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1.
Prenat Diagn ; 39(11): 986-992, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31273809

RESUMO

OBJECTIVE: Uniparental disomy (UPD) testing is currently recommended during pregnancy in fetuses carrying a balanced Robertsonian translocation (ROB) involving chromosome 14 or 15, both chromosomes containing imprinted genes. The overall risk that such a fetus presents a UPD has been previously estimated to be around ~0.6-0.8%. However, because UPD are rare events and this estimate has been calculated from a number of studies of limited size, we have reevaluated the risk of UPD in fetuses for whom one of the parents was known to carry a nonhomologous ROB (NHROB). METHOD: We focused our multicentric study on NHROB involving chromosome 14 and/or 15. A total of 1747 UPD testing were performed in fetuses during pregnancy for the presence of UPD(14) and/or UPD(15). RESULT: All fetuses were negative except one with a UPD(14) associated with a maternally inherited rob(13;14). CONCLUSION: Considering these data, the risk of UPD following prenatal diagnosis of an inherited ROB involving chromosome 14 and/or 15 could be estimated to be around 0.06%, far less than the previous estimation. Importantly, the risk of miscarriage following an invasive prenatal sampling is higher than the risk of UPD. Therefore, we do not recommend prenatal testing for UPD for these pregnancies and parents should be reassured.

2.
Am J Hum Genet ; 104(6): 1210-1222, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31079897

RESUMO

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

4.
Genet Med ; 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30206421

RESUMO

PURPOSE: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences. METHODS: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms. RESULTS: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments. CONCLUSION: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.

5.
Eur J Hum Genet ; 26(10): 1497-1501, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29899371

RESUMO

Helsmoortel-van der Aa (SWI/SNF autism-related or ADNP syndrome) is an autosomal dominant monogenic syndrome caused by de novo variants in the last exon of ADNP gene and no deletions have been documented to date. We report the first case of a 3 years and 10 months old boy exhibiting typical features of ADNP syndrome, including intellectual disability, autistic traits, facial dysmorphism, hyperlaxity, mood disorder, behavioral problems, and severe chronic constipation. 60K Agilent array-comparative genomic hybridization (CGH) identified a heterozygous interstitial microdeletion at 20q13.13 chromosome region, encompassing ADNP and DPM1. Taking into account the clinical phenotype of previously reported cases with ADNP single-point variants, genotype-phenotype correlation in the proband was established and the diagnosis of Helsmoortel-van der Aa syndrome was made. Our report thus confirms that ADNP haploinsufficiency is associated with Helsmoortel-van der Aa syndrome as well as highlights the utility of whole-genome array-CGH for detection of unbalanced submicroscopic chromosomal rearrangements in routine clinical setting in patients with unexplained intellectual disability and/or syndromic autism.

6.
Am J Med Genet B Neuropsychiatr Genet ; 177(4): 397-405, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29603867

RESUMO

Recurrent deletions and duplications at the 2q13 locus have been associated with developmental delay (DD) and dysmorphisms. We aimed to undertake detailed clinical characterization of individuals with 2q13 copy number variations (CNVs), with a focus on behavioral and psychiatric phenotypes. Participants were recruited via the Unique chromosomal disorder support group, U.K. National Health Service Regional Genetics Centres, and the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) database. A review of published 2q13 patient case reports was undertaken to enable combined phenotypic analysis. We present a new case series of 2q13 CNV carriers (21 deletion, 4 duplication) and the largest ever combined analysis with data from published studies, making a total of 54 deletion and 23 duplication carriers. DD/intellectual disabilities was identified in the majority of carriers (79% deletion, 70% duplication), although in the new cases 52% had an IQ in the borderline or normal range. Despite the median age of the new cases being only 9 years, 64% had a clinical psychiatric diagnosis. Combined analysis found attention deficit hyperactivity disorder (ADHD) to be the most frequent diagnosis (48% deletion, 60% duplication), followed by autism spectrum disorders (33% deletion, 17% duplication). Aggressive (33%) and self-injurious behaviors (33%) were also identified in the new cases. CNVs at 2q13 are typically associated with DD with mildly impaired intelligence, and a high rate of childhood psychiatric diagnoses-particularly ADHD. We have further characterized the clinical phenotype related to imbalances of the 2q13 region and identified it as a region of interest for the neurobiological investigation of ADHD.

7.
PLoS Genet ; 13(8): e1006957, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28859103

RESUMO

Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms "mental retardation". To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus.


