23 living cases and 30 fetuses) from 39 families. They benefited from a combined approach of deep phenotyping and IFT80 and DYNC2H1 molecular screening. RESULTS: Among the 23 postnatal cases, pulmonary insufficiency was noted in 60% of cases, with tracheotomy requirement in five cases. Renal and liver diseases occurred respectively in 17% and 22% of cases, whereas retinal alteration was present in 50% of cases aged more than 5 years. We identified DYNC2H1 mutations in 23 families (59%) and IFT80 mutations in two families (5%). However, in six families, only one heterozygote mutation in either IFT80 or DYNC2H1 was identified. Finally, the two genes were excluded in 14 families (36%). CONCLUSIONS: We conclude that DYNC2H1 is a major gene responsible for ATD, while IFT80 is rarely involved. The presence of only one mutation in six families and the exclusion of the two genes in 14 families support the involvement of other causal cilia genes. The long-term follow up emphasizes that the pulmonary prognosis is probably less pejorative and retinal involvement more frequent than previously thought.


Assuntos
Síndrome de Ellis-Van Creveld/genética , Aborto Induzido , Adolescente , Adulto , Criança , Pré-Escolar , Dineínas do Citoplasma/genética , Síndrome de Ellis-Van Creveld/diagnóstico , Síndrome de Ellis-Van Creveld/diagnóstico por imagem , Síndrome de Ellis-Van Creveld/patologia , Feminino , Feto/anormalidades , França , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Ultrassonografia Pré-Natal
13.
Clin Nephrol ; 80(6): 456-63, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22909780

RESUMO

Renal dysfunction is increasingly recognized as a potential clinical feature of mitochondrial cytopathies such as mitochondrial encephalomyopathy, lacticacidosis and stroke-like episodes (MELAS) syndrome. Five cases of MELAS syndrome with renal involvement from 4 unrelated families are presented in this case series. Three of the 5 patients had a history of maternally-inherited diabetes and/or deafness. Focal and segmental glomerulosclerosis and arteriolar hyaline thickening were the most striking findings on renal biopsy. In addition to clinical presentation with the typical symptoms of MELAS syndrome, genetic testing in these patients identified the A3243G point mutation in the tRNALeu gene of the mitochondrial DNA (mtDNA). The diagnosis of MELAS syndrome was thus considered to be unequivocal. The incidence of kidney disease in MELAS syndrome may be underestimated although a study is required to investigate this hypothesis. As the A3243G mtDNA mutation leads to a progressive adult-onset form of focal segmental glomerulosclerosis (FSGS), screening for the MELAS A3243G mtDNA mutation should therefore be performed especially in patients with maternally-inherited diabetes or hearing loss presenting with FSGS.


Assuntos
Nefropatias/etiologia , Síndrome MELAS/complicações , Adulto , DNA Mitocondrial/genética , Feminino , Humanos , Rim/patologia , Síndrome MELAS/genética , Síndrome MELAS/patologia , Masculino , Pessoa de Meia-Idade , Mutação
14.
Eur J Med Genet ; 55(5): 313-8, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22366253

RESUMO

Periventricular nodular heterotopia, the most common form of cortical malformation in adulthood, is characterized by nodules of neurons ectopically placed along the lateral ventricles. Classically, ectopic nodules are bilateral and symmetric defining bilateral periventricular nodular heterotopia (BPNH). BPNH can lead to epilepsy and intellectual disability of variable severity. The X-linked dominant form of BPNH, related to mutations in FLNA encoding filamin A, is the major cause of BPNH, causing prenatal and neonatal lethality in males that explain the excess of affected women. However, few living males have been described with this condition. In addition, mutations in FLNA have been also exceptionally associated with unilateral nodular heterotopia. We describe here three new patients, all carrying a novel missense mutation in FLNA. Two of the patients were adult males with BPNH; both had normal cognitive development and one did not manifest any seizure until he died at age 57. The last patient was a female adult with epilepsy and focal nodules essentially located along the right ventricle. We compare the clinical and imaging data of our patients with those of previously described similar cases. The type and location of FLNA mutations leading to such atypical presentations are discussed.


Assuntos
Proteínas Contráteis/genética , Proteínas dos Microfilamentos/genética , Heterotopia Nodular Periventricular/genética , Convulsões/genética , Adulto , Sequência de Bases , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Filaminas , Estudos de Associação Genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto
15.
Eur J Med Genet ; 54(2): 169-72, 2011 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21094705

RESUMO

Crane-Heise syndrome is a rare lethal and autosomal recessive condition which has been first reported in 1981 in three siblings presenting intrauterine growth retardation, a poorly mineralised calvarium, characteristic facial features comprising cleft lip and palate, hypertelorism, anteverted nares, low-set and posteriorly rotated ears, vertebral anomalies and absent clavicles. Since then, to our knowledge, only one isolated case and two siblings were reported with similar findings. We present two further cases, diagnosed after termination of pregnancy at 24 weeks' gestation in one case and straight after birth in the other, both very similar to the previously reported ones, and broaden the clinical spectrum of this entity. To our knowledge, no molecular mechanism has been identified in Crane-Heise syndrome so far.


