Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 60
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
J Med Genet ; 61(9): 878-885, 2024 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-38937076

RESUMEN

BACKGROUND: Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as DNA methyltransferase 3 alpha (DNMT3A)-overgrowth syndrome (DOS), was first described by Tatton-Brown in 2014. This syndrome is characterised by overgrowth, intellectual disability and distinctive facial features and is the consequence of germline loss-of-function variants in DNMT3A, which encodes a DNA methyltransferase involved in epigenetic regulation. Somatic variants of DNMT3A are frequently observed in haematological malignancies, including acute myeloid leukaemia (AML). To date, 100 individuals with TBRS with de novo germline variants have been described. We aimed to further characterise this disorder clinically and at the molecular level in a nationwide series of 24 French patients and to investigate the correlation between the severity of intellectual disability and the type of variant. METHODS: We collected genetic and medical information from 24 individuals with TBRS using a questionnaire released through the French National AnDDI-Rares Network. RESULTS: Here, we describe the first nationwide French cohort of 24 individuals with germline likely pathogenic/pathogenic variants in DNMT3A, including 17 novel variants. We confirmed that the main phenotypic features were intellectual disability (100% of individuals), distinctive facial features (96%) and overgrowth (87%). We highlighted novel clinical features, such as hypertrichosis, and further described the neurological features and EEG results. CONCLUSION: This study of a nationwide cohort of individuals with TBRS confirms previously published data and provides additional information and clarifies clinical features to facilitate diagnosis and improve care. This study adds value to the growing body of knowledge on TBRS and broadens its clinical and molecular spectrum.


Asunto(s)
ADN (Citosina-5-)-Metiltransferasas , ADN Metiltransferasa 3A , Discapacidad Intelectual , Humanos , Masculino , Femenino , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Francia/epidemiología , Niño , ADN (Citosina-5-)-Metiltransferasas/genética , Preescolar , Adolescente , Mutación de Línea Germinal/genética , Adulto , Fenotipo , Adulto Joven , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/patología , Lactante
2.
Clin Genet ; 106(3): 234-246, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38561231

RESUMEN

Xq28 int22h-1/int22h-2 duplication is the result of non-allelic homologous recombination between int22h-1/int22h-2 repeats separated by 0.5 Mb. It is responsible for a syndromic form of intellectual disability (ID), with recurrent infections and atopic diseases. Minor defects, nonspecific facial dysmorphic features, and overweight have also been described. Half of female carriers have been reported with ID, whereas all reported evaluated born males present mild to moderate ID, suggesting complete penetrance. We collected data on 15 families from eight university hospitals. Among them, 40 patients, 21 females (one fetus), and 19 males (two fetuses), were carriers of typical or atypical Xq28 int22h-1/int22h-2 duplication. Twenty-one individuals were considered asymptomatic (16 females and 5 males), without significantly higher rate of recurrent infections, atopia, overweight, or facial dysmorphism. Approximately 67% live-born males and 23% live-born female carriers of the typical duplication did not have obvious signs of intellectual disability, suggesting previously undescribed incomplete penetrance or low expression in certain carriers. The possibility of a second-hit or modifying factors to this possible susceptibility locus is yet to be studied but a possible observational bias should be considered in assessing such challenging X-chromosome copy number gains. Additional segregation studies should help to quantify this newly described incomplete penetrance.


Asunto(s)
Cromosomas Humanos X , Discapacidad Intelectual , Penetrancia , Humanos , Masculino , Femenino , Cromosomas Humanos X/genética , Discapacidad Intelectual/genética , Niño , Adulto , Adolescente , Preescolar , Fenotipo , Duplicación Cromosómica/genética , Duplicación de Gen , Linaje , Adulto Joven
3.
Am J Med Genet A ; 194(4): e63476, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37974505