Assuntos
Regulação da Expressão Gênica/genética , Hipotálamo/fisiologia , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Obesidade/genética , Fatores de Transcrição/genética , Adulto , Animais , Sistemas CRISPR-Cas , Linhagem Celular , Criança , Deleção Cromossômica , Cromossomos Humanos Par 2/genética , Feminino , Técnicas de Inativação de Genes , Humanos , Hipotálamo/metabolismo , Hipotálamo/patologia , Deficiência Intelectual/fisiopatologia , Masculino , Mutação , Obesidade/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética , Peixe-Zebra
8.
Eur J Hum Genet ; 24(1): 51-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25944382

RESUMO

We report on seven novel patients with a submicroscopic 22q12 deletion. The common phenotype constitutes a contiguous gene deletion syndrome on chromosome 22q12.1q12.2, featuring NF2-related schwannoma of the vestibular nerve, corpus callosum agenesis and palatal defects. Combining our results with the literature, eight patients are recorded with palatal defects in association with haploinsufficiency of 22q12.1, including the MN1 gene. These observations, together with the mouse expression data and the finding of craniofacial malformations including cleft palate in a Mn1-knockout mouse model, suggest that this gene is a candidate gene for cleft palate in humans.


Assuntos
Agenesia do Corpo Caloso/genética , Deleção Cromossômica , Cromossomos Humanos Par 22 , Fissura Palatina/genética , Neuroma Acústico/genética , Proteínas Supressoras de Tumor/deficiência , Adolescente , Agenesia do Corpo Caloso/diagnóstico , Agenesia do Corpo Caloso/metabolismo , Animais , Criança , Pré-Escolar , Mapeamento Cromossômico , Fissura Palatina/diagnóstico , Fissura Palatina/metabolismo , Feminino , Expressão Gênica , Haploinsuficiência , Humanos , Masculino , Camundongos , Camundongos Knockout , Neuroma Acústico/diagnóstico , Neuroma Acústico/metabolismo , Análise de Sequência de DNA , Proteínas Supressoras de Tumor/genética
9.
Am J Med Genet A ; 167A(1): 111-22, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25425167

RESUMO

Array comparative genomic hybridization (array CGH) has proven its utility in uncovering cryptic rearrangements in patients with X-linked intellectual disability. In 2009, Giorda et al. identified inherited and de novo recurrent Xp11.23p11.22 microduplications in two males and six females from a wide cohort of patients presenting with syndromic intellectual disability. To date, 14 females and 5 males with an overlapping microduplication have been reported in the literature. To further characterize this emerging syndrome, we collected clinical and microarray data from 17 new patients, 10 females, and 7 males. The Xp11.23p11.2 microduplications detected by array CGH ranged in size from 331 Kb to 8.9 Mb. Five patients harbored 4.5 Mb recurrent duplications mediated by non-allelic homologous recombination between segmental duplications and 12 harbored atypical duplications. The chromosomal rearrangement occurred de novo in eight patients and was inherited in six affected males from three families. Patients shared several common major characteristics including moderate to severe intellectual disability, early onset of puberty, language impairment, and age related epileptic syndromes such as West syndrome and focal epilepsy with activation during sleep evolving in some patients to continuous spikes-and-waves during slow sleep. Atypical microduplications allowed us to identify minimal critical regions that might be responsible for specific clinical findings of the syndrome and to suggest possible candidate genes: FTSJ1 and SHROOM4 for intellectual disability along with PQBP1 and SLC35A2 for epilepsy. Xp11.23p11.22 microduplication is a recently-recognized syndrome associated with intellectual disability, epilepsy, and early onset of puberty in females. In this study, we propose several genes that could contribute to the phenotype.


Assuntos
Cromossomos Humanos X/genética , Estudos de Associação Genética , Duplicações Segmentares Genômicas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Mapeamento Cromossômico , Hibridização Genômica Comparativa , Eletroencefalografia , Epilepsia/genética , Feminino , Humanos , Masculino , Fenótipo
10.
BMC Med Genet ; 15: 128, 2014 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-25472632

