RESUMO
Syndromic obesity is defined by the association of obesity with one or more feature(s) including developmental delay, dysmorphic traits, and/or congenital malformations. Over 25 syndromic forms of obesity have been identified. However, most cases remain of unknown etiology. The aim of this study was to identify new candidate loci associated with syndromic obesity to find new candidate genes and to better understand molecular mechanisms involved in this pathology. We performed oligonucleotide microarray-based comparative genomic hybridization in a cohort of 100 children presenting with syndromic obesity of unknown etiology, after exhaustive clinical, biological, and molecular studies. Chromosomal copy number variations were detected in 42% of the children in our cohort, with 23% of patients with potentially pathogenic copy number variants. Our results support that chromosomal rearrangements are frequently associated with syndromic obesity with a variety of contributory genes having relevance to either obesity or developmental delay. A list of inherited or apparently de novo duplications and deletions including their enclosed genes and not previously linked to syndromic obesity was established. Proteins encoded by several of these genes are involved in lipid metabolism (ACOXL, MSMO1, MVD, and PDZK1) linked with nervous system function (BDH1 and LINGO2), neutral lipid storage (PLIN2), energy homeostasis and metabolic processes (CDH13, CNTNAP2, CPPED1, NDUFA4, PTGS2, and SOCS6).
Assuntos
Obesidade/diagnóstico , Obesidade/genética , Fenótipo , Locos de Características Quantitativas , Criança , Pré-Escolar , Aberrações Cromossômicas , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Expressão Gênica , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Genômica , Humanos , Lactente , Masculino , SíndromeRESUMO
Filaminopathies A caused by mutations in the X-linked FLNA gene are responsible for a wide spectrum of rare diseases including 2 main phenotypes, the X-linked dominant form of periventricular nodular heterotopia (FLNA-PVNH) and the otopalatodigital syndrome spectrum of disorders. In platelets, filamin A (FLNa) tethers the principal receptors ensuring the platelet-vessel wall interaction, glycoprotein Ibα and integrin αIIbß3, to the underlying cytoskeleton. Hemorrhage, coagulopathy, and thrombocytopenia are mentioned in several reports on patients with FLNA-PVNH. Abnormal platelet morphology in 2 patients with FLNA-PVNH prompted us to examine a third patient with similar platelet morphology previously diagnosed with immunologic thrombocytopenic purpura. Her enlarged platelets showed signs of FLNa degradation in Western blotting, and a heterozygous missense mutation in FLNA was detected. An irregular distribution of FLNa within the total platelet population was shown by confocal microscopy for all 3 patients. In vitro megakaryocyte cultures showed an abnormal differentiation, including an irregular distribution of FLNa with a frayed aspect, the presence of enlarged α-granules, and an abnormal fragmentation of the cytoplasm. Mutations in FLNA may represent an unrecognized cause of macrothrombocytopenia with an altered platelet production and a modified platelet-vessel wall interaction.
Assuntos
Proteínas Contráteis/genética , Proteínas dos Microfilamentos/genética , Mutação , Trombocitopenia/classificação , Trombocitopenia/genética , Idoso , Células Cultivadas , Feminino , Filaminas , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Mutação/fisiologia , Contagem de Plaquetas , Síndrome , Trombocitopenia/sangue , Trombocitopenia/diagnósticoRESUMO
Patients with a submicroscopic deletion at 1q43q44 present with intellectual disability (ID), microcephaly, craniofacial anomalies, seizures, limb anomalies, and corpus callosum abnormalities. However, the precise relationship between most of deleted genes and the clinical features in these patients still remains unclear. We studied 11 unrelated patients with 1q44 microdeletion. We showed that the deletions occurred de novo in all patients for whom both parents' DNA was available (10/11). All patients presented with moderate to severe ID, seizures and non-specific craniofacial anomalies. By oligoarray-based comparative genomic hybridization (aCGH) covering the 1q44 region at a high resolution, we obtained a critical deleted region containing two coding genes-HNRNPU and FAM36A-and one non-coding gene-NCRNA00201. All three genes were expressed in different normal human tissues, including in human brain, with highest expression levels in the cerebellum. Mutational screening of the HNRNPU and FAM36A genes in 191 patients with unexplained isolated ID did not reveal any deleterious mutations while the NCRNA00201 non-coding gene was not analyzed. Nine of the 11 patients did not present with microcephaly or corpus callosum abnormalities and carried a small deletion containing HNRNPU, FAM36A, and NCRNA00201 but not AKT3 and ZNF238, two centromeric genes. These results suggest that HNRNPU, FAM36A, and NCRNA00201 are not major genes for microcephaly and corpus callosum abnormalities but are good candidates for ID and seizures.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 1 , Ribonucleoproteínas Nucleares Heterogêneas Grupo U/genética , Deficiência Intelectual/genética , RNA não Traduzido/genética , Convulsões/genética , Pré-Escolar , Hibridização Genômica Comparativa , Fácies , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Cariotipagem , Masculino , MutaçãoRESUMO
Oculocutaneous albinism type 2 (OCA2) represents about 30% of OCA worldwide. Using quantitative multiplex fluorescent PCR and very high-resolution array-CGH focussed on the OCA2 gene and surrounding regions in 15q12, we identified new rearrangements. Deletion 1, encompassing exons 3-20, was present in three patients (including one in the homozygous state), and Deletion 2 (exons 1-20) was found in one patient (heterozygous state). The duplication (exons 3-20) was found in one patient in the homozygous state. Using 14 microsatellite markers we determined haplotypes associated with these rearrangements. Deletion 1 was associated with the same haplotype in three patients who were all of Polish origin, which is strongly in favour of a founder effect. Deletion 2 was associated with a distinct haplotype. The homozygous duplication was inherited from the two unrelated parents of the patients on two different haplotypes. Analysis of the sequences around the breakpoints of these rearrangements showed that all occurred within complex arrays of repetitive sequences. The combined use of very high-resolution array-CGH and of microsatellites (including new intragenic ones described here) constitutes a powerful approach for the precise characterization of OCA2 rearrangements, which have been found in more than 20% of OCA2 patients.
