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1.
Prenat Diagn ; 2019 Jul 04.
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.
Eur J Hum Genet ; 27(3): 360-368, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30552424

RESUMO

Holt-Oram syndrome (HOS) is an autosomal dominant condition characterised by the association of congenital heart defect (CHD), with or without rhythm disturbances and radial defects, due to TBX5 variants. The diagnosis is challenged by the variability of expression and the large phenotypic overlap with other conditions, like Okihiro syndrome, TAR syndrome or Fanconi disease. We retrospectively reviewed 212 patients referred for suspicion of HOS between 2002 and 2014, who underwent TBX5 screening. A TBX5 variant has been identified in 78 patients, representing the largest molecular series ever described. In the cohort, 61 met the previously described diagnostic criteria and 17 have been considered with an uncertain HOS diagnosis. A CHD was present in 91% of the patients with a TBX5 variant, atrial septal defects being the most common (61.5%). The genotype-phenotype study highlights the importance of some critical features in HOS: the septal characteristic of the CHD, the bilateral and asymmetric characteristics of the radial defect and the presence of shoulder or elbow mobility defect. Besides, 21 patients presented with an overlapping condition. Among them, 13 had a typical HOS presentation. We discuss the strategies that could be adopted to improve the molecular delineation of the remaining typical patients.


Assuntos
Anormalidades Múltiplas/genética , Cardiopatias Congênitas/genética , Comunicação Interatrial/genética , Deformidades Congênitas das Extremidades Inferiores/genética , Fenótipo , Proteínas com Domínio T/genética , Deformidades Congênitas das Extremidades Superiores/genética , Anormalidades Múltiplas/patologia , Diagnóstico Diferencial , Cardiopatias Congênitas/patologia , Comunicação Interatrial/patologia , Humanos , Lactente , Deformidades Congênitas das Extremidades Inferiores/patologia , Mutação , Deformidades Congênitas das Extremidades Superiores/patologia
3.
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.

4.
Mol Metab ; 13: 1-9, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29784605

RESUMO

OBJECTIVE: The molecular diagnosis of extreme forms of obesity, in which accurate detection of both copy number variations (CNVs) and point mutations, is crucial for an optimal care of the patients and genetic counseling for their families. Whole-exome sequencing (WES) has benefited considerably this molecular diagnosis, but its poor ability to detect CNVs remains a major limitation. We aimed to develop a method (CoDE-seq) enabling the accurate detection of both CNVs and point mutations in one step. METHODS: CoDE-seq is based on an augmented WES method, using probes distributed uniformly throughout the genome. CoDE-seq was validated in 40 patients for whom chromosomal DNA microarray was available. CNVs and mutations were assessed in 82 children/young adults with suspected Mendelian obesity and/or intellectual disability and in their parents when available (ntotal = 145). RESULTS: CoDE-seq not only detected all of the 97 CNVs identified by chromosomal DNA microarrays but also found 84 additional CNVs, due to a better resolution. When compared to CoDE-seq and chromosomal DNA microarrays, WES failed to detect 37% and 14% of CNVs, respectively. In the 82 patients, a likely molecular diagnosis was achieved in >30% of the patients. Half of the genetic diagnoses were explained by CNVs while the other half by mutations. CONCLUSIONS: CoDE-seq has proven cost-efficient and highly effective as it avoids the sequential genetic screening approaches currently used in clinical practice for the accurate detection of CNVs and point mutations.

5.
Eur J Hum Genet ; 26(1): 85-93, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29184170

RESUMO

Syndromes caused by copy number variations are described as reciprocal when they result from deletions or duplications of the same chromosomal region. When comparing the phenotypes of these syndromes, various clinical features could be described as reversed, probably due to the opposite effect of these imbalances on the expression of genes located at this locus. The NFIX gene codes for a transcription factor implicated in neurogenesis and chondrocyte differentiation. Microdeletions and loss of function variants of NFIX are responsible for Sotos syndrome-2 (also described as Malan syndrome), a syndromic form of intellectual disability associated with overgrowth and macrocephaly. Here, we report a cohort of nine patients harboring microduplications encompassing NFIX. These patients exhibit variable intellectual disability, short stature and small head circumference, which can be described as a reversed Sotos syndrome-2 phenotype. Strikingly, such a reversed phenotype has already been described in patients harboring microduplications encompassing NSD1, the gene whose deletions and loss-of-function variants are responsible for classical Sotos syndrome. Even though the type/contre-type concept has been criticized, this model seems to give a plausible explanation for the pathogenicity of 19p13 microduplications, and the common phenotype observed in our cohort.

