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1.
Genet Med ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31578471

RESUMO

PURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated. RESULTS: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. CONCLUSIONS: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.

2.
Hum Pathol ; 92: 81-90, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31437522

RESUMO

Renal cell carcinomas (RCC) are divided in several subtypes, characterized by morphological and histological features, protein expression patterns and genetics criteria. The main subtypes include Clear cell renal cell carcinoma (CCRCC), Papillary RCC (PRCC), Chromophobe RCC (ChRCC), oncocytoma, TFE3 and TFEB Translocation renal cell carcinoma (TRCC). In most cases, RCC can be easily classified according to histological criteria and immunohistochemistry. Nevertheless, the subtyping process can be more complex in some cases: differential diagnosis (CCRCC or TFE3 TRCC, PRCC or TFE3 TRCC, oncocytic tumors corresponding to ChRCC or oncocytoma), molecular confirmation (TFEB TRCC) and unclassified RCC. Complementary analyses are required such as fluorescence in situ hybridization (FISH) for the detection of chromosomal abnormalities associated to each subtype. In this aim, this study assessed the performance of FISH analysis in the histological classification of 359 RCC exhibiting unusual histological characteristics and/or occurring in young people. FISH probes were selected according to the histological features of each tumor. FISH analysis contributed to the histological classification in 73% of the RCC (261/359). Conversely, FISH did not contribute to the diagnosis in 19% of the cases (69/359) and a hybridization failure was observed for the remaining tumors (8%; 29/359). Considering the different RCC subtypes, FISH analysis was highly efficient to confirm the histological diagnosis of CCRCC, PRCC, and TFE3 TRCC and to identify abnormalities of the TFEB gene. However, this strategy showed some limitations for the diagnosis of oncocytic tumors and unclassified RCC, suggesting that additional molecular assays should be evaluated in these cases.

3.
Asian J Androl ; 21(6): 570-576, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031333

RESUMO

Autophagy is involved in spermatogenesis by regulating germ cell maturation. This catabolic process increases with hyperthermic conditions to prevent the accumulation of damaged organelles. Cryptorchidism is associated with impairment of germ cell maturation revealed by the presence of immature forms of sperm cells in ejaculates. The aim of the present study was to evaluate the status of autophagy in sperm cells from cryptorchid patients. Semen samples of cryptorchid patients and normozoospermic controls were analyzed by immunocytochemistry and electron microscopy. Autophagy proteins, autophagy-related protein 9 (ATG9) and microtubule-associated protein, 1A/1B-light chain 3 (LC3) were localized by immunocytochemistry on the acrosome and on the equatorial segment of sperm cells. LC3 was also detected in the midpiece of cryptorchid sperm tail. Autophagy substrate p62 protein was present in the acrosome and in the postequatorial segment of sperm in control samples, but not in the cryptorchid ones. Transmission electron microscopy revealed double-membrane-limited autophagosomes in postequatorial part of spermatozoa head and midpiece in cryptorchid samples. Partly degraded mitochondria were frequently discerned in autophagic vacuoles. In conclusion, autophagy is increased in sperm cells from patients with cryptorchid history comparatively to control. Our work provides insights into the role of autophagy in the maturation and survival of human male gametes in pathological conditions. Thus, regulating autophagy could represent a potential way to improve sperm quality in cryptorchid men.

