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2.
Genet Med ; 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30245510

RESUMO

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

3.
Am J Hum Genet ; 100(6): 907-925, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28575647

RESUMO

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.


Assuntos
Cromatina/metabolismo , Haploinsuficiência/genética , Deficiência Intelectual/genética , Transcrição Genética , Fator de Transcrição YY1/genética , Acetilação , Adolescente , Sequência de Bases , Pré-Escolar , Imunoprecipitação da Cromatina , Estudos de Coortes , Elementos Facilitadores Genéticos/genética , Feminino , Ontologia Genética , Haplótipos/genética , Hemizigoto , Histonas/metabolismo , Humanos , Linfócitos/metabolismo , Masculino , Metilação , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Ligação Proteica/genética , Domínios Proteicos , Fator de Transcrição YY1/química
4.
Eur J Hum Genet ; 24(3): 373-80, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26059843

RESUMO

Copy number variations are a common cause of intellectual disability (ID). Determining the contribution of copy number variants (CNVs), particularly gains, to disease remains challenging. Here, we report four males with ID with sub-microscopic duplications at Xp11.2 and review the few cases with overlapping duplications reported to date. We established the extent of the duplicated regions in each case encompassing a minimum of three known disease genes TSPYL2, KDM5C and IQSEC2 with one case also duplicating the known disease gene HUWE1. Patients with a duplication encompassing TSPYL2, KDM5C and IQSEC2 without gains of nearby SMC1A and HUWE1 genes have not been reported thus far. All cases presented with ID and significant deficits of speech development. Some patients also manifested behavioral disturbances such as hyperactivity and attention-deficit/hyperactivity disorder. Lymphoblastic cell lines from patients show markedly elevated levels of TSPYL2, KDM5C and SMC1A, transcripts consistent with the extent of their CNVs. The duplicated region in our patients contains several genes known to escape X-inactivation, including KDM5C, IQSEC2 and SMC1A. In silico analysis of expression data in selected gene expression omnibus series indicates that dosage of these genes, especially IQSEC2, is similar in males and females despite the fact they escape from X-inactivation in females. Taken together, the data suggest that gains in Xp11.22 including IQSEC2 cause ID and are associated with hyperactivity and attention-deficit/hyperactivity disorder, and are likely to be dosage-sensitive in males.


Assuntos
Duplicação Cromossômica , Cromossomos Humanos X/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Histona Desmetilases/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas Nucleares/genética , Adolescente , Comportamento , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Criança , Pré-Escolar , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Linhagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Adulto Jovem
5.
Hum Mol Genet ; 24(25): 7171-81, 2015 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-26443594

RESUMO

Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals. We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.


Assuntos
Antígenos Nucleares/genética , Deficiência Intelectual/genética , Cromossomos Humanos X/genética , Variações do Número de Cópias de DNA/genética , Humanos , Masculino , Comportamento Problema , Reação em Cadeia da Polimerase Via Transcriptase Reversa
6.
Am J Med Genet A ; 167(6): 1330-6, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25899669

RESUMO

Isolated mitochondrial respiratory chain complex III deficiency has been described in a heterogeneous group of clinical presentations in children and adults. It has been associated with mutations in MT-CYB, the only mitochondrial DNA encoded subunit, as well as in nine nuclear genes described thus far: BCS1L, TTC19, UQCRB, UQCRQ, UQCRC2, CYC1, UQCC2, LYRM7, and UQCC3. BCS1L, TTC19, UQCC2, LYRM7, and UQCC3 are complex III assembly factors. We report on an 8-year-old girl born to consanguineous Iraqi parents presenting with slowly progressive encephalomyopathy, severe failure to thrive, significant delays in verbal and communicative skills and bilateral retinal cherry red spots on fundoscopy. SNP array identified multiple regions of homozygosity involving 7.5% of the genome. Mutations in the TTC19 gene are known to cause complex III deficiency and TTC19 was located within the regions of homozygosity. Sequencing of TTC19 revealed a homozygous nonsense mutation at exon 6 (c.937C > T; p.Q313X). We reviewed the phenotypes and genotypes of all 11 patients with TTC19 mutations leading to complex III deficiency (including our case). The consistent features noted are progressive neurodegeneration with Leigh-like brain MRI abnormalities. Significant variability was observed however with the age of symptom onset and rate of disease progression. The bilateral retinal cherry red spots and failure to thrive observed in our patient are unique features, which have not been described, in previously reported patients with TTC19 mutations. Interestingly, all reported TTC19 mutations are nonsense mutations. The severity of clinical manifestations however does not specifically correlate with the residual complex III enzyme activities.