6.
Genet Med ; 19(9): 989-997, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28151489

RESUMO

PURPOSE: Postzygotic activating mutations of PIK3CA cause a wide range of mosaic disorders collectively referred to as PIK3CA-related overgrowth spectrum (PROS). We describe the diagnostic yield and characteristics of PIK3CA sequencing in PROS. METHODS: We performed ultradeep next-generation sequencing (NGS) of PIK3CA in various tissues from 162 patients referred to our clinical laboratory and assessed diagnostic yield by phenotype and tissue tested. RESULTS: We identified disease-causing mutations in 66.7% (108/162) of patients, with mutant allele levels as low as 1%. The diagnostic rate was higher (74%) in syndromic than in isolated cases (35.5%; P = 9.03 × 10-5). We identified 40 different mutations and found strong oncogenic mutations more frequently in patients without brain overgrowth (50.6%) than in those with brain overgrowth (15.2%; P = 0.00055). Mutant allele levels were higher in skin and overgrown tissues than in blood and buccal samples (P = 3.9 × 10-25), regardless of the phenotype. CONCLUSION: Our data demonstrate the value of ultradeep NGS for molecular diagnosis of PROS, highlight its substantial allelic heterogeneity, and confirm that optimal diagnosis requires fresh skin or surgical samples from affected regions. Our findings may be of value in guiding future recommendations for genetic testing in PROS and other mosaic conditions.Genet Med advance online publication 02 February 2017.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Estudos de Associação Genética , Testes Genéticos , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Mutação , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Gerenciamento Clínico , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Mosaicismo , Fenótipo , Diagnóstico Pré-Natal , Análise de Sequência de DNA , Adulto Jovem
7.
Genet Mol Biol ; 39(3): 349-57, 2016 Jul-Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27561113

RESUMO

Deletion-induced hemizygosity may unmask deleterious autosomal recessive variants and be a cause of the phenotypic variability observed in microdeletion syndromes. We performed complete exome sequencing (WES) analysis to examine this possibility in a patient with 1p13.2 microdeletion. Since the patient displayed clinical features suggestive of Noonan Syndrome (NS), we also used WES to rule out the presence of pathogenic variants in any of the genes associated with the different types of NS. We concluded that the clinical findings could be attributed solely to the 1p13.2 haploinsufficiency. Retrospective analysis of other nine reported patients with 1p13.2 microdeletions showed that six of them also presented some characteristics of NS. In all these cases, the deleted segment included the NRAS gene. Gain-of-function mutations of NRAS gene are causally related to NS type 6. Thus, it is conceivable that NRAS haploinsufficiency and gain-of-function mutations may have similar clinical consequences. The same phenomenon has been described for two other genes belonging to the Ras/MAPK pathway: MAP2K2 and SHOC2. In conclusion, we here report genotype-phenotype correlations in patients with chromosome 1p13.2 microdeletions and we propose that NRAS may be a critical gene for the NS characteristics in the patients.