4.
J Med Genet ; 56(8): 526-535, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30923172

RESUMO

BACKGROUND: Balanced chromosomal rearrangements associated with abnormal phenotype are rare events, but may be challenging for genetic counselling, since molecular characterisation of breakpoints is not performed routinely. We used next-generation sequencing to characterise breakpoints of balanced chromosomal rearrangements at the molecular level in patients with intellectual disability and/or congenital anomalies. METHODS: Breakpoints were characterised by a paired-end low depth whole genome sequencing (WGS) strategy and validated by Sanger sequencing. Expression study of disrupted and neighbouring genes was performed by RT-qPCR from blood or lymphoblastoid cell line RNA. RESULTS: Among the 55 patients included (41 reciprocal translocations, 4 inversions, 2 insertions and 8 complex chromosomal rearrangements), we were able to detect 89% of chromosomal rearrangements (49/55). Molecular signatures at the breakpoints suggested that DNA breaks arose randomly and that there was no major influence of repeated elements. Non-homologous end-joining appeared as the main mechanism of repair (55% of rearrangements). A diagnosis could be established in 22/49 patients (44.8%), 15 by gene disruption (KANSL1, FOXP1, SPRED1, TLK2, MBD5, DMD, AUTS2, MEIS2, MEF2C, NRXN1, NFIX, SYNGAP1, GHR, ZMIZ1) and 7 by position effect (DLX5, MEF2C, BCL11B, SATB2, ZMIZ1). In addition, 16 new candidate genes were identified. Systematic gene expression studies further supported these results. We also showed the contribution of topologically associated domain maps to WGS data interpretation. CONCLUSION: Paired-end WGS is a valid strategy and may be used for structural variation characterisation in a clinical setting.

5.
Hum Mutat ; 40(7): 886-892, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30924587

RESUMO

Premature ovarian insufficiency involves amenorrhea and elevated follicle-stimulating hormone before age 40, and its genetic basis is poorly understood. Here, we study 13 premature ovarian insufficiency (POI) patients using whole-exome sequencing. We identify PREPL and TP63 causative variants, and variants in other potentially novel POI genes. PREPL deficiency is a known cause of syndromic POI, matching the patients' phenotype. A role for TP63 in ovarian biology has previously been proposed but variants have been described in multiorgan syndromes, and not isolated POI. One patient with isolated POI harbored a de novo nonsense TP63 variant in the terminal exon and an unrelated patient had a different nonsense variant in the same exon. These variants interfere with the repression domain while leaving the activation domain intact. We expand the phenotypic spectrum of TP63-related disorders, provide a new genotype:phenotype correlation for TP63 and identify a new genetic cause of isolated POI.

6.
Am J Med Genet A ; 179(6): 993-1000, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30888095

RESUMO

This report presents two families with interstitial 11q24.2q24.3 deletion, associated with malformations, hematologic features, and typical facial dysmorphism, observed in Jacobsen syndrome (JS), except for intellectual disability (ID). The smallest 700 Kb deletion contains only two genes: FLI1 and ETS1, and a long noncoding RNA, SENCR, narrowing the minimal critical region for some features of JS. Consistent with recent literature, it adds supplemental data to confirm the crucial role of FLI1 and ETS1 in JS, namely FLI1 in thrombocytopenia and ETS1 in cardiopathy and immune deficiency. It also supports that combined ETS1 and FLI1 haploinsufficiency explains dysmorphic features, notably ears, and nose anomalies. Moreover, it raises the possibility that SENCR, a long noncoding RNA, could be responsible for limb defects, because of its early role in endothelial cell commitment and function. Considering ID and autism spectrum disorder, which are some of the main features of JS, a participation of ETS1, FLI1, or SENCR cannot be excluded. But, considering the normal neurodevelopment of our patients, their role would be either minor or with an important variability in penetrance. Furthermore, according to literature, ARHGAP32 and KIRREL3 seem to be the strongest candidate genes in the 11q24 region for other Jacobsen patients.

7.
Prenat Diagn ; 39(6): 464-470, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30896039

RESUMO

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.

8.
J Hum Genet ; 63(5): 691-698, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29540854

RESUMO

Ovarian reserve represents the number of available follicles/oocytes within ovaries and it can be assessed by follicle stimulating hormone levels, anti-Müllerian hormone levels, and/or antral follicle count determined by ultrasounds. A low ovarian reserve is defined by an abnormal ovarian reserve test. This condition can be considered premature if it occurs before the age of 40, leading to premature ovarian insufficiency. Despite the growing knowledge concerning the genetic basis of ovarian deficiency, the majority of cases remain without a genetic diagnosis. Although 22q11.2 deletions and duplications have been associated with genitourinary malformations, ovarian deficiency is not a commonly reported feature. We report here four patients bearing a 22q11.2 rearrangement, identified during the clinical assessment of their low ovarian reserve or premature ovarian insufficiency, and discuss the molecular basis of the ovarian defects.


