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1.
Clin Genet ; 89(5): 584-9, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26701315

RESUMO

Cornelia de Lange syndrome is a multisystemic developmental disorder mainly related to de novo heterozygous NIPBL mutation. Recently, NIPBL somatic mosaicism has been highlighted through buccal cell DNA study in some patients with a negative molecular analysis on leukocyte DNA. Here, we present a series of 38 patients with a Cornelia de Lange syndrome related to a heterozygous NIPBL mutation identified by Sanger sequencing. The diagnosis was based on the following criteria: (i) intrauterine growth retardation and postnatal short stature, (ii) feeding difficulties and/or gastro-oesophageal reflux, (iii) microcephaly, (iv) intellectual disability, and (v) characteristic facial features. We identified 37 novel NIPBL mutations including 34 in leukocytes and 3 in buccal cells only. All mutations shown to have arisen de novo when parent blood samples were available. The present series confirms the difficulty in predicting the phenotype according to the NIPBL mutation. Until now, somatic mosaicism has been observed for 20 cases which do not seem to be consistently associated with a milder phenotype. Besides, several reports support a postzygotic event for those cases. Considering these elements, we recommend a first-line buccal cell DNA analysis in order to improve gene testing sensitivity in Cornelia de Lange syndrome and genetic counselling.


Assuntos
Síndrome de Cornélia de Lange/genética , Face/anormalidades , Assimetria Facial/genética , Mutação em Linhagem Germinativa , Mutação , Proteínas/genética , Proteínas de Ciclo Celular , Síndrome de Cornélia de Lange/diagnóstico , Assimetria Facial/diagnóstico , Fácies , Feminino , Humanos , Leucócitos/metabolismo , Masculino , Mucosa Bucal/metabolismo , Fenótipo , Análise de Sequência de DNA/métodos
2.
Hum Reprod ; 26(9): 2570-5, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21733853

RESUMO

BACKGROUND: Klinefelter syndrome (KS), a common sex chromosome aneuploidy (47,XXY) is diagnosed prenatally with an incidence of 0.15%. The diagnosis is generally incidental, since there are no typical malformations on ultrasound (US). Once detected, genetic counseling is often difficult and the parents' decision to continue or terminate the pregnancy is greatly dependent on the amount and nature of the information provided. We sought to assess the pregnancy outcomes (i.e. continuation versus termination) and the influence of multidisciplinary centers for prenatal diagnosis on parental decisions in cases of KS. METHODS: From 1985 to 2009, 188 prenatal diagnoses of KS were made by 11 participating laboratories in mainland France. In each case, the karyotype indication, parental ages, year of prenatal testing, sampling procedure, karyotype, associated US findings and outcome were recorded. RESULTS AND CONCLUSIONS: The pregnancy termination rate declined markedly over time, from 46.9% before 1997 to 11.6% thereafter, in line with the introduction of new legislation on prenatal diagnosis for medical reasons and, more specifically, the creation of multidisciplinary prenatal diagnosis centers. However, an additional microdeletion in one KS infant who exhibited echogenic bowel on US was unfortunately diagnosed postnatally. This raises the question as to whether array comparative genomic hybridization should be prenatally advised when US abnormalities are detected, in line with advice for fetuses with a normal karyotype.


Assuntos
Aborto Induzido/estatística & dados numéricos , Síndrome de Klinefelter/diagnóstico , Diagnóstico Pré-Natal , Revelação , Feminino , França , Aconselhamento Genético , Humanos , Cariótipo , Síndrome de Klinefelter/epidemiologia , Síndrome de Klinefelter/genética , Masculino , Gravidez , Resultado da Gravidez
3.
Clin Genet ; 77(3): 258-65, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19817772