8.
Am J Hum Genet ; 98(3): 541-552, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26942287

RESUMO

Intellectual disability (ID) and autism spectrum disorders (ASD) are genetically heterogeneous, and a significant number of genes have been associated with both conditions. A few mutations in POGZ have been reported in recent exome studies; however, these studies do not provide detailed clinical information. We collected the clinical and molecular data of 25 individuals with disruptive mutations in POGZ by diagnostic whole-exome, whole-genome, or targeted sequencing of 5,223 individuals with neurodevelopmental disorders (ID primarily) or by targeted resequencing of this locus in 12,041 individuals with ASD and/or ID. The rarity of disruptive mutations among unaffected individuals (2/49,401) highlights the significance (p = 4.19 × 10(-13); odds ratio = 35.8) and penetrance (65.9%) of this genetic subtype with respect to ASD and ID. By studying the entire cohort, we defined common phenotypic features of POGZ individuals, including variable levels of developmental delay (DD) and more severe speech and language delay in comparison to the severity of motor delay and coordination issues. We also identified significant associations with vision problems, microcephaly, hyperactivity, a tendency to obesity, and feeding difficulties. Some features might be explained by the high expression of POGZ, particularly in the cerebellum and pituitary, early in fetal brain development. We conducted parallel studies in Drosophila by inducing conditional knockdown of the POGZ ortholog row, further confirming that dosage of POGZ, specifically in neurons, is essential for normal learning in a habituation paradigm. Combined, the data underscore the pathogenicity of loss-of-function mutations in POGZ and define a POGZ-related phenotype enriched in specific features.


Assuntos
Transtorno do Espectro Autista/genética , Deficiência Intelectual/genética , Transposases/genética , Adolescente , Adulto , Animais , Transtorno do Espectro Autista/diagnóstico , Criança , Pré-Escolar , Estudos de Coortes , Regulação para Baixo , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Exoma , Feminino , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/genética , Modelos Lineares , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Mutação , Fenótipo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
9.
Eur J Med Genet ; 58(3): 140-7, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25596525

RESUMO

Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients. This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease). Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, 'de novo' microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients. Our results support the hypothesis that 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia/genética , Cardiopatias/genética , Deficiência Intelectual/genética , Transtornos Mentais/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Pré-Escolar , Aberrações Cromossômicas , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Estudos de Coortes , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/diagnóstico , Epilepsia/diagnóstico , Feminino , Cardiopatias/congênito , Cardiopatias/diagnóstico , Humanos , Hibridização in Situ Fluorescente , Lactente , Deficiência Intelectual/diagnóstico , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Transtornos Mentais/diagnóstico , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Fenótipo , Distúrbios da Fala/genética , Adulto Jovem
10.
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
11.
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
12.
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
13.
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
14.
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
15.
Hum Genet ; 132(10): 1177-85, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23783460

RESUMO

Loss-of-function mutations in several different neuronal pathways have been related to intellectual disability (ID). Such mutations often are found on the X chromosome in males since they result in functional null alleles. So far, microdeletions at Xq24 reported in males always have been associated with a syndromic form of ID due to the loss of UBE2A. Here, we report on overlapping microdeletions at Xq24 that do not include UBE2A or affect its expression, in patients with non-syndromic ID plus some additional features from three unrelated families. The smallest region of overlap, confirmed by junction sequencing, harbors two members of the mitochondrial solute carrier family 25, SLC25A5 and SLC25A43. However, identification of an intragenic microdeletion including SLC25A43 but not SLC25A5 in a healthy boy excluded a role for SLC25A43 in cognition. Therefore, our findings point to SLC25A5 as a novel gene for non-syndromic ID. This highly conserved gene is expressed ubiquitously with high levels in cortex and hippocampus, and a presumed role in mitochondrial exchange of ADP/ATP. Our data indicate that SLC25A5 is involved in memory formation or establishment, which could add mitochondrial processes to the wide array of pathways that regulate normal cognitive functions.


Assuntos
Translocador 2 do Nucleotídeo Adenina/metabolismo , Deleção Cromossômica , Cromossomos Humanos X/genética , Deficiência Intelectual/genética , Mitocôndrias/metabolismo , Translocador 2 do Nucleotídeo Adenina/genética , Elementos Alu , Sequência de Bases , Encéfalo/metabolismo , Encéfalo/patologia , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Heterozigoto , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Mitocôndrias/genética , Dados de Sequência Molecular , Linhagem , Inativação do Cromossomo X
16.
Am J Med Genet A ; 161A(3): 572-7, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23401077