Assuntos
Cromossomos Humanos Par 22 , Reserva Ovariana/genética , Insuficiência Ovariana Primária/diagnóstico , Insuficiência Ovariana Primária/genética , Translocação Genética , Adulto , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Fenótipo
9.
Eur J Hum Genet ; 25(8): 930-934, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28612834

RESUMO

Sex chromosome aneuploidies (SCA) is a group of conditions in which individuals have an abnormal number of sex chromosomes. SCA, such as Klinefelter's syndrome, XYY syndrome, and Triple X syndrome are associated with a large range of neurological outcome. Another genetic event such as another cytogenetic abnormality may explain a part of this variable expressivity. In this study, we have recruited fourteen patients with intellectual disability or developmental delay carrying SCA associated with a copy-number variant (CNV). In our cohort (four patients 47,XXY, four patients 47,XXX, and six patients 47,XYY), seven patients were carrying a pathogenic CNV, two a likely pathogenic CNV and five a variant of uncertain significance. Our analysis suggests that CNV might be considered as an additional independent genetic factor for intellectual disability and developmental delay for patients with SCA and neurodevelopmental disorder.


Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Transtornos dos Cromossomos Sexuais/genética , Trissomia/genética , Cariótipo XYY/genética , Cromossomos Humanos X/genética , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/diagnóstico , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Fenótipo , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/diagnóstico , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/diagnóstico , Trissomia/diagnóstico , Cariótipo XYY/diagnóstico
10.
J Med Genet ; 54(7): 502-510, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28270404

RESUMO

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) represent a significant healthcare burden since it is the primary cause of chronic kidney in children. CNVs represent a recurrent molecular cause of CAKUT but the culprit gene remains often elusive. Our study aimed to define the gene responsible for CAKUT in patients with an 1q23.3q24.1 microdeletion. METHODS: We describe eight patients presenting with CAKUT carrying an 1q23.3q24.1 microdeletion as identified by chromosomal microarray analysis (CMA). Clinical features were collected, especially the renal and urinary tract phenotype, and extrarenal features. We characterised PBX1 expression and localisation in fetal and adult kidneys using quantitative RT-PCR and immunohistochemistry. RESULTS: We defined a 276-kb minimal common region (MCR) that only overlaps with the PBX1 gene. All eight patients presented with syndromic CAKUT. CAKUT were mostly bilateral renal hypoplasia (75%). The most frequent extrarenal symptoms were developmental delay and ear malformations. We demonstrate that PBX1 is strongly expressed in fetal kidneys and brain and expression levels decreased in adult samples. In control fetal kidneys, PBX1 was localised in nuclei of medullary, interstitial and mesenchymal cells, whereas it was present in endothelial cells in adult kidneys. CONCLUSIONS: Our results indicate that PBX1 haploinsufficiency leads to syndromic CAKUT as supported by the Pbx1-null mice model. Correct PBX1 dosage appears to be critical for normal nephrogenesis and seems important for brain development in humans. CMA should be recommended in cases of fetal renal anomalies to improve genetic counselling and pregnancy management.


Assuntos
Haploinsuficiência/genética , Fator de Transcrição 1 de Leucemia de Células Pré-B/genética , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Criança , Pré-Escolar , Feminino , Feto/metabolismo , Genoma Humano , Humanos , Lactente , Rim/anormalidades , Rim/embriologia , Rim/metabolismo , Rim/patologia , Masculino , Síndrome
11.
J Ovarian Res ; 9(1): 63, 2016 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-27716277

