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1.
J Matern Fetal Neonatal Med ; : 1-7, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30880510

RESUMO

BACKGROUND: Discordant malformation between monochorionic twins is a rare and unknown phenomenon. OBJECTIVES: To estimate the incidence of discordant monochorionic twins and to describe their characteristics. STUDY DESIGN: A retrospective multicenter cohort of pregnancies between 2002 and 2015 in La Reunion Island was analyzed, thanks to a population-based register. Only monochorionic pregnancies were included in order to analyze specifically monozygotic twins. We defined as discordant twin pairs those in which different malformations were identified for each twin and those with only one fetus showing a malformation. RESULTS: During the study period, 203,807 births occurred, including 410 monochorionic twin pairs. Congenital anomalies rate for monochorionic twin pairs was 10.7%. We included 38 monochorionic twin pairs with discordant phenotypes, which represent 9.3% of monochorionic twin pairs and 86.4% of monochorionic twin pairs affected by congenital anomalies. Among them, both twins were affected by different congenital anomalies in 7 pairs (18.4%), and only one twin was affected in 31 pairs (81.6%). We identified 20 congenital heart anomalies (44.4%), 5 brain anomalies (11.1%), 5 genital anomalies (11.1%), 4 axial bones and skull anomalies (8.9%), 4 limb anomalies (8.9%), 4 facial anomalies (8.9%), 3 urological anomalies (6.6%), 2 thoracic anomalies (4.4%), 1 bile duct anomaly (2,2%), 1 abdominal parietal defect (2.2%), and 1 aneuploidy (2.2%). Among them, 3 (6.6%) fetuses had an association of malformations. Among the 45 fetuses with malformations, 37 fetuses (82.2%) were born alive and 21 (46.6%) had postnatal surgery. CONCLUSIONS: Despite a supposed identical genome, discordant congenital anomalies in monochorionic twin pregnancies are not exceptional and related to genetic and epigenetic mechanisms. Sonographers and pediatricians should know that in monochorionic twin a pair, the occurrence of discordant phenotypes is high (9.3%).

2.
Clin Genet ; 95(3): 420-426, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30633342

RESUMO

Rubinstein-Taybi syndrome (RSTS; OMIM 180849) is an autosomal dominant developmental disorder characterized by facial dysmorphism, broad thumbs and halluces associated with intellectual disability. RSTS is caused by alterations in CREBBP (about 60%) and EP300 genes (8%). RSTS is often diagnosed at birth or during early childhood but generally not suspected during antenatal period. We report nine cases of well-documented fetal RSTS. Two cases were examined after death in utero at 18 and 35 weeks of gestation and seven cases after identification of ultrasound abnormalities and termination of pregnancy. On prenatal sonography, a large gallbladder was detected in two cases, and brain malformations were noted in four cases, especially cerebellar hypoplasia. However, the diagnosis of RSTS has not been suggested during pregnancy. Fetal autopsy showed that all fetuses had large thumbs and/or suggestive facial dysmorphism. A CREBBP gene anomaly was identified in all cases. Alterations were similar to those found in typical RSTS children. This report will contribute to a better knowledge of the fetal phenotype to consider the hypothesis of RSTS during pregnancy. Genotyping allows reassuring genetic counseling.

3.
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.

4.
Eur J Hum Genet ; 26(3): 340-349, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29330547

RESUMO

Fryns syndrome (FS) is a multiple malformations syndrome with major features of congenital diaphragmatic hernia, pulmonary hypoplasia, craniofacial dysmorphic features, distal digit hypoplasia, and a range of other lower frequency malformations. FS is typically lethal in the fetal or neonatal period. Inheritance is presumed autosomal recessive. Although no major genetic cause has been identified for FS, biallelic truncating variants in PIGN, encoding a component of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, have been identified in a limited number of cases with a phenotype compatible with FS. Biallelic variants in PIGN, typically missense or compound missense with truncating, also cause multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1). Here we report six further patients with FS with or without congenital diaphragmatic hernia and recessive loss of function PIGN alleles, including an intragenic deletion with a likely founder effect in La Réunion and other Indian Ocean islands. Our results support the hypothesis that a spectrum of phenotypic severity is associated with recessive PIGN variants, ranging from FS at the extreme end, caused by complete loss of function, to MCAHS1, in which some residual PIGN function may remain. Our data add FS resulting from PIGN variants to the catalog of inherited GPI deficiencies caused by the disruption of the GPI-anchor biosynthesis pathway.