Assuntos
Deleção de Genes , Proteínas de Membrana Transportadoras/genética , Albinismo Oculocutâneo/etnologia , Albinismo Oculocutâneo/genética , Efeito Fundador , Haplótipos , Humanos , Repetições de Microssatélites , Análise de Sequência com Séries de Oligonucleotídeos/métodos , População Branca/genéticaRESUMO
Oculoauriculovertebral spectrum (OAVS) is a clinically and genetically heterogeneous congenital disorder. We performed high density oligonucleotide array-CGH on 86 OAVS patients and identified in 11 patients 12 novel genomic rearrangements (4 deletions and 8 duplications) ranging in size from 2.7 kb to 2.3 Mb. We discuss the potential pathogenic role of these chromosomal aberrations, and describe new candidate regions for OAVS.
Assuntos
Aberrações Cromossômicas , Perfilação da Expressão Gênica , Síndrome de Goldenhar/genética , Análise de Sequência com Séries de Oligonucleotídeos , Adolescente , Adulto , Biomarcadores/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Hibridização Genômica Comparativa , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Adulto JovemRESUMO
The SNORD116 locus lies in the 15q11-13 region of paternally expressed genes implicated in Prader-Willi Syndrome (PWS), a complex disease accompanied by obesity and severe neurobehavioural disturbances. Cases of PWS patients with a deletion encompassing the SNORD116 gene cluster, but preserving the expression of flanking genes, have been described. We report a 23-year-old woman who presented clinical criteria of PWS, including the behavioural and nutritional features, obesity, developmental delay and endocrine dysfunctions with hyperghrelinemia. We found a paternally transmitted highly restricted deletion of the SNORD116 gene cluster, the shortest described to date (118 kb). This deletion was also present in the father. This finding in a human case strongly supports the current hypothesis that lack of the paternal SNORD116 gene cluster has a determinant role in the pathogenesis of PWS. Moreover, targeted analysis of the SNORD116 gene cluster, complementary to SNRPN methylation analysis, should be carried out in subjects with a phenotype suggestive of PWS.
Assuntos
Deleção de Genes , Síndrome de Prader-Willi/genética , RNA Nucleolar Pequeno/genética , Adulto , Feminino , Humanos , Masculino , Síndrome de Prader-Willi/diagnóstico , RNA Nucleolar Pequeno/metabolismoRESUMO
Oculocutaneous albinism (OCA) is caused by mutations in six different genes, and their molecular diagnosis encompasses the search for point mutations and intragenic rearrangements. Here, we used high-resolution array-comparative genome hybridization (CGH) to search for rearrangements across exons, introns and regulatory sequences of four OCA genes: TYR, OCA2, TYRP1, and SLC45A2. We identified a total of ten new deletions in TYR, OCA2, and SLC45A2. A complex rearrangement of OCA2 was found in two unrelated patients. Whole-genome sequencing showed deletion of a 184-kb fragment (identical to a deletion previously found in Polish patients), whereby a large portion of the deleted sequence was re-inserted after severe reshuffling into intron 1 of OCA2. The high-resolution array-CGH presented here is a powerful tool to detect gene rearrangements. Finally, we review all known deletions of the OCA1-4 genes reported so far in the literature and show that deletions or duplications account for 5.6% of all mutations identified in the OCA1-4 genes.