RESUMO

BACKGROUND: Ovarian failure (OF) is considered premature if it occurs before the age of 40. This study investigates the genetic aetiology underlying OF in women under the age of 40 years. METHODS: We conducted an experimental prospective study performing all genome microarrays in 60 patients younger than 40 years presenting an OF revealed by a decrease of circulating Anti-Müllerian Hormone (AMH) and leading to an oocyte donation program. RESULTS: We identified nine significant copy number variations (CNVs) including candidate genes potentially implicated in reproductive function. These genes are principally involved in cell division and chromosome segregation (SYCE1, CLASP1, CENP-A, CDC16), in ciliary development and/or function (RSPH1, KIF24), are linked with known gonadal genes or expressed in female genital tract (CSMD1, SEMA6D, KIAA1324). CONCLUSIONS: Our data strengthen the idea that microarrays should be used in combination with karyotype for aetiological assessment of patients with OF. This analysis may have a therapeutic impact as the identification of new molecular actors for gonadal development or ovarian physiology is useful for the prediction of an ovarian reserve decline and makes possible preventive fertility preservation.


Assuntos
Hormônio Antimülleriano/metabolismo , Infertilidade Feminina/genética , Doenças Ovarianas/genética , Ovário/metabolismo , Adulto , Hormônio Antimülleriano/genética , Hibridização Genômica Comparativa , Feminino , Preservação da Fertilidade , Regulação da Expressão Gênica , Humanos , Infertilidade Feminina/metabolismo , Infertilidade Feminina/patologia , Doação de Oócitos/métodos , Doenças Ovarianas/metabolismo , Doenças Ovarianas/patologia , Ovário/crescimento & desenvolvimento
12.
Prenat Diagn ; 36(6): 523-9, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27018091

RESUMO

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.


Assuntos
Aborto Induzido/estatística & dados numéricos , Aborto Espontâneo/epidemiologia , Resultado da Gravidez/epidemiologia , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/epidemiologia , Transtornos dos Cromossomos Sexuais/epidemiologia , Cariótipo XYY/epidemiologia , Aborto Induzido/tendências , Adulto , Amniocentese , Amostra da Vilosidade Coriônica , Cromossomos Humanos X , Estudos de Coortes , Feminino , Morte Fetal , França/epidemiologia , Humanos , Idade Materna , Gravidez , Diagnóstico Pré-Natal , Estudos Retrospectivos , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/diagnóstico , Transtornos dos Cromossomos Sexuais/diagnóstico por imagem , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/diagnóstico , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/diagnóstico por imagem , Trissomia/diagnóstico , Cariótipo XYY/diagnóstico , Cariótipo XYY/diagnóstico por imagem
13.
Eur J Med Genet ; 59(1): 11-5, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26691665

RESUMO

BACKGROUND: While array-comparative genomic hybridization (a-CGH) and next-generation sequencing (NGS or exome) technologies have swiftly spread throughout the medical field, karyotype has gradually lost its leading role among genetic tests. Several international guidelines recommend starting with a-CGH screening then going on with exome analysis when investigating a patient with intellectual disability (ID) and no precise clinical diagnosis. A-CGH and whole exome sequencing increase etiologic diagnoses rate up to 30% in case of ID. However, physicians have to deal with the lack of qualitative information of the genome. Especially, exome and a-CGH analysis fail to detect chromosomal rearrangements because breakpoints are either located in introns or not associated with a gain or loss of genetic material. If these technologies cannot easily identify chromosomal translocations or inversions which sometimes split a gene, karyotype can. DISCUSSION: For the 5 cases described, karyotype provided the right diagnosis for a Mendelian disease while molecular analysis remained unsuccessful. We conclude that when a Mendelian disease is strongly suggested clinically, if molecular analysis is normal, it could be very useful to carry out a karyotype in order to demonstrate a chromosomal rearrangement involving the targeted gene. If this gene is disrupted, the physician can confirm the suspected disease and give appropriate genetic counseling. SUMMARY: This article aims at keeping in mind that karyotype, this old-fashioned genetic tool, can still remain powerful and useful within some genetic issues. Even in this modern period of whole exome sequencing, young geneticists should know that karyotype remains a powerful and cheap technology, available throughout the world and can still do a lot for families.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Cariotipagem/métodos , Adulto , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Recém-Nascido , Cariotipagem/economia , Masculino , Gravidez
14.
Am J Med Genet A ; 167(6): 1252-61, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25847481