5.
J Inherit Metab Dis ; 41(1): 129-139, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28924877

RESUMO

BACKGROUND AND AIM: To improve the diagnostic work-up of patients with diverse neurological diseases, we have elaborated specific clinical and CSF neurotransmitter patterns. METHODS: Neurotransmitter determinations in CSF from 1200 patients revealed abnormal values in 228 (19%) cases. In 54/228 (24%) patients, a final diagnosis was identified. RESULTS: We have reported primary (30/54, 56%) and secondary (24/54, 44%) monoamine neurotransmitter disorders. For primary deficiencies, the most frequently mutated gene was DDC (n = 9), and the others included PAH with neuropsychiatric features (n = 4), PTS (n = 5), QDPR (n = 3), SR (n = 1), and TH (n = 1). We have also identified mutations in SLC6A3, FOXG1 (n = 1 of each), MTHFR (n = 3), FOLR1, and MTHFD (n = 1 of each), for dopamine transporter, neuronal development, and folate metabolism disorders, respectively. For secondary deficiencies, we have identified POLG (n = 3), ACSF3 (n = 1), NFU1, and SDHD (n = 1 of each), playing a role in mitochondrial function. Other mutated genes included: ADAR, RNASEH2B, RNASET2, SLC7A2-IT1 A/B lncRNA, and EXOSC3 involved in nuclear and cytoplasmic metabolism; RanBP2 and CASK implicated in post-traductional and scaffolding modifications; SLC6A19 regulating amino acid transport; MTM1, KCNQ2 (n = 2), and ATP1A3 playing a role in nerve cell electrophysiological state. Chromosome abnormalities, del(8)(p23)/dup(12) (p23) (n = 1), del(6)(q21) (n = 1), dup(17)(p13.3) (n = 1), and non-genetic etiologies (n = 3) were also identified. CONCLUSION: We have classified the final 54 diagnoses in 11 distinctive biochemical profiles and described them through 20 clinical features. To identify the specific molecular cause of abnormal NT profiles, (targeted) genomics might be used, to improve diagnosis and allow early treatment of complex and rare neurological genetic diseases.

6.
Birth Defects Res ; 109(15): 1204-1211, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28722320

RESUMO

BACKGROUND: The different mechanisms leading to a solitary kidney should be differentiated because the long-term outcome might be different. The fetal period is the best moment to make a true diagnosis of congenital unilateral renal agenesis (URA). The objective was to determine the prevalence of URA at birth. The secondary objectives were to describe the evolution of sensitivity of prenatal diagnosis over time and the different forms of URA (isolated and associated with other malformations) detected up to 1 year. METHODS: The cases were retrospectively identified through two French population-based birth defect registries (Auvergne and Bas-Rhin) between 1995 and 2013. Stillbirths and fetuses up to 22 weeks of gestation and infants up to 1 year old with URA were included. RESULTS: A total of 177 cases of URA were registered. The prevalence at birth was 4.0/10,000. The overall prenatal prevalence was 3.6/10,000 (isolated URA: 2.8/10,000). URA were isolated (59.9%), associated with isolated contralateral congenital anomaly of kidney or urinary tract (CAKUT) (7.3%) and with other extra-renal anomalies (32.8%). The total proportion of contralateral CAKUT was 15%. Only three cases presented an aneuploidy, prenatally detected and conducting to a termination of pregnancy. The sensitivity of prenatal diagnosis improved over time (from 54.2% in 1995 to 1997 to 95.8% in 2010 to 2013; p = 0.002). CONCLUSION: Our study provides estimates of prevalence of URA at birth. A longitudinal cohort from the antenatal period to puberty should be performed to determine the prognosis of the contralateral kidney among these children with isolated, associated with contralateral CAKUT and URA with extra-renal anomalies. Birth Defects Research 109:1204-1211, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Anormalidades Congênitas/etiologia , Nefropatias/congênito , Rim/anormalidades , Rim Único/etiologia , Estudos Transversais , Feminino , Feto , França , Humanos , Lactente , Recém-Nascido , Nefropatias/complicações , Nefropatias/etiologia , Masculino , Gravidez , Diagnóstico Pré-Natal , Prevalência , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Sistema Urinário
7.
J Med Genet ; 54(6): 371-380, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28289185

RESUMO

Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753 and IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231 and WDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype.