Assuntos
Códon sem Sentido , Complexo III da Cadeia de Transporte de Elétrons/deficiência , Insuficiência de Crescimento/genética , Transtornos do Desenvolvimento da Linguagem/genética , Proteínas de Membrana/genética , Doenças Mitocondriais/genética , Encefalomiopatias Mitocondriais/genética , Proteínas Mitocondriais/genética , Adolescente , Adulto , Criança , Consanguinidade , Progressão da Doença , Complexo III da Cadeia de Transporte de Elétrons/genética , Insuficiência de Crescimento/patologia , Insuficiência de Crescimento/fisiopatologia , Feminino , Variação Genética , Genótipo , Homozigoto , Humanos , Lactente , Transtornos do Desenvolvimento da Linguagem/patologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/patologia , Doenças Mitocondriais/fisiopatologia , Encefalomiopatias Mitocondriais/patologia , Encefalomiopatias Mitocondriais/fisiopatologia , Linhagem , Fenótipo , Retina/metabolismo , Retina/patologia
7.
Am J Med Genet A ; 167A(1): 174-9, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25424989

RESUMO

AKT3 (v-akt murine thymoma viral oncogene homolog 3) is located at chromosome 1q44 and encodes a 479 amino acid protein, a member of the protein kinase B (PKB) family. This gene is frequently involved in 1q44 deletion syndrome in patients with microcephaly, intellectual disability, and dysmorphic features. Phenotype and genotype studies of patients with 1q44 deletion syndrome have suggested that deletion of the AKT3 gene is responsible for the microcephaly in these patients. However, the phenotype of pure AKT3 deletion has not been studied. We report on a 1q44 deletion involving only AKT3 in a boy and his father. The boy has microcephaly, hypotonia, feeding difficulties, developmental delay, and minor dysmorphic features. His father does not have microcephaly and is of normal intelligence. We also analyzed the available information on the phenotypes of 13 individuals carrying a pure AKT3 gene deletion identified through literature review and database search. To our knowledge, this is the first report of a paternally inherited pure AKT3 deletion with full clinical description. This is also the first report to suggest that (1) AKT3 deletion is associated with microcephaly and intellectual disability with incomplete penetrance; (2) a pure AKT3 deletion is likely to be inherited in contrast to the larger 1q44 deletions, which are mostly de novo and (3) there seems to be no consistent or characteristic dysmorphism associated with pure AKT3 deletion.


Assuntos
Cromossomos Humanos Par 1/genética , Deleção de Genes , Proteínas Proto-Oncogênicas c-akt/genética , Adulto , Pré-Escolar , Deleção Cromossômica , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo
9.
Pathology ; 46(1): 41-5, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24300712