RESUMEN

Cat Eye Syndrome (CES) is a rare genetic disease caused by the presence of a small supernumerary marker chromosome derived from chromosome 22, which results in a partial tetrasomy of 22p-22q11.21. CES is classically defined by association of iris coloboma, anal atresia, and preauricular tags or pits, with high clinical and genetic heterogeneity. We conducted an international retrospective study of patients carrying genomic gain in the 22q11.21 chromosomal region upstream from LCR22-A identified using FISH, MLPA, and/or array-CGH. We report a cohort of 43 CES cases. We highlight that the clinical triad represents no more than 50% of cases. However, only 16% of CES patients presented with the three signs of the triad and 9% not present any of these three signs. We also highlight the importance of other impairments: cardiac anomalies are one of the major signs of CES (51% of cases), and high frequency of intellectual disability (47%). Ocular motility defects (45%), abdominal malformations (44%), ophthalmologic malformations (35%), and genitourinary tract defects (32%) are other frequent clinical features. We observed that sSMC is the most frequent chromosomal anomaly (91%) and we highlight the high prevalence of mosaic cases (40%) and the unexpectedly high prevalence of parental transmission of sSMC (23%). Most often, the transmitting parent has mild or absent features and carries the mosaic marker at a very low rate (<10%). These data allow us to better delineate the clinical phenotype associated with CES, which must be taken into account in the cytogenetic testing for this syndrome. These findings draw attention to the need for genetic counseling and the risk of recurrence.


Asunto(s)
Aneuploidia , Trastornos de los Cromosomas , Cromosomas Humanos Par 22 , Anomalías del Ojo , Cardiopatías Congénitas , Humanos , Estudios Retrospectivos , Hibridación Fluorescente in Situ , Cromosomas Humanos Par 22/genética , Cardiopatías Congénitas/genética
4.
Clin Genet ; 103(4): 401-412, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36576162

RESUMEN

Chromoanagenesis is a cellular mechanism that leads to complex chromosomal rearrangements (CCR) during a single catastrophic event. It may result in loss and/or gain of genetic material and may be responsible for various phenotypes. These rearrangements are usually sporadic. However, some familial cases have been reported. Here, we studied six families in whom an asymptomatic or paucisymptomatic parent transmitted a CCR to its offspring in an unbalanced manner. The rearrangements were characterized by karyotyping, fluorescent in situ hybridization, chromosomal microarray (CMA) and/or whole genome sequencing (WGS) in the carrier parents and offspring. We then hypothesized meiosis-pairing figures between normal and abnormal parental chromosomes that may have led to the formation of new unbalanced rearrangements through meiotic recombination. Our work indicates that chromoanagenesis might be associated with a normal phenotype and normal fertility, even in males, and that WGS may be the only way to identify these events when there is no imbalance. Subsequently, the CCR can be transmitted to the next generation in an unbalanced and unpredictable manner following meiotic recombination. Thereby, prenatal diagnosis using CMA should be proposed to these families to detect any pathogenic imbalances in the offspring.


Asunto(s)
Aberraciones Cromosómicas , Reordenamiento Génico , Masculino , Femenino , Embarazo , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Meiosis , Translocación Genética
5.
Am J Med Genet A ; 188(1): 314-318, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34558179

RESUMEN

Congenital combined vitamin K-dependent clotting factors deficiency (VKCFD) is a rare autosomal recessive disease resulting in hemorrhagic symptoms usually associated with developmental disorders and bone abnormalities. Pathogenic variants in two genes encoding enzymes of the vitamin K cycle, GGCX and VKORC1, can lead to this disorder. We present the case of a male fetus with a brachytelephalangic chondrodysplasia punctata (CDP), absence of nasal bone, growth restriction, and bilateral ventriculomegaly at 18 weeks of gestation. Pathological examination showed a Binder phenotype, hypoplastic distal phalanges, stippled epiphyses, and brain abnormalities suggestive of a brain hemorrhage. Two GGCX pathogenic variants inherited respectively from the mother and the father were identified. To our knowledge, this is the first prenatal description of VKCFD. Even if it remains a rare etiology, which is mostly described in children or adult patients, VKCFD should be considered in fetuses with CDP.