Assuntos
Pé Torto Equinovaro , Anormalidades Congênitas , Pé Torto Equinovaro/diagnóstico , Pé Torto Equinovaro/diagnóstico por imagem , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Craniofaciais/diagnóstico por imagem , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Anormalidades Musculoesqueléticas/diagnóstico por imagem , Gravidez , Segundo Trimestre da Gravidez , Ultrassonografia
16.
Hum Mutat ; 31(6): E1506-18, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20513137

RESUMO

In 5-10% of patients, neurofibromatosis type 1 (NF1) results from microdeletions that encompass the entire NF1 gene and a variable number of flanking genes. Two recurrent microdeletion types are found in most cases, with microdeletion breakpoints located in paralogous regions flanking NF1 (proximal NF1-REP-a and distal NF1-REP-c for the 1.4 Mb type-1 microdeletion, and SUZ12 and SUZ12P for the 1.2 Mb type-2 microdeletion). A more severe phenotype is usually associated with NF1 microdeletion patients than in those with intragenic mutations. We characterized NF1 microdeletions in 70 unrelated NF1 microdeleted patients using a high-resolution NF1 custom array comparative genomic hybridization (CGH). Genotype-phenotype correlations were studied in 58 of these microdeletion patients and compared to 389 patients with intragenic truncating NF1 mutations and phenotyped in the same standardized way. Our results confirmed in an unbiased manner the existence of a contiguous gene syndrome with a significantly higher incidence of learning disabilities and facial dysmorphism in microdeleted patients compared to patients with intragenic NF1 mutations. Microdeleted NF1 patients also showed a trend toward significance for childhood overgrowth. High-resolution array-CGH identified a new recurrent approximately 1.0 Mb microdeletion type, designated as type-3, with breakpoints in the paralogous regions middle NF1-REP-b and distal NF1-REP-c.


Assuntos
Predisposição Genética para Doença , Neurofibromatose 1/genética , Neurofibromina 1/genética , Deleção de Sequência , Adulto , Hibridização Genômica Comparativa , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neurofibromatose 1/patologia , Fenótipo , Análise de Regressão , Adulto Jovem
17.
Eur J Hum Genet ; 18(8): 872-80, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20179744

RESUMO

Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation-dependent amplification analysis was used for the detection of intragenic deletions. We identified 77 different COL2A1 mutations in 100 affected individuals. Analysis of the splice site mutations showed unusual RNA isoforms, most of which contained a premature stop codon. Vitreous anomalies and retinal detachments were found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group (P<0.01). Overall, 20 of 23 sporadic patients with a COL2A1 mutation had either a cleft palate or retinal detachment with vitreous anomalies. The presence of vitreous anomalies, retinal tears or detachments, cleft palate and a positive family history were shown to be good indicators for a COL2A1 defect. In conclusion, we confirm that Stickler syndrome type 1 is predominantly caused by loss-of-function mutations in the COL2A1 gene as >90% of the mutations were predicted to result in nonsense-mediated decay. On the basis of binary regression analysis, we developed a scoring system that may be useful when evaluating patients with Stickler syndrome.


Assuntos
Artrite/genética , Colágeno Tipo II/genética , Doenças do Tecido Conjuntivo/genética , Perda Auditiva Neurossensorial/genética , Descolamento Retiniano/genética , Anormalidades Múltiplas/genética , Fissura Palatina/genética , Colágeno Tipo II/metabolismo , Doenças do Tecido Conjuntivo/metabolismo , Anormalidades Craniofaciais/genética , Análise Mutacional de DNA , Estudos de Associação Genética , Humanos , Análise de Sequência de DNA , Análise de Sequência de RNA
18.
Eur J Hum Genet ; 16(12): 1459-66, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18648396

RESUMO

We describe a large germline deletion removing the NF1 locus, identified by heterozygosity mapping based on microsatellite markers, in an 8-year-old French girl with a particularly severe NF1 contiguous gene syndrome. We used gene-dose mapping with sequence-tagged site real-time PCR to locate the deletion end points, which were precisely characterized by means of long-range PCR and nucleotide sequencing. The deletion is located on chromosome arm 17q and is exactly 7 586 986 bp long. It encompasses the entire NF1 locus and about 100 other genes, including numerous chemokine genes, an attractive in silico-selected cerebrally expressed candidate gene (designated NUFIP2, for nuclear fragile X mental retardation protein interacting protein 2; NM_020772) and four microRNA genes. Interestingly, the centromeric breakpoint is located in intron 4 of the PIPOX gene (pipecolic acid oxidase; NM_016518) and the telomeric breakpoint in intron 5 of the GGNBP2 gene (gametogenetin binding protein 2; NM_024835) coding a transcription factor. As PIPOX and GGNBP2 have the same transcriptional orientation, we postulated, and then confirmed, the existence of a chimeric transcript. This transcript, and/or haploinsufficiency of one or several deleted genes, could explain the clinical severity of the syndrome in this patient.


Assuntos
Deleção de Genes , Genes da Neurofibromatose 1 , Mutação em Linhagem Germinativa , Neurofibromatose 1/genética , Sequência de Bases , Criança , Mapeamento de Sequências Contíguas , Análise Mutacional de DNA , Feminino , Ordem dos Genes , Humanos , Linhagem , Síndrome
19.
Eur J Med Genet ; 51(1): 87-91, 2008 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18053786

RESUMO

We here report a boy presenting with developmental delay, growth retardation, facial dysmorphisms, vermis hypoplasia, micropolygyria and corpus callosum agenesis. Conventional and high resolution cytogenetic analyses were normal but high resolution oligonucleotide array-CGH, performed at the age of 4 years, allowed the characterisation of a de novo 6.9 Mb 1qter deletion/4.4 Mb 18pter duplication. Numerous 1qter deletions have already been described associated with brain malformations. Among 1q44 deleted genes, AKT3 is the strongest candidate gene for vermis hypoplasia and corpus callosum agenesis.


Assuntos
Anormalidades Múltiplas/genética , Encéfalo/anormalidades , Cromossomos Humanos Par 1/genética , Microcefalia/genética , Deleção de Sequência , Agenesia do Corpo Caloso , Sequência de Bases , Pré-Escolar , Humanos , Masculino , Análise em Microsséries , Hibridização de Ácido Nucleico , Proteínas Proto-Oncogênicas c-akt/genética
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