RESUMO

The aim of this study was to determine prospectively the frequency of pathogenic chromosomal microdeletions and microduplications in a large group of referred patients with developmental delay (DD), intellectual disability (ID) or autism spectrum disorders (ASD) within a genetic diagnostic service. First tier testing was applied using a standardised oligo-array comparative genomic hybridization (CGH) platform, replacing conventional cytogenetic testing that would have been used in the past. Copy number variants (CNVs) found to be responsible for the clinical condition on the request form could all be subdivided into three groups: well established pathogenic microdeletion/microduplication/aneuploidy syndromes, predicted pathogenic CNVs as interpreted by the laboratory, and recently established pathogenic disease susceptibility CNVs. Totalled from these three groups, with CNVs of uncertain significance excluded, detection rates were: DD (13.0%), ID (15.6%), ASD (2.3%), ASD with DD (8.2%), ASD with ID (12.7%) and unexplained epilepsy with DD, ID and ASD (10.9%). The greater diagnostic sensitivity arising from routine application of array CGH, compared with previously used conventional cytogenetics, outweighs the interpretative issues for the reporting laboratory and referring clinician arising from detection of CNVs of uncertain significance. Precise determination of any previously hidden molecular defect responsible for the patient's condition is translated to improved genetic counselling.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Hibridização Genômica Comparativa/métodos , Deficiências do Desenvolvimento/diagnóstico , Deficiência Intelectual/diagnóstico , Austrália , Transtornos Globais do Desenvolvimento Infantil/complicações , Transtornos Globais do Desenvolvimento Infantil/genética , Estudos de Coortes , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Epilepsia/complicações , Epilepsia/diagnóstico , Epilepsia/genética , Duplicação Gênica , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Estudos Prospectivos , Deleção de Sequência
10.
Eur J Hum Genet ; 22(1): 40-5, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23695280

RESUMO

Recent studies have established the role of rare copy number variants (CNVs) in several neurological disorders but the contribution of rare CNVs to cerebral palsy (CP) is not known. Fifty Caucasian families having children with CP were studied using two microarray designs. Potentially pathogenic, rare (<1% population frequency) CNVs were identified, and their frequency determined, by comparing the CNVs found in cases with 8329 adult controls with no known neurological disorders. Ten of the 50 cases (20%) had rare CNVs of potential relevance to CP; there were a total of 14 CNVs, which were observed in <0.1% (<8/8329) of the control population. Eight inherited from an unaffected mother: a 751-kb deletion including FSCB, a 1.5-Mb duplication of 7q21.13, a 534-kb duplication of 15q11.2, a 446-kb duplication including CTNND2, a 219-kb duplication including MCPH1, a 169-kb duplication of 22q13.33, a 64-kb duplication of MC2R, and a 135-bp exonic deletion of SLC06A1. Three inherited from an unaffected father: a 386-kb deletion of 12p12.2-p12.1, a 234-kb duplication of 10q26.13, and a 4-kb exonic deletion of COPS3. The inheritance was unknown for three CNVs: a 157-bp exonic deletion of ACOX1, a 693-kb duplication of 17q25.3, and a 265-kb duplication of DAAM1. This is the first systematic study of CNVs in CP, and although it did not identify de novo mutations, has shown inherited, rare CNVs involving potentially pathogenic genes and pathways requiring further investigation.


Assuntos
Paralisia Cerebral/genética , Variações do Número de Cópias de DNA/genética , Análise em Microsséries , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Complexo do Signalossomo COP9 , Cateninas/genética , Paralisia Cerebral/etiologia , Paralisia Cerebral/patologia , Éxons , Feminino , Frequência do Gene , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas Proto-Oncogênicas/genética , Deleção de Sequência
12.
Am J Med Genet B Neuropsychiatr Genet ; 162B(1): 24-35, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23184456