RESUMO

Silver-Russell syndrome (SRS) is characterized by pre- and post-natal growth restriction that spares head growth, feeding difficulties, and variable dysmorphic facial features without major malformations. Hypomethylation of the paternal 11p15 imprinting control region 1 (ICR1) and maternal uniparental disomy of chromosome 7 are found in 50-60% and in 5-10% of SRS patients, respectively. We report on the pre- and post-natal features of three unrelated SRS patients with unusual congenital heart defects (CHDs). Two patients born prematurely had total anomalous pulmonary venous return and died shortly after birth, and a third patient, now 4 years old, had cor triatriatum sinistrum, which was surgically corrected. In all three patients, the underlying molecular defect was 11p15 ICR1 hypomethylation. Based on a large cohort with molecularly proven SRS, the prevalence of CHD in SRS is estimated at 5.5%. We suggest that the occurrence of CHD in SRS with 11p15 ICR1 hypomethylation is not coincidental, but specific to this genotype.


Assuntos
Anormalidades Múltiplas/diagnóstico , Cromossomos Humanos Par 11/genética , Cardiopatias Congênitas/diagnóstico , Síndrome de Silver-Russell/diagnóstico , Anormalidades Múltiplas/genética , Pré-Escolar , Metilação de DNA , Evolução Fatal , Feminino , Estudos de Associação Genética , Cardiopatias Congênitas/genética , Humanos , Recém-Nascido , Masculino , Síndrome de Silver-Russell/genética
17.
J Med Genet ; 50(3): 174-86, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23315542

RESUMO

BACKGROUND: Auriculocondylar syndrome (ACS) is a rare craniofacial disorder consisting of micrognathia, mandibular condyle hypoplasia and a specific malformation of the ear at the junction between the lobe and helix. Missense heterozygous mutations in the phospholipase C, ß 4 (PLCB4) and guanine nucleotide binding protein (G protein), α inhibiting activity polypeptide 3 (GNAI3) genes have recently been identified in ACS patients by exome sequencing. These genes are predicted to function within the G protein-coupled endothelin receptor pathway during craniofacial development. RESULTS: We report eight additional cases ascribed to PLCB4 or GNAI3 gene lesions, comprising six heterozygous PLCB4 missense mutations, one heterozygous GNAI3 missense mutation and one homozygous PLCB4 intragenic deletion. Certain residues represent mutational hotspots; of the total of 11 ACS PLCB4 missense mutations now described, five disrupt Arg621 and two disrupt Asp360. The narrow distribution of mutations within protein space suggests that the mutations may result in dominantly interfering proteins, rather than haploinsufficiency. The consanguineous parents of the patient with a homozygous PLCB4 deletion each harboured the heterozygous deletion, but did not present the ACS phenotype, further suggesting that ACS is not caused by PLCB4 haploinsufficiency. In addition to ACS, the patient harbouring a homozygous deletion presented with central apnoea, a phenotype that has not been previously reported in ACS patients. CONCLUSIONS: These findings indicate that ACS is not only genetically heterogeneous but also an autosomal dominant or recessive condition according to the nature of the PLCB4 gene lesion.


Assuntos
Otopatias/genética , Orelha/anormalidades , Mutação , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Orelha/patologia , Otopatias/patologia , Feminino , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Linhagem , Fosfolipase C beta/genética , Reação em Cadeia da Polimerase
18.
Eur J Med Genet ; 56(1): 26-31, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23063576

RESUMO

The introduction of molecular karyotyping technologies into the diagnostic work-up of patients with congenital disorders permitted the identification and delineation of novel microdeletion and microduplication syndromes. Interstitial 16p13.3 duplication, encompassing the CREBBP gene, which is mutated or deleted in the Rubinstein-Taybi syndrome, have been proposed to cause a recognisable syndrome with variable intellectual disability, normal growth, mild facial dysmorphism, mild anomalies of the extremities, and occasional findings such as developmental defects of the heart, genitalia, palate or the eyes. We here report the phenotypic and genotypic delineation of 9 patients carrying a submicroscopic 16p13.3 duplication, including the smallest 16p13.3 duplication reported so far. Careful clinical assessment confirms the distinctive clinical phenotype and also defines frequent associated features : marked speech problems, frequent ocular region involvement with upslanting of the eyes, narrow palpebral fissures, ptosis and strabismus, frequent proximal implantation of thumbs, cleft palate/bifid uvula and inguinal hernia. It also confirms that CREBBP is the critical gene involved in the duplication 16p13.3 syndrome.