RESUMO

Tetrasomy 9p is a generic term describing the presence of a supernumerary chromosome incorporating two copies of the 9p arm. Two varieties exist: isodicentric chromosome 9p (i(9p)), where the two 9p arms are linked by a single centromeric region, and pseudodicentric 9p (idic(9p)), where one active and one inactive centromere are linked together by a proximal segment of 9q that may incorporate euchromatic material. In living patients, i(9p) and idic(9p) are usually present in a mosaic state. Fifty-four cases, including fetuses, have been reported, of which only two have been molecularly characterized using array-CGH. Tetrasomy 9p leads to a variable phenotype ranging from multiple congenital anomalies with severe intellectual disability and growth delay to subnormal cognitive and physical developments. Hypertelorism, abnormal ears, microretrognathia and bulbous nose are the most common dysmorphic traits. Microcephaly, growth retardation, joint dislocation, scoliosis, cardiac and renal anomalies were reported in several cases. Those physical anomalies are often, but not universally, accompanied by intellectual disability. The most recurrent breakpoints, defined by conventional cytogenetics, are 9p10, 9q12 and 9q13. We report on 12 new patients with tetrasomy 9p (3 i(9p), 8 idic(9p) and one structurally uncharacterized), including the first case of parental germline mosaicism. All rearrangements have been characterized by DNA microarray. Based on our results and a review of the literature, we further delineate the prenatal and postnatal clinical spectrum of this imbalance. Our results show poor genotype-phenotype correlations and underline the need of precise molecular characterization of the supernumerary marker.


Assuntos
Anormalidades Múltiplas/genética , Aneuploidia , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Trissomia , Anormalidades Múltiplas/patologia , Adolescente , Criança , Pré-Escolar , Bandeamento Cromossômico , Cromossomos Humanos Par 9 , Deficiências do Desenvolvimento/patologia , Feminino , Feto , Estudos de Associação Genética , Heterogeneidade Genética , Humanos , Deficiência Intelectual/patologia , Cariotipagem , Masculino , Mosaicismo , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Síndrome
15.
Eur J Hum Genet ; 23(8): 1010-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25351778

RESUMO

6q16 deletions have been described in patients with a Prader-Willi-like (PWS-like) phenotype. Recent studies have shown that certain rare single-minded 1 (SIM1) loss-of-function variants were associated with a high intra-familial risk for obesity with or without features of PWS-like syndrome. Although SIM1 seems to have a key role in the phenotype of patients carrying 6q16 deletions, some data support a contribution of other genes, such as GRIK2, to explain associated behavioural problems. We describe 15 new patients in whom de novo 6q16 deletions were characterised by comparative genomic hybridisation or single-nucleotide polymorphism (SNP) array analysis, including the first patient with fetopathological data. This fetus showed dysmorphic facial features, cerebellar and cerebral migration defects with neuronal heterotopias, and fusion of brain nuclei. The size of the deletion in the 14 living patients ranged from 1.73 to 7.84 Mb, and the fetus had the largest deletion (14 Mb). Genotype-phenotype correlations confirmed the major role for SIM1 haploinsufficiency in obesity and the PWS-like phenotype. Nevertheless, only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency. This study in the largest series reported to date confirms that the PWS-like phenotype is strongly linked to 6q16.2q16.3 deletions and varies considerably in its clinical expression. The possible involvement of other genes in the 6q16.2q16.3-deletion phenotype is discussed.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Obesidade/genética , Penetrância , Síndrome de Prader-Willi/genética , Proteínas Repressoras/genética , Feto Abortado , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos Humanos Par 6/genética , Hibridização Genômica Comparativa , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Obesidade/complicações , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/patologia , Gravidez
16.
Prenat Diagn ; 35(1): 35-43, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25118001