Assuntos
Face/anormalidades , Síndromes Orofaciodigitais/genética , Anormalidades Múltiplas/genética , Transtornos da Motilidade Ciliar/genética , Encefalocele/genética , Feminino , Heterozigoto , Humanos , Masculino , Mutação/genética , Doenças Renais Policísticas/genética , Proteínas/genética , Retinite Pigmentosa
9.
Neurology ; 86(18): 1716-25, 2016 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-27053714

RESUMO

OBJECTIVE: To test previous signals of a risk of orofacial cleft (OC) and clubfoot with exposure to the antiepileptic lamotrigine, and to investigate risk of other congenital anomalies (CA). METHODS: This was a population-based case-malformed control study based on 21 EUROCAT CA registries covering 10.1 million births (1995-2011), including births to 2005 in which the clubfoot signal was generated and a subsequent independent study population of 6.3 million births. A total of 226,806 babies with CA included livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis. First-trimester lamotrigine monotherapy exposure in OC cases and clubfoot cases was compared to other nonchromosomal CA (controls). Odds ratios (OR) were adjusted for registry. An exploratory analysis compared the proportion of each standard EUROCAT CA subgroup among all babies with nonchromosomal CA exposed to lamotrigine monotherapy with non-AED exposed pregnancies. RESULTS: There were 147 lamotrigine monotherapy-exposed babies with nonchromosomal CA. For all OC, ORadj was 1.31 (95% confidence interval [CI] 0.73-2.33), isolated OC 1.45 (95% CI 0.80-2.63), isolated cleft palate 1.69 (95% CI 0.69-4.15). Overall ORadj for clubfoot was 1.83 (95% CI 1.01-3.31) and 1.43 (95% CI 0.66-3.08) in the independent study population. No other specific CA were significantly associated with lamotrigine monotherapy. CONCLUSIONS: The risk of OC was not significantly raised and we estimate the excess risk of OC to be less than 1 in every 550 exposed babies. We have not found strong independent evidence of a risk of clubfoot subsequent to our original signal. Our study cannot assess the general malformation risk among lamotrigine-exposed pregnancies.


Assuntos
Anormalidades Induzidas por Medicamentos/epidemiologia , Anticonvulsivantes/efeitos adversos , Fenda Labial/induzido quimicamente , Fissura Palatina/induzido quimicamente , Triazinas/efeitos adversos , Adulto , Anticonvulsivantes/uso terapêutico , Estudos de Casos e Controles , Fenda Labial/epidemiologia , Fissura Palatina/epidemiologia , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Humanos , Lamotrigina , Razão de Chances , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/epidemiologia , Primeiro Trimestre da Gravidez , Sistema de Registros , Risco , Sensibilidade e Especificidade , Triazinas/uso terapêutico
10.
Orphanet J Rare Dis ; 11: 26, 2016 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-27004399

RESUMO

BACKGROUND: Deficient nucleotide excision repair (NER) activity causes a variety of autosomal recessive diseases including xeroderma pigmentosum (XP) a disorder which pre-disposes to skin cancer, and the severe multisystem condition known as Cockayne syndrome (CS). In view of the clinical overlap between NER-related disorders, as well as the existence of multiple phenotypes and the numerous genes involved, we developed a new diagnostic approach based on the enrichment of 16 NER-related genes by multiplex amplification coupled with next-generation sequencing (NGS). METHODS: Our test cohort consisted of 11 DNA samples, all with known mutations and/or non pathogenic SNPs in two of the tested genes. We then used the same technique to analyse samples from a prospective cohort of 40 patients. Multiplex amplification and sequencing were performed using AmpliSeq protocol on the Ion Torrent PGM (Life Technologies). RESULTS: We identified causative mutations in 17 out of the 40 patients (43%). Four patients showed biallelic mutations in the ERCC6(CSB) gene, five in the ERCC8(CSA) gene: most of them had classical CS features but some had very mild and incomplete phenotypes. A small cohort of 4 unrelated classic XP patients from the Basque country (Northern Spain) revealed a common splicing mutation in POLH (XP-variant), demonstrating a new founder effect in this population. Interestingly, our results also found ERCC2(XPD), ERCC3(XPB) or ERCC5(XPG) mutations in two cases of UV-sensitive syndrome and in two cases with mixed XP/CS phenotypes. CONCLUSIONS: Our study confirms that NGS is an efficient technique for the analysis of NER-related disorders on a molecular level. It is particularly useful for phenotypes with combined features or unusually mild symptoms. Targeted NGS used in conjunction with DNA repair functional tests and precise clinical evaluation permits rapid and cost-effective diagnosis in patients with NER-defects.