RESUMO

The oral-facial-digital syndrome type I (OFD I) is characterized by multiple congenital malformations of the face, oral cavity and digits. A polycystic kidney disease (PKD) is found in about one-third of patients but long-term outcome and complications are not well described in the international literature. Renal findings have been retrospectively collected in a cohort of 34 females all carrying a pathogenic mutation in the OFD1 gene with ages ranging from 1 to 65 years. Twelve patients presented with PKD - 11/16 (69%) if only adults were considered -with a median age at diagnosis of 29 years [IQR (interquartile range) = (23.5-38)]. Among them, 10 also presented with renal impairment and 6 were grafted (median age = 38 years [IQR = (25-48)]. One grafted patient under immunosuppressive treatment died from a tumor originated from a native kidney. The probability to develop renal failure was estimated to be more than 50% after the age of 36 years. Besides, neither genotype-phenotype correlation nor clinical predictive association with renal failure could be evidenced. These data reveal an unsuspected high incidence rate of the renal impairment outcome in OFD I syndrome. A systematic ultrasound (US) and renal function follow-up is therefore highly recommended for all OFD I patients.


Assuntos
Envelhecimento , Síndromes Orofaciodigitais/complicações , Insuficiência Renal/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Estudos de Associação Genética , Humanos , Lactente , Rim/patologia , Pessoa de Meia-Idade , Síndromes Orofaciodigitais/genética , Síndromes Orofaciodigitais/patologia , Síndromes Orofaciodigitais/fisiopatologia , Proteínas/genética , Adulto Jovem
4.
Clin Genet ; 76(4): 357-71, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19793311

RESUMO

The CDKL5 gene has been implicated in the molecular etiology of early-onset intractable seizures with infantile spasms (IS), severe hypotonia and atypical Rett syndrome (RTT) features. So far, 48 deleterious alleles have been reported in the literature. We screened the CDKL5 gene in a cohort of 177 patients with early-onset seizures, including 30 men and 10 girls with Aicardi syndrome. The screening was negative for all men as well as for women with Aicardi syndrome, excluding the CDKL5 gene as a candidate for this neurodevelopmental disorder. We report 11 additional de novo mutations in CDKL5 in female patients. For the first time, the MLPA approach allowed the identification of a partial deletion encompassing the promoter and the first two exons of CDKL5. The 10-point mutations consist of five missenses (with recurrent amino acid changes at p.Ala40 and p.Arg178), four splicing variants and a 1-base pair duplication. We present a review of all mutated alleles published in the literature. In our study, the overall frequency of mutations in CDKL5 in women with early-onset seizures is around 8.6%, a result comparable with previous reports. Noteworthy, the CDKL5 mutation rate is high (28%) in women with early-onset seizures and IS.


Assuntos
Predisposição Genética para Doença/genética , Mutação/genética , Fenótipo , Proteínas Serina-Treonina Quinases/genética , Síndrome de Rett/genética , Convulsões/genética , Western Blotting , Células Cultivadas , Pré-Escolar , Primers do DNA/genética , Feminino , Citometria de Fluxo , França , Frequência do Gene , Testes Genéticos , Humanos , Lactente , Recém-Nascido , Linhagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa
5.
J Med Genet ; 45(7): 438-46, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18424508

RESUMO

BACKGROUND: Many unclassified variants (UV) of BRCA1 or BRCA2 may have an effect on pre-mRNA splicing. Patient blood samples suitable for RNA extraction are not always available for testing UVs at the RNA level. METHODS: Analyses of RNA from patient peripheral blood were performed, using a one-step reverse transcriptase-PCR (RT-PCR) protocol, and were compared with an ex vivo splicing assay based on PCR-amplified patient DNA inserted into a splicing reporter minigene. Using both methods 20 variants found in 17 patients were examined. RESULTS: Data from patient RNA and from the minigene assay were fully concordant, but the ex vivo splicing assay, which is monoallelic, clarified several ambiguities in the patient RNA data. Two intronic variants induced strong splicing defects: BRCA1 c.4987-5T-->A (IVS16-5T-->A) induced exon 17 skipping and BRCA2 c.316+5G-->C (IVS3+5G-->C) induced complete skipping of exon 3. Of the exonic variants, BRCA2 c.7805G-->C (p.Arg2602Thr), at the last base of exon 16, induced both exon skipping and activation of a cryptic exonic donor site, and BRCA2 c.8023A-->G (p.Ile2675Val) generated a strong donor site within exon 18. These four variants were thus classified as pathogenic, because of the total absence of a normal transcript from the corresponding allele. Variant BRCA2 c.9501+3A-->T (IVS25+3A-->T) induced incomplete skipping of exon 25, suggesting a mutation with incomplete penetrance, and BRCA2 c.8257_8259del (p.Leu2753del) modified the alternative splicing of exons 17 and 18. CONCLUSIONS: We show that functional analysis using a splicing reporter minigene is sensitive and specific, and should be used for initial screening of potential splicing defects, especially when patient RNA is not readily available.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Neoplasias Ovarianas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Algoritmos , Processamento Alternativo , Feminino , Genes Reporter , Predisposição Genética para Doença , Variação Genética , Humanos , Mutação , RNA Mensageiro/química , RNA Mensageiro/genética
6.
J Inherit Metab Dis ; 30(5): 722-34, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17705025