Asunto(s)
Ligasas de Carbono-Carbono , Condrodisplasia Punctata , Factores de Coagulación Sanguínea , Ligasas de Carbono-Carbono/genética , Condrodisplasia Punctata/diagnóstico , Condrodisplasia Punctata/genética , Femenino , Feto , Humanos , Masculino , Embarazo , Vitamina K , Vitamina K 1 , Vitamina K Epóxido Reductasas/genética
6.
Prenat Diagn ; 42(1): 118-135, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34894355

RESUMEN

OBJECTIVE: Terminal 6q deletion is a rare genetic condition associated with a neurodevelopmental disorder characterized by intellectual disability and structural brain anomalies. Interestingly, a similar phenotype is observed in patients harboring pathogenic variants in the DLL1 gene. Our study aimed to further characterize the prenatal phenotype of this syndrome as well as to attempt to establish phenotype-genotype correlations. METHOD: We collected ultrasound findings from 22 fetuses diagnosed with a pure 6qter deletion. We reviewed the literature and compared our 22 cases with 14 fetuses previously reported as well as with patients with heterozygous DLL1 pathogenic variants. RESULTS: Brain structural alterations were observed in all fetuses. The most common findings (>70%) were cerebellar hypoplasia, ventriculomegaly, and corpus callosum abnormalities. Gyration abnormalities were observed in 46% of cases. Occasional findings included cerebral heterotopia, aqueductal stenosis, vertebral malformations, dysmorphic features, and kidney abnormalities. CONCLUSION: This is the first series of fetuses diagnosed with pure terminal 6q deletion. Based on our findings, we emphasize the prenatal sonographic anomalies, which may suggest the syndrome. Furthermore, this study highlights the importance of chromosomal microarray analysis to search for submicroscopic deletions of the 6q27 region involving the DLL1 gene in fetuses with these malformations.


Asunto(s)
Proteínas de Unión al Calcio/análisis , Trastornos de los Cromosomas/complicaciones , Proteínas de la Membrana/análisis , Adulto , Proteínas de Unión al Calcio/genética , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 6/genética , Femenino , Humanos , Proteínas de la Membrana/genética , Fenotipo , Embarazo , Estudios Retrospectivos , Trisomía/genética , Virulencia/genética , Virulencia/fisiología
7.
Hum Mutat ; 42(7): 848-861, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33856728

RESUMEN

The X-linked PTCHD1 gene, encoding a synaptic membrane protein, has been involved in neurodevelopmental disorders with the description of deleterious genomic microdeletions or truncating coding mutations. Missense variants were also identified, however, without any functional evidence supporting their pathogenicity level. We investigated 13 missense variants of PTCHD1, including eight previously described (c.152G>A,p.(Ser51Asn); c.217C>T,p.(Leu73Phe); c.517A>G,p.(Ile173Val); c.542A>C,p.(Lys181Thr); c.583G>A,p.(Val195Ile); c.1076A>G,p.(His359Arg); c.1409C>A,p.(Ala470Asp); c.1436A>G,p.(Glu479Gly)), and five novel ones (c.95C>T,p.(Pro32Leu); c.95C>G,p.(Pro32Arg); c.638A>G,p.(Tyr213Cys); c.898G>C,p.(Gly300Arg); c.928G>C,p.(Ala310Pro)) identified in male patients with intellectual disability (ID) and/or autism spectrum disorder (ASD). Interestingly, several of these variants involve amino acids localized in structural domains such as transmembrane segments. To evaluate their potentially deleterious impact on PTCHD1 protein function, we performed in vitro overexpression experiments of the wild-type and mutated forms of PTCHD1-GFP in HEK 293T and in Neuro-2a cell lines as well as in mouse hippocampal primary neuronal cultures. We found that six variants impaired the expression level of the PTCHD1 protein, and were retained in the endoplasmic reticulum suggesting abnormal protein folding. Our functional analyses thus provided evidence of the pathogenic impact of missense variants in PTCHD1, which reinforces the involvement of the PTCHD1 gene in ID and in ASD.