RESUMO

BACKGROUND: Point mutations or genomic deletions of FOXF1 result in a lethal developmental lung disease Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. However, the clinical consequences of the constitutively increased dosage of FOXF1 are unknown. METHODS: Copy-number variations and their parental origin were identified using a combination of array CGH, long-range PCR, DNA sequencing, and microsatellite analyses. Minisatellite sequences across different species were compared using a gready clustering algorithm and genome-wide analysis of the distribution of minisatellite sequences was performed using R statistical software. RESULTS: We report four unrelated families with 16q24.1 duplications encompassing entire FOXF1. In a 4-year-old boy with speech delay and a café-au-lait macule, we identified an ~15 kb 16q24.1 duplication inherited from the reportedly healthy father, in addition to a de novo ~1.09 Mb mosaic 17q11.2 NF1 deletion. In a 13-year-old patient with autism and mood disorder, we found an ~0.3 Mb duplication harboring FOXF1 and an ~0.5 Mb 16q23.3 duplication, both inherited from the father with bipolar disorder. In a 47-year old patient with pyloric stenosis, mesenterium commune, and aplasia of the appendix, we identified an ~0.4 Mb duplication in 16q24.1 encompassing 16 genes including FOXF1. The patient transmitted the duplication to her daughter, who presented with similar symptoms. In a fourth patient with speech and motor delay, and borderline intellectual disability, we identified an ~1.7 Mb FOXF1 duplication adjacent to a large minisatellite. This duplication has a complex structure and arose de novo on the maternal chromosome, likely as a result of a DNA replication error initiated by the adjacent large tandem repeat. Using bioinformatic and array CGH analyses of the minisatellite, we found a large variation of its size in several different species and individuals, demonstrating both its evolutionarily instability and population polymorphism. CONCLUSIONS: Our data indicate that constitutional duplication of FOXF1 in humans is not associated with any pediatric lung abnormalities. We propose that patients with gut malrotation, pyloric or duodenal stenosis, and gall bladder agenesis should be tested for FOXF1 alterations. We suggest that instability of minisatellites greater than 1 kb can lead to structural variation due to DNA replication errors.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 16/genética , Fatores de Transcrição Forkhead/genética , Duplicação Gênica , Anormalidades Múltiplas/patologia , Adolescente , Animais , Pré-Escolar , Evolução Molecular , Feminino , Dosagem de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites , Linhagem
11.
Obesity (Silver Spring) ; 22(12): 2621-4, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25234154

RESUMO

OBJECTIVE: Several deletions of chromosome 6q, including SIM1, were reported in obese patients with developmental delay. Furthermore, rare loss-of-function SIM1 mutations were shown to contribute to severe obesity, yet the role of these mutations in developmental delay remained unclear. Here, SIM1 in children with neurodevelopmental abnormalities was screened and the functional effect of the identified mutations was investigated. METHODS: SIM1 was sequenced in 283 children presenting with developmental delay and at least overweight. The effect of the identified mutations on SIM1 transcriptional activity in stable human cell lines was assessed using luciferase gene reporter assays. RESULTS: Two novel mutations (c.886A>G/p.R296G and c.925A>G/p.S309G) in two boys with variable degrees of cognitive deficits and weight issues were identified. The child mutated for p.R296G presented with a generally more severe phenotype than the p.S309G carrier (obesity, compulsive eating, neonatal hypotonia versus overweight only), while both mutations had strong loss-of-function effects on SIM1 transcriptional activity. CONCLUSIONS: Severe loss-of-function SIM1 mutations can be associated with a spectrum of developmental delay phenotypes and obesity. Our data suggest that SIM1 sequencing should be performed more systematically in patients with developmental delay, even in the absence of severe obesity. These results deserve further SIM1 screening studies.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Deficiências do Desenvolvimento/genética , Obesidade Mórbida/genética , Proteínas Repressoras/genética , Criança , Análise Mutacional de DNA , Deficiências do Desenvolvimento/complicações , Feminino , Humanos , Luciferases/genética , Masculino , Obesidade Mórbida/complicações , Obesidade Mórbida/fisiopatologia , Fenótipo , Ativação Transcricional
12.
Eur J Med Genet ; 56(8): 420-5, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23727450