RESUMO

Deficiency of liver glycogen phosphorylase in glycogen storage disease (GSD) type VI results in a reduced ability to mobilize glucose from glycogen. Six mutations of the PYGL gene, which encodes the liver isoform of the enzyme, have been identified in the literature. We have characterized eight patients from seven families with GSD type VI and identified 11 novel PYGL gene defects. The majority of the mutations were missense, resulting in the substitution of highly conserved residues. These could be grouped into those that were predicted to affect substrate binding (p.V456M, p.E673K, p.S675L, p.S675T), pyridoxal phosphate binding (p.R491C, p.K681T), or activation of glycogen phosphorylase (p.Q13P) or that had an unknown effect (p.N632I and p.D634H). Two mutations were predicted to result in null alleles, p.R399X and [c.1964_1969inv6;c.1969+1_+4delGTAC]. Only 7 of the 23 (30%) reported PYGL alleles carry nonsense, splice site or frameshift mutations compared to 68-80% of affected alleles of the highly homologous muscle glycogen phosphorylase gene, PYGM, that underlie McArdle disease. There was heterogeneity in the clinical symptoms observed in affected individuals. These varied from hepatomegaly and subclinical hypoglycaemia, to severe hepatomegaly with recurrent severe hypoglycaemia and postprandial lactic acidosis. We conclude that deficiency of liver glycogen phosphorylase is predominantly the result of missense mutations affecting enzyme activity. There are no common mutations and the severity of clinical symptoms varies significantly.


Assuntos
Glicogênio Fosforilase Hepática/genética , Doença de Depósito de Glicogênio Tipo IV/genética , Fígado/enzimologia , Mutação de Sentido Incorreto , Sequência de Aminoácidos , Animais , Glicemia/metabolismo , Pré-Escolar , Análise Mutacional de DNA , Éxons , Feminino , Predisposição Genética para Doença , Genótipo , Glicogênio Fosforilase Hepática/química , Glicogênio Fosforilase Hepática/deficiência , Doença de Depósito de Glicogênio Tipo IV/enzimologia , Humanos , Lactente , Íntrons , Ácido Láctico/sangue , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Linhagem , Fenótipo , Conformação Proteica , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Índice de Gravidade de Doença
7.
J Med Genet ; 43(1): 54-61, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16397067

RESUMO

Oral-facial-digital syndrome type 1 (OFD1) is characterised by an X linked dominant mode of inheritance with lethality in males. Clinical features include facial dysmorphism with oral, tooth, and distal abnormalities, polycystic kidney disease, and central nervous system malformations. Large interfamilial and intrafamilial clinical variability has been widely reported, and 18 distinct mutations have been previously reported within OFD1. A French and Belgian collaborative study collected 25 cases from 16 families. OFD1 was analysed using direct sequencing and phenotype-genotype correlation was performed using chi2 test. X inactivation studies were performed on blood lymphocytes. In 11 families, 11 novel mutations, including nine frameshift, one nonsense, and one missense mutation were identified, which spanned nine different exons. A combination of our results with previously reported cases showed that the majority of mutations (65.5%) was located in exons 3, 8, 9, 13, and 16. There was phenotype-genotype correlation between (a) polycystic kidney disease and splice mutations; (b) mental retardation and mutations located in exons 3, 8, 9, 13, and 16; and (c) tooth abnormalities and mutations located in coiled coil domains. Comparing the phenotype of the families with a pathogenic mutation to families with absence of OFD1 mutation, polycystic kidneys and short stature were significantly more frequent in the group with no OFD1 mutation, whereas lingual hamartomas were significantly more frequent in the group with OFD1 mutation. Finally, an X inactivation study showed non-random X inactivation in a third of the samples. Differential X inactivation between mothers and daughters in two families with high intrafamilial variability was of particular interest. Slight phenotype-genotype correlations were established, and X inactivation study showed that skewed X inactivation could be partially involved in the pathogenesis of intrafamilial clinical variability.