RESUMO

The clinical significance of chromosomal microdeletions and microduplications was predicted based on their gene content, de novo or familial inheritance and accumulated knowledge recorded on public databases. A patient group comprised of 247 cases with epilepsy and its common co-morbidities of developmental delay, intellectual disability, autism spectrum disorders, and congenital abnormalities was reviewed prospectively in a diagnostic setting using a standardized oligo-array CGH platform. Seventy-three (29.6%) had copy number variations (CNVs) and of these 73 cases, 27 (37.0%) had CNVs that were likely causative. These 27 cases comprised 10.9% of the 247 cases reviewed. The range of pathogenic CNVs associated with seizures was consistent with the existence of many genetic determinants for epilepsy.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/complicações , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Transtornos Cognitivos/complicações , Transtornos Cognitivos/diagnóstico , Hibridização Genômica Comparativa , Epilepsia/complicações , Epilepsia/diagnóstico , Adolescente , Adulto , Idoso , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Pré-Escolar , Deleção Cromossômica , Duplicação Cromossômica/genética , Transtornos Cognitivos/genética , Variações do Número de Cópias de DNA/genética , Epilepsia/genética , Feminino , Aconselhamento Genético , Predisposição Genética para Doença , Humanos , Achados Incidentais , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
Am J Med Genet A ; 158A(12): 3168-73, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23169673

RESUMO

Mutations in the NK2 homeobox 1 gene (NKX2-1) cause a rare syndrome known as choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome (OMIM 610978). Here we present the first reported patient with this condition caused by a 14q13.3 deletion which is adjacent to but does not interrupt NKX2-1, and review the literature on this condition. The infant presented at 23 months with a history of developmental delay, hyperkinesia, recurrent respiratory infections, neonatal respiratory distress, and hypothyroidism. Choreiform movements and delayed motor milestones were first noted at 6-8 months of age. TSH levels had been consistently elevated from 8 months of age. The clinical presentation was suggestive of an NKX2-1 mutation. Sequencing of all exons and splice site junctions of NKX2-1 was performed but was normal. Array CGH was then performed and a 3.29 Mb interstitial deletion at 14q13.1-q13.3 was detected. The distal region of loss of the deletion disrupted the surfactant associated 3 (SFTA3) gene but did disrupt NKX2-1. Findings were confirmed on high resolution SNP array and multiplex semiquanitative PCR. NKX2-1 encodes transcriptional factors involved in the developmental pathways for thyroid, lung, and brain. We hypothesize that the region centromeric to NKX2-1 is important for the normal functioning of this gene and when interrupted produces a phenotype that is typical of the choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome, as seen in our patient. We conclude that deletions at 14q13.3 adjacent to but not involving NKX2-1 can cause choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome.


Assuntos
Atetose/genética , Coreia/genética , Hipotireoidismo Congênito/genética , Proteínas Nucleares/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Fatores de Transcrição/genética , Deleção Cromossômica , Cromossomos Humanos Par 14 , Feminino , Humanos , Lactente , Recém-Nascido , Fator Nuclear 1 de Tireoide
15.
Epileptic Disord ; 12(3): 192-8, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20643615

RESUMO

Seizures often occur in patients with microchromosomal aberrations responsible for moderate to severe intellectual disability. We hypothesised that epilepsy alone could be caused by microdeletions or microduplications, which might also relate to epilepsy refractory to medication. Chromosomes from 20 subjects with epilepsy and repeated failure of antiepileptic medication were examined using molecular methods. Firstly, the 41 subtelomeric regions were scanned using fluorescence in situ hybridization and multiplex ligation-dependent probe amplification. Secondly, a genome-wide scan was carried out using oligonucleotide-array comparative genome hybridisation on two platforms: Nimblegen and Agilent. Two aberrations (2/20) were identified: a recurrent microdeletion at 15q13.3 previously characterised in patients with seizures that generally respond to medication, and a novel 1.15 Mb microchromosomal duplication at 10q21.2 also present in the unaffected mother. We conclude that gene content of microchromosomal aberrations is not a major cause of refractory seizures, but that microchromosomal anomalies are found in an appreciable fraction of such cases.


Assuntos
Aberrações Cromossômicas , Epilepsia/genética , Adolescente , Adulto , Pré-Escolar , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 15/genética , Hibridização Genômica Comparativa , Epilepsia/patologia , Feminino , Amplificação de Genes , Humanos , Hibridização in Situ Fluorescente , Masculino , Projetos Piloto , Deleção de Sequência , Telômero/patologia , Adulto Jovem
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