RESUMO

Autism Spectrum Disorders (ASD) are complex neurodevelopmental conditions characterized by delays in social interactions and communication as well as displays of restrictive/repetitive interests. DNA copy number variants have been identified as a genomic susceptibility factor in ASDs and imply significant genetic heterogeneity. We report a 7-year-old female with ADOS-G and ADI-R confirmed autistic disorder harbouring a de novo 4 Mb duplication (18q12.1). Our subject displays severely deficient expressive language, stereotypic and repetitive behaviours, mild intellectual disability (ID), focal epilepsy, short stature and absence of significant dysmorphic features. Search of the PubMed literature and DECIPHER database identified 4 additional cases involving 18q12.1 associated with autism and/or ID that overlap our case: one duplication, two deletions and one balanced translocation. Notably, autism and ID are seen with genomic gain or loss at 18q12.1, plus epilepsy and short stature in duplication cases, and hypotonia and tall stature in deletion cases. No consistent dysmorphic features were noted amongst the reviewed cases. We review prospective ASD/ID candidate genes integral to 18q12.1, including those coding for the desmocollin/desmoglein cluster, ring finger proteins 125 and 138, trafficking protein particle complex 8 and dystrobrevin-alpha. The collective clinical and molecular features common to microduplication 18q12.1 suggest that dosage-sensitive, position or contiguous gene effects may be associated in the etiopathogenesis of this autism-ID-epilepsy syndrome.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Variações do Número de Cópias de DNA , Estudos de Associação Genética , Trissomia , Criança , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Cromossomos Humanos Par 18 , Hibridização Genômica Comparativa , Facies , Feminino , Humanos
13.
Eur J Med Genet ; 54(2): 194-7, 2011 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21145994

RESUMO

Interstitial 18q deletions encompassing band 18q12.3 define the del(18)(q12.2q21.1) syndrome. Usual manifestations are mild dysmorphic features, mental retardation, behaviour abnormalities and lack of serious malformation. Seizures have also been found. Recently, more specifically, impairment of expressive language has been reported. We report on two patients with de novo 18q interstitial deletions characterized by oligonucleotide array CGH. The smallest, a 5.3Mb deletion (35.7-40.9Mb) within band q12.3, was found in a 4-year-old girl who suffered mainly from expressive dysphasia. A larger 9.5Mb deletion (34.6-43.9Mb) was observed in a 20-year-old man with a more severe clinical picture including seizures and limited speech. Among the four genes located in the 5.3Mb region, RIT2 (Ras-like without CAAX 2) and SYT4 (synaptotagmin IV), both strongly expressed in the brain, are pointed out as likely candidate genes for language development.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 18 , Transtornos do Desenvolvimento da Linguagem/genética , Feminino , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Sinaptotagminas , Adulto Jovem
14.
Hum Genet ; 129(2): 199-208, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21085994

RESUMO

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 , Grupo com Ancestrais do Continente Europeu/genética , Efeito Fundador , Haplótipos , Humanos , Repetições de Microssatélites , Análise de Sequência com Séries de Oligonucleotídeos/métodos
15.
Eur J Med Genet ; 54(2): 144-51, 2011 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21094706

RESUMO

Chromosome 17q21.31 microdeletion was one of the first genomic disorders identified by chromosome microarrays. We report here the clinical and molecular characterization of a new series of 14 French patients with this microdeletion syndrome. The most frequent clinical features were hypotonia, developmental delay and facial dysmorphism, but scaphocephaly, prenatal ischemic infarction and perception deafness were also described. Genotyping of the parents showed that the parent from which the abnormality was inherited carried the H2 inversion polymorphism, confirming that the H2 allele is necessary, but not sufficient to generate the 17q21.31 microdeletion. Previously reported molecular analyses of patients with 17q21.31 microdeletion syndrome defined a 493 kb genomic fragment that was deleted in most patients after taking into account frequent copy number variations in normal controls, but the deleted interval was significantly smaller (205 kb) in one of our patients, encompassing only the MAPT, STH and KIAA1267 genes. As this patient presents the classical phenotype of 17q21.31 syndrome, these data make it possible to define a new minimal critical region of 160.8 kb, strengthening the evidence for involvement of the MAPT gene in this syndrome.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 17/genética , Deficiência Intelectual/genética , Sequência de Bases , Deficiências do Desenvolvimento/genética , França , Humanos , Hipotonia Muscular/genética , Proteínas tau/genética
16.
Eur J Med Genet ; 52(5): 291-6, 2009 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19505601

RESUMO

Investigations of apparently balanced chromosomal rearrangements in patients with abnormal phenotype by molecular cytogenetics tools, especially by array CGH, revealed a proportion of unsuspected imbalances. It was estimated recently that 40% of apparently balanced de novo translocations with abnormal phenotype were associated with cryptic deletion. We explored 47 unrelated mental retardation patients carrying an apparently balanced chromosomal rearrangement with high-resolution oligonucleotides arrays. We included 33 de novo cases (21 translocations, 7 inversions and 5 complex chromosomal rearrangements (CCR)) and 14 inherited cases (7 translocations, 5 inversions and 2 CCR). Twenty of the 47 cases (42.6%) carried a cryptic deletion ranging from 60 kb to 15.37 Mb. It concerned 16/33 de novo rearrangements (8/21 translocations, 4/7 inversions and 4/5 CCR) and 4/14 inherited rearrangements (1/7 translocations, 2/5 inversions and 1/2 CCR). The proportion of imbalances was not statistically different between de novo and inherited cases. Our results support that about 40% apparently balanced chromosomal rearrangements with abnormal phenotype are in fact imbalanced and that these rearrangements should be systematically investigated by array CGH independently of their de novo or inherited character.