Assuntos
Reparo do DNA/genética , Síndrome de Cockayne/genética , DNA Helicases/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , DNA Polimerase Dirigida por DNA/genética , Endonucleases/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação , Proteínas Nucleares/genética , Fenótipo , Proteínas de Ligação a Poli-ADP-Ribose , Fatores de Transcrição/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética
11.
PLoS Biol ; 14(3): e1002416, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26982032

RESUMO

Cilia have a unique diffusion barrier ("gate") within their proximal region, termed transition zone (TZ), that compartmentalises signalling proteins within the organelle. The TZ is known to harbour two functional modules/complexes (Meckel syndrome [MKS] and Nephronophthisis [NPHP]) defined by genetic interaction, interdependent protein localisation (hierarchy), and proteomic studies. However, the composition and molecular organisation of these modules and their links to human ciliary disease are not completely understood. Here, we reveal Caenorhabditis elegans CEP-290 (mammalian Cep290/Mks4/Nphp6 orthologue) as a central assembly factor that is specific for established MKS module components and depends on the coiled coil region of MKS-5 (Rpgrip1L/Rpgrip1) for TZ localisation. Consistent with a critical role in ciliary gate function, CEP-290 prevents inappropriate entry of membrane-associated proteins into cilia and keeps ARL-13 (Arl13b) from leaking out of cilia via the TZ. We identify a novel MKS module component, TMEM-218 (Tmem218), that requires CEP-290 and other MKS module components for TZ localisation and functions together with the NPHP module to facilitate ciliogenesis. We show that TZ localisation of TMEM-138 (Tmem138) and CDKL-1 (Cdkl1/Cdkl2/Cdkl3/Cdlk4 related), not previously linked to a specific TZ module, similarly depends on CEP-290; surprisingly, neither TMEM-138 or CDKL-1 exhibit interdependent localisation or genetic interactions with core MKS or NPHP module components, suggesting they are part of a distinct, CEP-290-associated module. Lastly, we show that families presenting with Oral-Facial-Digital syndrome type 6 (OFD6) have likely pathogenic mutations in CEP-290-dependent TZ proteins, namely Tmem17, Tmem138, and Tmem231. Notably, patient fibroblasts harbouring mutated Tmem17, a protein not yet ciliopathy-associated, display ciliogenesis defects. Together, our findings expand the repertoire of MKS module-associated proteins--including the previously uncharacterised mammalian Tmem80--and suggest an MKS-5 and CEP-290-dependent assembly pathway for building a functional TZ.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Cílios/fisiologia , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Sequência de Aminoácidos , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Quinases Ciclina-Dependentes/metabolismo , Humanos , Proteínas de Membrana/genética , Dados de Sequência Molecular , Síndromes Orofaciodigitais/genética
12.
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
13.
Eur J Hum Genet ; 24(2): 228-36, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26014430

RESUMO

The etiology of congenital heart defect (CHD) combines environmental and genetic factors. So far, there were studies reporting on the screening of a single gene on unselected CHD or on familial cases selected for specific CHD types. Our goal was to systematically screen a proband of familial cases of CHD on a set of genetic tests to evaluate the prevalence of disease-causing variant identification. A systematic screening of GATA4, NKX2-5, ZIC3 and Multiplex ligation-dependent probe amplification (MLPA) P311 Kit was setup on the proband of 154 families with at least two cases of non-syndromic CHD. Additionally, ELN screening was performed on families with supravalvular arterial stenosis. Twenty-two variants were found, but segregation analysis confirmed unambiguously the causality of 16 variants: GATA4 (1 ×), NKX2-5 (6 ×), ZIC3 (3 ×), MLPA (2 ×) and ELN (4 ×). Therefore, this approach was able to identify the causal variant in 10.4% of familial CHD cases. This study demonstrated the existence of a de novo variant even in familial CHD cases and the impact of CHD variants on adult cardiac condition even in the absence of CHD. This study showed that the systematic screening of genetic factors is useful in familial CHD cases with up to 10.4% elucidated cases. When successful, it drastically improved genetic counseling by discovering unaffected variant carriers who are at risk of transmitting their variant and are also exposed to develop cardiac complications during adulthood thus prompting long-term cardiac follow-up. This study provides an important baseline at dawning of the next-generation sequencing era.