Asunto(s)
Trastorno del Espectro Autista , Discapacidad Intelectual , Proteínas de la Membrana , Animales , Trastorno del Espectro Autista/genética , Membrana Celular/metabolismo , Humanos , Discapacidad Intelectual/genética , Masculino , Proteínas de la Membrana/genética , Ratones , Mutación Missense
8.
Cytogenet Genome Res ; 160(2): 72-79, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32187601

RESUMEN

In this report, we present a new case of mosaic trisomy 13 with prolonged survival, firstly detected by array-CGH analysis which was carried out because of moderate intellectual disability with postaxial hexadactyly, dermatologic features, ventricular septal defect, bicuspid aortic valve, and aortic dystrophy in a 19-year-old male patient. In a subset of 15% of the cells, the patient carried a derivative chromosome 10 generated by a nonreciprocal (10;13) translocation inherited from his healthy mother who carried the translocation in a balanced and homogeneous state. FISH analyses showed interstitial telomeric sequences at the breakpoints. To our knowledge, this is the second report of a patient with trisomy 13 mosaicism displaying a severe aortic root dilatation. We also discuss the mechanisms which could explain the mosaic state, the most likely one being related to the instability of the interstitial telomere.


Asunto(s)
Aorta/anomalías , Síndrome de Marfan/etiología , Mosaicismo , Síndrome de la Trisomía 13/diagnóstico , Cromosomas Humanos Par 10/genética , Cromosomas Humanos Par 13/genética , Hibridación Genómica Comparativa , Humanos , Hibridación Fluorescente in Situ , Masculino , Translocación Genética , Síndrome de la Trisomía 13/genética , Adulto Joven
9.
Cytogenet Genome Res ; 157(3): 141-147, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30947196

RESUMEN

Chromosomal microarray (CMA) is currently considered as a first-tier test in the genetic assessment of patients presenting with intellectual disability and/or multiple congenital abnormalities. The distinction between pathogenic CNVs, polymorphisms, and variants of unknown significance can be a diagnostic dilemma for cytogeneticists. The size of the CNV has been proposed as a useful criterion. We herein report the characterization of a 13.6-Mb interstitial duplication 20p11.1p12.1, found in a child presenting with mild global developmental delay, by standard karyotype and CMA. Unexpectedly, the same CNV was detected in the patient's mother and pregnant sister, who were healthy. On the basis of these results, an implication of this CNV in the neurological problems observed in the proband was considered to be unlikely. This report underlines the complexity of genetic counseling concerning rare chromosomal abnormalities, when little information is available either in the literature or in international cytogenetic databases.


Asunto(s)
Duplicación Cromosómica , Pintura Cromosómica/métodos , Anomalías Congénitas/genética , Discapacidad Intelectual/genética , Niño , Variaciones en el Número de Copia de ADN , Femenino , Asesoramiento Genético , Humanos , Masculino , Madres , Linaje , Hermanos
10.
11.
Genet Med ; 21(5): 1058-1064, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30245510

RESUMEN

PURPOSE: Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.3 microdeletions that are distinct from previously published deletion syndromes. METHODS: Clinical information on the patients and bioinformatic scores for the deleted genes were analyzed. RESULTS: All individuals in our cohort displayed developmental delay, intellectual disability, and various forms of seizures. Six individuals were microcephalic and two had strabismus. The deletion was absent in all 13 parents who were available for testing. The area of overlap encompasses seven genes including TBC1D24, ATP6V0C, and PDPK1 (also known as PDK1). Bi-allelic TBC1D24 pathogenic variants are known to cause nonsyndromic deafness, epileptic disorders, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). Sanger sequencing of the nondeleted TBC1D24 allele did not yield any additional pathogenic variants. CONCLUSIONS: We propose that 16p13.3 microdeletions resulting in simultaneous haploinsufficiencies of TBC1D24, ATP6V0C, and PDPK1 cause a novel rare contiguous gene deletion syndrome of microcephaly, developmental delay, intellectual disability, and epilepsy.