Assuntos
Anormalidades Múltiplas/genética , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Deficiência Intelectual/genética , Análise de Sequência com Séries de Oligonucleotídeos , Aberrações Cromossômicas/estatística & dados numéricos , Inversão Cromossômica/genética , Inversão Cromossômica/estatística & dados numéricos , Feminino , Deleção de Genes , Rearranjo Gênico/genética , Genoma , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Reação em Cadeia da Polimerase , Translocação Genética/genética
17.
Eur J Med Genet ; 52(1): 62-6, 2009 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19022414

RESUMO

We report on a 28-year old woman carrying a 0.8 Mb de novo interstitial deletion in 19q13.32 detected by high-resolution array-CGH. She has severe mental retardation, tetralogy of Fallot, cleft lip and palate, deafness, megacolon and other dysmorphic features. Only a few cases of constitutional deletions located at the long arm of chromosome 19 have been previously described and this is the first report involving 19q13.32. The deleted region encompasses 15 genes, among which 3 candidate genes for genotype-phenotype correlation could be delineated. Since SLC8A2 is broadly expressed in brain and plays a potential role during embryonic development, its haploinsufficiency could possibly be related to mental retardation; as it is also expressed in aortic and intestinal smooth muscles, SLC8A2 could be related to the aortic defect of the complex cardiac malformation and to the megacolon. SAE1, a SUMO-1 activating enzyme subunit, may be related to cleft lip and palate. KPTN coding region may be a candidate gene for hearing loss. Further experimental studies on either in vivo models or diagnostic materials are needed to elucidate the role of these potential candidate genes for the phenotypic abnormalities observed in the investigated patient.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 19 , Anormalidades Congênitas/genética , Adulto , Fenda Labial/genética , Fissura Palatina/genética , Hibridização Genômica Comparativa , Feminino , Humanos , Deficiência Intelectual/genética , Gravidez
18.
Eur J Med Genet ; 51(4): 373-81, 2008 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18463015

RESUMO

We report on a 6-years-old boy with psychomotor retardation, mild dysmorphic features and behavioral disturbances associated with epilepsy. Conventional cytogenetic analysis concluded to an interstitial de novo 6p21.2p22.3 duplication. Molecular cytogenetic analysis, including array-CGH technology, allows characterization of this 7.3Mb interstitial tandem duplication. The phenotype of this small 6p duplication reported to date is compared to other cases in the literature. Presence of epilepsy, although rare in patients with 6p duplication may be linked to genes involved in brain function and synaptic transmission in the 6p21.2p22.1 duplicated region (GABBR1, BRD2 and GRM4).


Assuntos
Cromossomos Humanos Par 6/genética , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Duplicação Gênica , Criança , Pré-Escolar , Análise Citogenética , Deficiências do Desenvolvimento/diagnóstico , Genoma Humano , Humanos , Hibridização in Situ Fluorescente , Masculino , Análise de Sequência com Séries de Oligonucleotídeos
19.
Eur J Med Genet ; 51(1): 87-91, 2008 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18053786

RESUMO

We here report a boy presenting with developmental delay, growth retardation, facial dysmorphisms, vermis hypoplasia, micropolygyria and corpus callosum agenesis. Conventional and high resolution cytogenetic analyses were normal but high resolution oligonucleotide array-CGH, performed at the age of 4 years, allowed the characterisation of a de novo 6.9 Mb 1qter deletion/4.4 Mb 18pter duplication. Numerous 1qter deletions have already been described associated with brain malformations. Among 1q44 deleted genes, AKT3 is the strongest candidate gene for vermis hypoplasia and corpus callosum agenesis.


Assuntos
Anormalidades Múltiplas/genética , Encéfalo/anormalidades , Cromossomos Humanos Par 1/genética , Microcefalia/genética , Deleção de Sequência , Agenesia do Corpo Caloso , Sequência de Bases , Pré-Escolar , Humanos , Masculino , Análise em Microsséries , Hibridização de Ácido Nucleico , Proteínas Proto-Oncogênicas c-akt/genética
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