RESUMO

OBJECTIVE: Microduplication 22q11.2 is primarily characterized by a highly variable clinical phenotype, which ranges from apparently normal or slightly dysmorphic features (in the presence or absence of learning disorders) to severe malformations with profound mental retardation. Hence, genetic counseling is particularly challenging when microduplication 22q11.2 is identified in a prenatal diagnosis. Here, we report on 24 prenatal cases of microduplication 22q11.2. METHODS: Seventeen of the cases were also reanalyzed by microarray analysis, in order to determine copy number variations (CNVs, which are thought to influence expressivity). We also searched for possible correlations between fetal phenotypes, indications for invasive prenatal diagnosis, inheritance, and pregnancy outcomes. RESULTS: Of the 24 cases, 15 were inherited, six occurred de novo, and three were of unknown origin. Termination of pregnancy occurred in seven cases and was mainly decided on the basis of ultrasound findings. Moreover, additional CNVs were found in some patients and we try to make a genotype-phenotype correlation. CONCLUSION: We discuss the complexity of genetic counseling for microduplication 22q11.2 and comment on possible explanations for the clinical heterogeneity of this syndrome. In particular, we assessed the co-existence of additional CNVs and their contribution to phenotypic variations in chromosome 22q11.2 microduplication syndrome.


Assuntos
Anormalidades Múltiplas/diagnóstico , Síndrome de DiGeorge/diagnóstico , Estudos de Associação Genética , Diagnóstico Pré-Natal/métodos , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/genética , Duplicação Cromossômica/genética , Cromossomos Humanos Par 22/genética , Estudos de Coortes , Hibridização Genômica Comparativa , Análise Citogenética , Síndrome de DiGeorge/epidemiologia , Síndrome de DiGeorge/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Gravidez , Resultado da Gravidez/epidemiologia
17.
Am J Med Genet A ; 164A(10): 2504-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24975584

RESUMO

Inversion duplication and terminal deletion of the long arm of chromosome 13 (inv dup del 13q) is a rare chromosomal rearrangement: only five patients have been reported, mostly involving a ring chromosome 13. We report on additional three fetuses with pure inv dup del 13q: Patient 1 had macrosomia, enlarged kidneys, hypersegmented lungs, unilateral moderate ventriculomegaly, and a mild form of hand and feet preaxial polydactyly; Patient 2 had intrauterine growth retardation, widely spaced eyes, left microphthalmia, right anophthalmia, short nose, bilateral absent thumbs, cutaneous syndactyly of toes 4 and 5, bifid third metacarpal, a small left kidney, hyposegmented lungs, and partial agenesis of the corpus callosum; Patient 3 had widely spaced eyes, long and smooth philtrum, low-set ears, median notch in the upper alveolar ridge, bifid tongue, cutaneous syndactyly of toes 2 and 3, enlarged kidneys and pancreas, arhinencephaly, and partial agenesis of the corpus callosum. We compared the phenotypes of these patients to those previously reported for ring chromosome 13, pure 13q deletions and duplications. We narrowed some critical regions previously reported for lung, kidney and fetal growth, and for thumb, cerebral, and eye anomalies.


Assuntos
Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Inversão Cromossômica/genética , Feto/patologia , Duplicação Gênica/genética , Deleção Cromossômica , Cromossomos Humanos Par 13/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Fenótipo , Cromossomos em Anel
18.
Eur J Med Genet ; 57(5): 195-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24486987

RESUMO

Insertions are rare chromosomal rearrangements resulting from a three breaks mechanism. The risk of chromosomal imbalance in the offspring is estimated to be 15-50%. We have identified a familial history of direct, paracentric intrachromosomal 9q insertion, balanced in healthy members. For intrachromosomal insertions, unbalanced products in the offspring are always recombinants and in our case, reciprocal deletion and duplication of the inserted segment (9q22.31-9q31.1) were observed. These imbalances involved several genes, including PTCH1. PTCH1 haploinsufficiency causes Gorlin syndrome, an autosomal dominant disorder usually linked to the gene mutation but sometimes due to a 9q deletion. Clinical findings are different in 9q deletions and duplications including PTCH1, notably concerning the predisposition to benign and malignant tumors reported in the Gorlin syndrome. Furthermore, some features may be reciprocal. This history of intrachromosomal insertion highlights the importance of morphological cytogenetic analyses to provide an accurate genetic counseling.