Assuntos
Albinismo Oculocutâneo/genética , Antígenos de Neoplasias/genética , Sequência de Bases , Proteínas de Membrana Transportadoras/genética , Monofenol Mono-Oxigenase/genética , Deleção de Sequência , Hibridização Genômica Comparativa , Estudo de Associação Genômica AmplaRESUMO
Obesity is a common but highly, clinically, and genetically heterogeneous disease. Deletion of the terminal region of the short arm of chromosome 2 is rare and has been reported in about 13 patients in the literature often associated with a Prader-Willi-like phenotype. We report on five unrelated patients with 2p25 deletion of paternal origin presenting with early-onset obesity, hyperphagia, intellectual deficiency, and behavioural difficulties. Among these patients, three had de novo pure 2pter deletions, one presented with a paternal derivative der(2)t(2;15)(p25.3;q26) with deletion in the 2pter region and the last patient presented with an interstitial 2p25 deletion. The size of the deletions was characterized by SNP array or array-CGH and was confirmed by fluorescence in situ hybridization (FISH) studies. Four patients shared a 2p25.3 deletion with a minimal critical region estimated at 1.97 Mb and encompassing seven genes, namely SH3HYL1, ACP1, TMEMI8, SNTG2, TPO, PXDN, and MYT1L genes. The fifth patient had a smaller interstitial deletion encompassing the TPO, PXDN, and MYT1L genes. Paternal origin of the deletion was determined by genotyping using microsatellite markers. Analysis of the genes encompassed in the deleted region led us to speculate that the ACP1, TMEM18, and/or MYT1L genes might be involved in early-onset obesity. In addition, intellectual deficiency and behavioural troubles can be explained by the heterozygous loss of the SNTG2 and MYT1L genes. Finally, we discuss the parent-of-origin of the deletion.
Assuntos
Cromossomos Humanos Par 2/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Obesidade/genética , Proteínas Tirosina Fosfatases/genética , Proteínas Proto-Oncogênicas/genética , Deleção de Sequência , Fatores de Transcrição/genética , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hibridização in Situ Fluorescente , Masculino , Obesidade/complicações , Obesidade/diagnóstico , Fenótipo , Polimorfismo de Nucleotídeo Único , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/genética , Análise de Sequência de DNARESUMO
Array-CGH or Chromosomal Microarray Analysis (CMA) is increasingly used in prenatal diagnosis throughout the world. However, routine practices are very different among centers and countries, regarding CMA indications, design and resolution of microarrays, notification and interpretation of Copy Number Alterations (CNA). We present our data and experience from our Fetal Medicine Center on 224 prospective prenatal diagnoses. Our approach is practical, and aims to propose a strategy to offer Chromosomal Microarray Analysis (CMA) to selected fetuses and to help to interpret CNA. We hope that this publication could encourage development of CMA in centers that have not started yet this activity in prenatal routine, and could contribute to edict guidelines in this field.
Assuntos
Hibridização Genômica Comparativa , Diagnóstico Pré-Natal/métodos , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Cromossomos Humanos , Variações do Número de Cópias de DNA , Feminino , França , Testes Genéticos , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez , Estudos ProspectivosRESUMO
We report on a boy presenting with features of OAVS (Oculoauriculovertebral spectrum) and carrying a 1.5 Mb microdeletion in 15q24.1q24.2. This recurrent deletion usually leads to a broad clinical spectrum but has never been found associated with features of OAVS such as ear agenesis. This observation is in accordance with OAVS being a genetically heterogeneous disorder, and points out the importance of array-CGH screening in this disorder.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Síndrome de Goldenhar/genética , Hibridização Genômica Comparativa , Humanos , Masculino , FenótipoRESUMO
We report a 19 year-old patient carrying a terminal 20p microdeletion. She displayed clinical features resembling those of two other previously described patients. We suggest that a specific phenotype can be associated with this chromosomal anomaly. Mental retardation, epilepsy, and dysmorphic signs including low-set ears and overfolded helices seem highly characteristic of this syndrome and may define major diagnostic criteria of a recognizable phenotype. Delayed closure of fontanella, delayed permanent teeth eruption, visual disturbances, prominent ear lobes, prominent nasal root and ridge, thin upper lip and brachydactyly may represent inconstant minor criteria.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Deleção Cromossômica , Cromossomos Humanos Par 20/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Anormalidades Múltiplas/genética , Adolescente , Feminino , Humanos , Proteína Jagged-1 , Fenótipo , Proteínas Serrate-JaggedAssuntos
Albinismo/genética , Proteínas do Olho/genética , Loci Gênicos , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Mutação/genética , Deleção Cromossômica , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Masculino , Linhagem , FenótipoRESUMO
Metanephric stromal tumor is a rare benign entity belonging to the group of metanephric renal tumors in children. Although metanephric stromal tumors can be cured by simple nephrectomy, differential diagnosis based on histopathologic criteria with other pediatric renal tumors requiring aggressive chemotherapy can be difficult. To our knowledge, cytogenetic characterization of metanephric stromal tumor has never been reported. We describe conventional ("R-bands" karyotyping) and molecular [fluorescence in situ hybridization (FISH), multicolor FISH, oligo array-comparative genomic hybridization] cytogenetic examinations of a metanephric stromal tumor in a 3-year-old boy. Cytogenetic analysis revealed a complex homogeneous gain between bands 17q22 and 17q25.3, resulting in partial triplication of the segment between bands 17q22 and 17q24.3, and duplication of the segment between bands 17q24.3 and 17q25.3. Cytogenetic confirmatory studies in metanephric stromal tumors are currently needed to assess 17q22q25.3 gain as a recurring cytogenetic abnormality of metanephric stromal tumors.