Asunto(s)
Proteínas Quinasas Dependientes de 3-Fosfoinosítido/genética , Deleción Cromosómica , Discapacidades del Desarrollo/genética , Epilepsia/genética , Proteínas de la Membrana/genética , Microcefalia/genética , Proteínas del Tejido Nervioso/genética , ATPasas de Translocación de Protón Vacuolares/genética , Adolescente , Adulto , Niño , Preescolar , Cromosomas Humanos Par 16 , Estudios de Cohortes , Femenino , Proteínas Activadoras de GTPasa , Humanos , Lactante , Discapacidad Intelectual/genética , Masculino , Síndrome , Adulto Joven
12.
Prenat Diagn ; 39(10): 871-882, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31172545

RESUMEN

OBJECTIVE/METHOD: 1p36 deletion syndrome is considered to be the most common deletion after 22q11.2 deletion. It is characterized by specific facial features, developmental delay, and organ defects. The primary objective of the present multicenter study was to survey all the cases of 1p36 deletion diagnosed prenatally by French cytogenetics laboratories using a chromosomal microarray. We then compared these new cases with the literature data. RESULTS: Ten new cases were reported. On average, the 1p36 deletion was diagnosed at 19 weeks of gestation. The size of the deletion ranged from 1.6 to 16 Mb. The 1p36 deletion was the only chromosomal abnormality in eight cases and was associated with a complex chromosome 1 rearrangement in the two remaining cases. The invasive diagnostic procedure had always been prompted by abnormal ultrasound findings: elevated nuchal translucency, structural brain abnormality, retrognathia, or a cardiac defect. Multiple anomalies were present in all cases. DISCUSSION: We conclude that 1p36 deletion is not associated with any specific prenatal signs. We suggest that a prenatal observation of ventriculomegaly, congenital heart defect, or facial dysmorphism should prompt the clinician to consider a diagnosis of 1p36 deletion syndrome.


Asunto(s)
Trastornos de los Cromosomas/diagnóstico , Diagnóstico Prenatal , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Adulto , Deleción Cromosómica , Trastornos de los Cromosomas/epidemiología , Cromosomas Humanos Par 1/genética , Femenino , Francia/epidemiología , Humanos , Cariotipificación/métodos , Análisis por Micromatrices/métodos , Embarazo , Diagnóstico Prenatal/métodos , Diagnóstico Prenatal/estadística & datos numéricos , Estudios Retrospectivos , Adulto Joven
13.
Prenat Diagn ; 39(6): 464-470, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30896039

RESUMEN

OBJECTIVES: Congenital heart defects (CHDs) may be isolated or associated with other malformations. The use of chromosome microarray (CMA) can increase the genetic diagnostic yield for CHDs by between 4% and 10%. The objective of this study was to evaluate the value of CMA after the prenatal diagnosis of an isolated CHD. METHODS: In a retrospective, nationwide study performed in France, we collected data on all cases of isolated CHD that had been explored using CMAs in 2015. RESULTS: A total of 239 fetuses were included and 33 copy number variations (CNVs) were reported; 19 were considered to be pathogenic, six were variants of unknown significance, and eight were benign variants. The anomaly detection rate was 10.4% overall but ranged from 0% to 16.7% as a function of the isolated CHD in question. The known CNVs were 22q11.21 deletions (n = 10), 22q11.21 duplications (n = 2), 8p23 deletions (n = 2), an Alagille syndrome (n = 1), and a Kleefstra syndrome (n = 1). CONCLUSION: The additional diagnostic yield was clinically significant (3.1%), even when anomalies in the 22q11.21 region were not taken into account. Hence, patients with a suspected isolated CHD and a normal karyotype must be screened for chromosome anomalies other than 22q11.21 duplications and deletions.