Assuntos
Proteína de Ligação a CREB/genética , Duplicação Cromossômica , Cromossomos Humanos Par 16 , Fenótipo , Síndrome de Rubinstein-Taybi/genética , Adolescente , Criança , Pré-Escolar , Cromossomos Humanos Par 16/genética , Hibridização Genômica Comparativa , Facies , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome
19.
Eur J Hum Genet ; 21(6): 602-12, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23073310

RESUMO

The 2q37 locus is one of the most commonly deleted subtelomeric regions. Such a deletion has been identified in >100 patients by telomeric fluorescence in situ hybridization (FISH) analysis and, less frequently, by array-based comparative genomic hybridization (array-CGH). A recognizable '2q37-deletion syndrome' or Albright's hereditary osteodystrophy-like syndrome has been previously described. To better map the deletion and further refine this deletional syndrome, we formed a collaboration with the Association of French Language Cytogeneticists to collect 14 new intellectually deficient patients with a distal or interstitial 2q37 deletion characterized by FISH and array-CGH. Patients exhibited facial dysmorphism (13/14) and brachydactyly (10/14), associated with behavioural problems, autism or autism spectrum disorders of varying severity and overweight or obesity. The deletions in these 14 new patients measured from 2.6 to 8.8 Mb. Although the major role of HDAC4 has been demonstrated, the phenotypic involvement of several other genes in the deleted regions is unknown. We further refined the genotype-phenotype correlation for the 2q37 deletion. To do this, we examined the smallest overlapping deleted region for candidate genes for skeletal malformations (facial dysmorphism and brachydactyly), overweight, behavioural problems and seizures, using clinical data, a review of the literature, and the Manteia database. Among the candidate genes identified, we focus on the roles of PRLH, PER2, TWIST2, CAPN10, KIF1A, FARP2, D2HGDH and PDCD1.


Assuntos
Comportamento , Braquidactilia/complicações , Braquidactilia/genética , Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/genética , Displasia Fibrosa Poliostótica/complicações , Displasia Fibrosa Poliostótica/genética , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Sobrepeso/complicações , Sobrepeso/genética , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Mapeamento Cromossômico , Cromossomos Humanos Par 2/genética , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Adulto Jovem
20.
Eur J Hum Genet ; 21(1): 82-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22713806

RESUMO

Speech sound disorders are heterogeneous conditions, and sporadic and familial cases have been described. However, monogenic inheritance explains only a small proportion of such disorders, in particular in cases with childhood apraxia of speech (CAS). Deletions of <5 Mb involving the 12p13.33 locus is one of the least commonly deleted subtelomeric regions. Only four patients have been reported with such a deletion diagnosed with fluorescence in situ hybridisation telomere analysis or array CGH. To further delineate this rare microdeletional syndrome, a French collaboration together with a search in the Decipher database allowed us to gather nine new patients with a 12p13.33 subtelomeric or interstitial rearrangement identified by array CGH. Speech delay was found in all patients, which could be defined as CAS when patients had been evaluated by a speech therapist (5/9 patients). Intellectual deficiency was found in 5/9 patients only, and often associated with psychiatric manifestations of various severity. Two such deletions were inherited from an apparently healthy parent, but reevaluation revealed abnormal speech production at least in childhood, suggesting variable expressivity. The ELKS/ERC1 gene, which encodes for a synaptic factor, is found in the smallest region of overlap. These results reinforce the hypothesis that deletions of the 12p13.33 locus may be responsible for variable phenotypes including CAS associated with neurobehavioural troubles and that the presence of CAS justifies a genetic work-up.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Apraxias/genética , Deleção Cromossômica , Cromossomos Humanos Par 12 , Proteínas do Tecido Nervoso/genética , Apraxias/etiologia , Criança , Pré-Escolar , Família , Feminino , França , Predisposição Genética para Doença , Humanos , Hibridização in Situ Fluorescente , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Gravidez , Fala
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