Assuntos
Testes Genéticos , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Feminino , Fator de Transcrição GATA4/genética , Variação Genética , Cardiopatias Congênitas/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/genética , Humanos , Masculino , Reação em Cadeia da Polimerase Multiplex , Mutação , Linhagem , Fatores de Transcrição/genética
14.
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
15.
J Med Genet ; 53(2): 98-110, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26502894

RESUMO

BACKGROUND: Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders. METHODS: We designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption. RESULTS: We discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases. CONCLUSIONS: We have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease. TRIAL REGISTRATION NUMBERS: NCT01746121 and NCT02397824.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Anormalidades Dentárias/genética , Amelogênese Imperfeita/genética , Autoantígenos/genética , Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 11/genética , Estudos de Coortes , Coloboma/genética , Displasia da Dentina/genética , França , Perda Auditiva Neurossensorial/genética , Humanos , Colágenos não Fibrilares/genética , Reprodutibilidade dos Testes
16.
Hum Mutat ; 36(9): 894-902, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26077438

RESUMO

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder associating macroglossia, abdominal wall defects, visceromegaly, and a high risk of childhood tumor. Molecular anomalies are mostly epigenetic; however, mutations of CDKN1C are implicated in 8% of cases, including both sporadic and familial forms. We aimed to describe the phenotype of BWS patients with CDKN1C mutations and develop a functional test for CDKN1C mutations. For each propositus, we sequenced the three exons and intron-exon boundaries of CDKN1C in patients presenting a BWS phenotype, including abdominal wall defects, without 11p15 methylation defects. We developed a functional test based on flow cytometry. We identified 37 mutations in 38 pedigrees (50 patients and seven fetuses). Analysis of parental samples when available showed that all mutations tested but one was inherited from the mother. The four missense mutations led to a less severe phenotype (lower frequency of exomphalos) than the other 33 mutations. The following four tumors occurred: one neuroblastoma, one ganglioneuroblastoma, one melanoma, and one acute lymphoid leukemia. Cases of BWS caused by CDKN1C mutations are not rare. CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS.


Assuntos
Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Estudos de Associação Genética , Impressão Genômica , Fenótipo , Alelos , Sequência de Aminoácidos , Substituição de Aminoácidos , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Feminino , Genótipo , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Alinhamento de Sequência
17.
Eur J Hum Genet ; 23(1): 49-53, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24755949

RESUMO

First described as a variant of Larsen syndrome in Reunion Island (LRS) in the southern Indian Ocean, 'Larsen of Reunion Island syndrome' is characterized by dwarfism, hyperlaxity, multiple dislocations and distinctive facial features. It overlaps with Desbuquois dysplasia, Larsen syndrome and spondyloepiphyseal dysplasia with dislocations ascribed to CANT1, FLNB and CHST3 mutations, respectively. We collected the samples of 22 LRS cases. After exclusion of CANT1, FLNB and CHST3 genes, an exome sequencing was performed in two affected second cousins and one unaffected sister. We identified a homozygous missense mutation in B4GALT7, NM_007255.2: c.808C>T p.(Arg270Cys) named p.R270C, in the two affected cases, not present in the unaffected sister. The same homozygous mutation was subsequently identified in the remaining 20 LRS cases. Our findings demonstrate that B4GALT7 is the causative gene for LRS. The identification of a unique homozygous mutation argues in favor of a founder effect. B4GALT7 encodes a galactosyltransferase, required for the initiation of glycoaminoglycan side chain synthesis of proteoglycans. This study expands the phenotypic spectrum of B4GALT7 mutations, initially described as responsible for the progeroid variant of Ehlers-Danlos syndrome. It further supports a common physiopathological basis involving proteoglycan synthesis in skeletal disorders with dislocations.