Asunto(s)
Pruebas Genéticas/métodos , Cardiopatías Congénitas/genética , Análisis por Micromatrices/métodos , Diagnóstico Prenatal/métodos , Adulto , Aberraciones Cromosómicas , Cromosomas/química , Cromosomas/genética , Hibridación Genómica Comparativa/métodos , Variaciones en el Número de Copia de ADN , Femenino , Feto/química , Feto/metabolismo , Francia , Cardiopatías Congénitas/diagnóstico , Humanos , Cariotipificación , Embarazo , Estudios Retrospectivos , Síndrome
14.
Cytogenet Genome Res ; 153(3): 117-124, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29268249

RESUMEN

We report on a prenatally diagnosed unusual case of inverted terminal duplication of the short arm of chromosome 2, leading to interstitial telomeric sequences (ITSs) and partial trisomy 2p. To our knowledge, there are only 4 further cases of pure partial trisomy 2p reported prenatally. Here, the mother was referred at 22 weeks of gestation for isolated fetal congenital heart malformation at ultrasound. The karyotype of amniotic fluid cells displayed a large duplication of the short arm of chromosome 2 that was further investigated by array-CGH, which detected a 1-copy gain of 43.75 Mb in chromosome 2 at 2p21p25.3. FISH confirmed the presence of an inverted duplication in the short arm of chromosome 2 involving the region 2p21pter and revealed the presence of ITSs at the breakpoint in chromosome 2p21. This report contributes to the prenatal description of the syndrome. We also discuss the possible mechanisms leading to this duplication and the formation of ITSs which are rarely described in constitutional rearrangements.


Asunto(s)
Cromosomas Humanos Par 2/genética , Enfermedades Fetales/genética , Diagnóstico Prenatal , Telómero/genética , Trisomía/genética , Bandeo Cromosómico , Hibridación Genómica Comparativa , Femenino , Enfermedades Fetales/diagnóstico , Humanos , Hibridación Fluorescente in Situ , Embarazo , Trisomía/diagnóstico
15.
Prenat Diagn ; 36(6): 523-9, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27018091

RESUMEN

OBJECTIVE: Sex chromosome aneuploidies are frequently detected fortuitously in a prenatal diagnosis. Most cases of 47, XXX and 47, XYY syndromes are diagnosed in this context, and parents are thus faced with an unexpected situation. The objective of the present study was to characterize a French cohort of prenatally diagnosed cases of 47, XXX and 47, XYY and to evaluate the termination of pregnancy (TOP) rate before and after France's implementation of multidisciplinary centres for prenatal diagnosis in 1997. METHODS: This retrospective study identified respectively 291 and 175 cases of prenatally diagnosed 47, XXX and 47, XYY between 1976 and 2012. For each case, the indication, maternal age, karyotype and outcome were recorded. RESULTS: Most diagnoses of the two conditions were fortuitous. The occurrence of 47, XXX was associated with advanced maternal age. The overall TOP rate was higher for 47, XXX (22.9%) than for 47, XYY (14.6%), although this difference was not statistically significant. However, the TOP rates fell significantly after 1997 (from 41.1% to 11.8% for 47, XXX and from 25.8% to 6.7% for 47, XYY). CONCLUSION: The TOP rates after prenatal diagnoses of 47, XXX and 47, XYY fell significantly after 1997, following France's implementation of multidisciplinary centres for prenatal diagnosis. © 2016 John Wiley & Sons, Ltd.


Asunto(s)
Aborto Inducido/estadística & datos numéricos , Aborto Espontáneo/epidemiología , Resultado del Embarazo/epidemiología , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/epidemiología , Trastornos de los Cromosomas Sexuales/epidemiología , Cariotipo XYY/epidemiología , Aborto Inducido/tendencias , Adulto , Amniocentesis , Muestra de la Vellosidad Coriónica , Cromosomas Humanos X , Estudios de Cohortes , Femenino , Muerte Fetal , Francia/epidemiología , Humanos , Edad Materna , Embarazo , Diagnóstico Prenatal , Estudios Retrospectivos , Aberraciones Cromosómicas Sexuales , Trastornos de los Cromosomas Sexuales/diagnóstico , Trastornos de los Cromosomas Sexuales/diagnóstico por imagen , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/diagnóstico , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/diagnóstico por imagen , Trisomía/diagnóstico , Cariotipo XYY/diagnóstico , Cariotipo XYY/diagnóstico por imagen
16.
Cytogenet Genome Res ; 147(2-3): 111-7, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26669311