Assuntos
Síndromes Orofaciodigitais/genética , Síndromes Orofaciodigitais/patologia , Proteínas/genética , Adulto , Bélgica , Análise Mutacional de DNA , Feminino , França , Ligação Genética , Genótipo , Humanos , Mutação/genética , Linhagem , Fenótipo , Inativação do Cromossomo X/genética
8.
Arch Pediatr ; 5(4): 397-9, 1998 Apr.
Artigo em Francês | MEDLINE | ID: mdl-9759159

RESUMO

BACKGROUND: Neonatal myoclonic encephalopathy is of lesional or metabolic origin; non ketotic hyperglycinemia is one of its causes. CASE REPORT: A girl, born from consanguineous parents, died from myoclonic epileptic encephalopathy at the age of 3 months. Screening for metabolic disease was negative, except for increased levels of urine serotonin and 5-hydroxyindol-acetic in cerebrospinal fluid, blood and urine. Two sisters died with non ketotic hyperglycinemia, corpus callosum agenesis and clubfoot. CONCLUSION: Familial occurrence of non ketotic hyperglycinemia and early myoclonic epileptic encephalopathy is uncommon.


Assuntos
Consanguinidade , Epilepsias Mioclônicas/genética , Hiperglicemia/genética , Eletroencefalografia , Epilepsias Mioclônicas/congênito , Epilepsias Mioclônicas/fisiopatologia , Feminino , Humanos , Hiperglicemia/congênito , Hiperglicemia/fisiopatologia , Recém-Nascido , Masculino
9.
Arch Pediatr ; 6(11): 1193-5, 1999 Nov.
Artigo em Francês | MEDLINE | ID: mdl-10587744

RESUMO

UNLABELLED: The association of aplasia cutis congenita and aortic coarctation could be a coincidence. CASE REPORT: A neonate was born with an aplasia cutis congenita in the midline of the scalp. When she was two months old, an aortie coarctation was detected and surgically resected. Spontaneously, the scalp gradually cicatrized. CONCLUSION: A search for a candidate gene in this second reported case is mandated.


Assuntos
Coartação Aórtica/complicações , Displasia Ectodérmica/complicações , Coartação Aórtica/genética , Coartação Aórtica/patologia , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Feminino , Predisposição Genética para Doença , Humanos , Recém-Nascido
11.
Prenat Diagn ; 25(11): 997-9, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16231297

RESUMO

Gorlin syndrome (GS), also known as nevoid basal cell carcinoma syndrome, is a rare autosomal dominant condition with an estimated prevalence of 1:57 000. GS is associated with congenital malformations and predisposition to neoplasms. The main features observed in patients with GS are basal cell carcinomas, odontogenic keratocysts, skeletal anomalies including scoliosis and bifid ribs, palmar and plantar epidermal cysts, facial dysmorphism, and cerebral falx calcification. More than 100 other clinical manifestations have also been described in the literature including ovarian fibroma, enlarged cerebral ventricles, and lymphatic as well as chylous mesenteric cysts. The Patched (PTCH) gene is responsible for GS when mutated. Here, we report on a prenatal diagnosis of GS in a girl with a chylothorax, a previously unreported feature in GS. We discuss the clinical features observed in this family and we comment on the molecular studies that allowed us to describe a previously unreported Patched gene mutation.


Assuntos
Síndrome do Nevo Basocelular/diagnóstico , Quilotórax/etiologia , Diagnóstico Pré-Natal , Adulto , Síndrome do Nevo Basocelular/complicações , Síndrome do Nevo Basocelular/genética , Feminino , Fibroma/diagnóstico , Neoplasias Cardíacas/diagnóstico , Humanos , Recém-Nascido , Mutação , Gravidez
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