Assuntos
Anormalidades Múltiplas/diagnóstico , Cromossomos Humanos Par 9/genética , Deficiências do Desenvolvimento/diagnóstico , Receptores de Superfície Celular/genética , Anormalidades Múltiplas/genética , Adulto , Deleção Cromossômica , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Lactente , Masculino , Mutagênese Insercional , Receptores Patched , Receptor Patched-1 , Linhagem
19.
Eur J Med Genet ; 56(12): 643-7, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24161495

RESUMO

This report concerns a 3-year-old girl with prenatal bilateral nephroblastomatosis and a family history of nephroblastoma. This girl had a chromosome 8 pericentric inversion inherited from her father. This inversion was observed in healthy individuals of the family and was absent in other individuals suffering from embryonic kidney tumor. We then supposed that another genetic anomaly predisposed her to tumorogenesis. Additional cryptic imbalances are reported in cases of apparently balanced chromosomal rearrangements with an abnormal phenotype. Array-CGH analysis showed a 569 kb duplication at 2p24.3 including the DDX1 and MYCN genes. This duplication was inherited from the patient's father who also had a nephroblastoma. A link between germline MYCN duplication and the occurrence of other embryonic cancers such as neuroblastoma has already been described. We supposed that germline DDX1-MYCN duplication could also be involved in the apparition of nephroblastomas.


Assuntos
RNA Helicases DEAD-box/genética , Duplicação Gênica , Mutação em Linhagem Germinativa , Neoplasias Renais/genética , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Tumor de Wilms/genética , Adulto , Carcinogênese/genética , Pré-Escolar , Cromossomos Humanos Par 8/genética , Hibridização Genômica Comparativa , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Renais/diagnóstico , Masculino , Proteína Proto-Oncogênica N-Myc , Linhagem , Tumor de Wilms/diagnóstico
20.
Hum Pathol ; 44(10): 2106-15, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23806527

RESUMO

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer. The aim of this study was to define specific chromosomal imbalances in ccRCC that could be related to clinical or histologic prognostic factors. Tumors and karyotypes of 89 patients who underwent nephrectomy for ccRCC were analyzed from April 2009 to July 2012. The mean number of chromosomal aberrations was significantly higher (7.8; P < .05) in Fuhrman grade 4 (F4) than in F3 (4) and F2 (3.4) cases. The results were similar, considering separately the mean number of chromosomal losses and gains. The F4 cases had a distinct pattern with more frequent losses of chromosomes 9, 13, 14, 18, 21, 22, and Y and gains of chromosome 20. Necrosis was associated with losses of chromosomes 7, 9, 18, and 22; sarcomatoid component, losses of chromosomes 7, 9, and 14 and gains of 20; and T stage, losses of chromosomes 18 and Y. After multivariate analysis, renal fat invasion, renal vein emboli, and microscopic vascular invasion were, respectively, associated with losses of chromosomes 13 and Y, loss of chromosome 13, and loss of chromosome 14 and gains of chromosomes 7 and 20. F4 was independently associated with losses of chromosomes 9 and Y; sarcomatoid component, loss of chromosome 9 and gain of 20; necrosis, loss of chromosome 18; and T stage, loss of chromosome Y. These chromosomal imbalances can be detected routinely by karyotype or fluorescence in situ hybridization analyses to stratify patients for risk of progression.


Assuntos
Aneuploidia , Carcinoma de Células Renais/secundário , Neoplasias Renais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/cirurgia , Feminino , Humanos , Cariótipo , Neoplasias Renais/genética , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Necrose , Gradação de Tumores , Invasividade Neoplásica , Nefrectomia , Prognóstico , Estudos Prospectivos
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