RESUMEN

Supernumerary ring chromosomes (SRC) are usually derived from regions adjacent to the centromere. Their identification may be challenging, particularly in case of low mosaicism. Here, we report on a patient who was referred for major in utero growth retardation, severe developmental delay, facial dysmorphism, cleft palate, and hypospadias. The karyotype showed a small SRC in mosaic. The combination of FISH, M-FISH and array-CGH was necessary for a complete characterization of this SRC. M-FISH revealed that the SRC originated from chromosome 7. Array-CGH performed with a 400K oligonucleotide array showed a gain in region 7q22.1q31.1 present in low mosaic. This result was confirmed by FISH using BAC probes specific for chromosome 7. The SRC was a neocentric ring derived from 7q22.1q31.1 and was found in only 8% of the cells. This is the first patient carrying a mosaic neocentric SRC derived from the long arm of chromosome 7. Our study emphasizes the need to combine different techniques and to use adapted bioinformatic tools for low-mosaicism marker identification. It also contributes to the delineation of the partial trisomy 7q phenotype.


Asunto(s)
Anomalías Múltiples/genética , Cromosomas Humanos Par 7/genética , Mosaicismo , Cromosomas en Anillo , Centrómero/genética , Niño , Preescolar , Bandeo Cromosómico , Hibridación Genómica Comparativa , Discapacidades del Desarrollo , Cara/anomalías , Retardo del Crecimiento Fetal , Estudios de Seguimiento , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Cariotipificación , Masculino
17.
Am J Med Genet A ; 167A(1): 164-8, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25425123

RESUMEN

We report here on an 8-year-old girl and her mother, both displaying similar facial dysmorphism, speech delay, and mild to moderate intellectual disability. Array-CGH studies revealed the same interstitial 3q26.32 microdeletion encompassing a single coding gene, TBL1XR1, in both patients. The TBL1XR1 protein, which has four WD40 repeats, has been shown to bind the nuclear corepressor (NCOR) and histone deacetylase-3 complexes (HDAC3). TBL1XR1 mutations have recently been implicated in autism spectrum disorders, but our patients displayed no autistic behavior. Our findings suggest that TBL1XR1 haploinsufficiency can cause intellectual disability with a recognizable dysmorphism, without necessarily causing autistic behavior.


Asunto(s)
Deleción Cromosómica , Facies , Discapacidad Intelectual/genética , Proteínas Nucleares/genética , Receptores Citoplasmáticos y Nucleares/genética , Proteínas Represoras/genética , Adulto , Niño , Preescolar , Cromosomas Humanos Par 3/genética , Hibridación Genómica Comparativa , Femenino , Humanos , Lactante , Recién Nacido , Embarazo , Síndrome
18.
Am J Med Genet A ; 167A(5): 1008-17, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25728055

RESUMEN

Interstitial deletion 1q24q25 is a rare rearrangement associated with intellectual disability, growth retardation, abnormal extremities and facial dysmorphism. In this study, we describe the largest series reported to date, including 18 patients (4M/14F) aged from 2 days to 67 years and comprising two familial cases. The patients presented with a characteristic phenotype including mild to moderate intellectual disability (100%), intrauterine (92%) and postnatal (94%) growth retardation, microcephaly (77%), short hands and feet (83%), brachydactyly (70%), fifth finger clinodactyly (78%) and facial dysmorphism with a bulbous nose (72%), abnormal ears (67%) and micrognathia (56%). Other findings were abnormal palate (50%), single transverse palmar crease (53%), renal (38%), cardiac (38%), and genital (23%) malformations. The deletions were characterized by chromosome microarray. They were of different sizes (490 kb to 20.95 Mb) localized within chromosome bands 1q23.3-q31.2 (chr1:160797550-192912120, hg19). The 490 kb deletion is the smallest deletion reported to date associated with this phenotype. We delineated three regions that may contribute to the phenotype: a proximal one (chr1:164,501,003-167,022,133), associated with cardiac and renal anomalies, a distal one (chr1:178,514,910-181,269,712) and an intermediate 490 kb region (chr1:171970575-172460683, hg19), deleted in the most of the patients, and containing DNM3, MIR3120 and MIR214 that may play an important role in the phenotype. However, this genetic region seems complex with multiple regions giving rise to the same phenotype.