Assuntos
Efeito Fundador , Galactosiltransferases/deficiência , Galactosiltransferases/genética , Homozigoto , Mutação , Adolescente , Adulto , Criança , Facies , Feminino , Fluorenos , Frequência do Gene , Humanos , Hidantoínas , Masculino , Pessoa de Meia-Idade , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Linhagem , Fenótipo , Análise de Sequência de DNA , Adulto Jovem
18.
Fetal Diagn Ther ; 37(1): 6-17, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25402326

RESUMO

CONTEXT AND OBJECTIVE: Considering the lack of accurate and up-to-date information available about neural tube defects (NTDs) in France, the purpose of this study was to review clinical and epidemiological data of NTDs and to evaluate the current efficiency of prenatal diagnosis in Alsace (northeastern France). METHODS: A population-based retrospective study was performed from data of the Registry of Congenital Malformations of Alsace between 1995 and 2009. Data were analyzed as a whole and according to the anatomical type of the malformation (anencephaly, cephalocele and spina bifida). Statistical analyses were carried out using the Statistical Package for the Social Sciences. RESULTS: 272 NTDs were recorded divided in 113 cases of anencephaly (42%), 35 cases of cephalocele (13%) and 124 cases of spina bifida (45%). The total prevalence at birth of 14/10,000 (95% CI 13-16) was stable throughout the reporting period. A chromosome abnormality was identified in 27 cases (12% of all karyotyped cases). NTDs were prenatally diagnosed by ultrasound in 88% of the cases. The mean age upon prenatal diagnosis slightly declined during the 15-year period, significantly for spina bifida only. The global rate of terminations of pregnancy following prenatal diagnosis was 97% (230/238). CONCLUSION: This work constitutes a unique population-based study providing accurate and specific up-to-date data from a unique center over a longer period (1995-2009). The most important information concerns the high and stable prevalence, which calls into question the efficiency of the primary prevention by folic acid supplementation and the efficiency of prenatal diagnosis.


Assuntos
Defeitos do Tubo Neural/diagnóstico , Defeitos do Tubo Neural/epidemiologia , Adulto , Feminino , França/epidemiologia , Humanos , Masculino , Gravidez , Diagnóstico Pré-Natal , Prevalência , Sistema de Registros , Estudos Retrospectivos
19.
Arch Dis Child Fetal Neonatal Ed ; 100(2): F137-44, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25411443

RESUMO

INTRODUCTION: Published prevalence rates of congenital diaphragmatic hernia (CDH) vary. This study aims to describe the epidemiology of CDH using data from high-quality, population-based registers belonging to the European Surveillance of Congenital Anomalies (EUROCAT). METHODS: Cases of CDH delivered between 1980 and 2009 notified to 31 EUROCAT registers formed the population-based case series. Prevalence over time was estimated using multilevel Poisson regression, and heterogeneity between registers was evaluated from the random component of the intercept. RESULTS: There were 3373 CDH cases reported among 12 155 491 registered births. Of 3131 singleton cases, 353 (10.4%) were associated with a chromosomal anomaly, genetic syndrome or microdeletion, 784 (28.2%) were associated with other major structural anomalies. The male to female ratio of CDH cases overall was 1:0.69. Total prevalence was 2.3 (95% CI 2.2 to 2.4) per 10 000 births and 1.6 (95% CI 1.6 to 1.7) for isolated CDH cases. There was a small but significant increase (relative risk (per year)=1.01, 95% credible interval 1.00-1.01; p=0.030) in the prevalence of total CDH over time but there was no significant increase for isolated cases (ie, CDH cases that did not occur with any other congenital anomaly). There was significant variation in total and isolated CDH prevalence between registers. The proportion of cases that survived to 1 week was 69.3% (1392 cases) for total CDH cases and 72.7% (1107) for isolated cases. CONCLUSIONS: This large population-based study found an increase in total CDH prevalence over time. CDH prevalence also varied significantly according to geographical location. No significant association was found with maternal age.


Assuntos
Hérnias Diafragmáticas Congênitas/epidemiologia , Anormalidades Múltiplas/epidemiologia , Adolescente , Adulto , Peso ao Nascer , Europa (Continente)/epidemiologia , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Idade Materna , Vigilância da População , Prevalência , Sistema de Registros , Análise de Sobrevida , Adulto Jovem
20.
J Med Genet ; 51(11): 724-36, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25167861

RESUMO

BACKGROUND: Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation. METHODS: We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases. RESULTS: We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients' clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders. CONCLUSIONS: With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Técnicas de Diagnóstico Molecular/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Análise de Sequência de DNA/métodos , Adulto Jovem
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