Asunto(s)
Anomalías Múltiples/genética , Deleción Cromosómica , Estudios de Asociación Genética , Discapacidad Intelectual/genética , Anomalías Múltiples/clasificación , Anomalías Múltiples/fisiopatología , Adolescente , Adulto , Anciano , Niño , Preescolar , Cromosomas Humanos Par 1/genética , Hibridación Genómica Comparativa , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Discapacidad Intelectual/clasificación , Discapacidad Intelectual/fisiopatología , Masculino , Persona de Mediana Edad , Fenotipo
19.
Nat Genet ; 38(8): 910-6, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16845400

RESUMEN

Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding any one of its three subunits. Our findings demonstrate a role for ribonuclease H in human neurological disease and suggest an unanticipated relationship between ribonuclease H2 and the antiviral immune response that warrants further investigation.


Asunto(s)
Trastornos Heredodegenerativos del Sistema Nervioso/enzimología , Trastornos Heredodegenerativos del Sistema Nervioso/genética , Ribonucleasa H/genética , Secuencia de Aminoácidos , Secuencia de Bases , ADN/genética , Encefalitis Viral/congénito , Femenino , Humanos , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Mutación , Estructura Cuaternaria de Proteína , Subunidades de Proteína , Ribonucleasa H/química , Ribonucleasa H/metabolismo , Síndrome
20.
J Cell Biochem ; 115(4): 666-77, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24453043

RESUMEN

Interpatient heterogeneity of hepatocellular carcinoma has been in-depth addressed. Intrapatient heterogeneity is less known. Four clones were freshly isolated from an Edmondson grade I HCV-associated hepatocellular carcinoma. Biochemical approaches, functional assays and cytogenetics were used. Albumin inducibility was uncoupled from canonical cytokeratin profiles, suggesting pathological combinations of hepatospecific and biliary markers. Poor differentiation and TGFß's proproliferative effect on all clones were observed. TGFß, Interferon α and doxorubicin sensitivity levels were found highly heterogeneous. Progenitor and stem cells markers OV6 and EpCAM were mutually exclusively expressed. All clones were CD44+, while none expressed CD90, CD133, or CD117. Three clones displayed a liver progenitor OV6+ phenotype, and were susceptible to hepatocytic differentiation, among which one fibroblastoid clone displayed intrahepatic parenchymal engraftment capability. A fourth clone, the less motile, displayed a cancer stem cell EpCAM+ phenotype, was essentially ß-catenin negative, and was as expected devoid of hepatocytic differentiation capability, yet the most sensitive to doxorubicin treatment. Cytogenetics evidenced in all clones a t(12;22)(p11;q11) translocation found in several myelodysplastic syndromes. All clones, that probably derive from EpCAM+ tumor cells, display aberrant E-cadherin cytosolic localization. Because of their diverse pathophysiolocal features, these freshly isolated, low population doubling-defined, HCC clones may provide novel opportunities to tackle HCC heterogeneity in a single patient background for therapy improvement purposes, especially regarding recently developed targeted strategies.


Asunto(s)
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Translocación Genética , Anciano , Animales , Antígenos de Neoplasias , Biomarcadores de Tumor/genética , Cadherinas/genética , Cadherinas/metabolismo , Pruebas de Carcinogenicidad , Moléculas de Adhesión Celular , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Proliferación Celular , Células Clonales , Molécula de Adhesión Celular Epitelial , Femenino , Neoplasias Hematológicas/genética , Humanos , Receptores de Hialuranos/metabolismo , Cariotipificación , Ratones Desnudos , Células Madre/patología , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Células Tumorales Cultivadas , beta Catenina/genética , beta Catenina/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA