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1.
Am J Hum Genet ; 104(4): 758-766, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30929739

RESUMO

By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.

2.
Genet Med ; 21(9): 2059-2069, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30923367

RESUMO

PURPOSE: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. METHODS: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. RESULTS: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). CONCLUSION: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.

3.
Eur J Hum Genet ; 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30291343

RESUMO

Clinical genomic sequencing can identify pathogenic variants unrelated to the initial clinical question, but of medical relevance to the patients and their families. With ongoing discussions on the utility of disclosing or searching for such variants, it is of crucial importance to obtain unbiased insight in the prevalence of these incidental or secondary findings, in order to better weigh potential risks and benefits. Previous studies have reported a broad range of secondary findings ranging from 1 to 9%, merely attributable to differences in study design, cohorts tested, sequence technology used and genes analyzed. Here, we analyzed WES data of 1640 anonymized healthy Dutch individuals to establish the frequency of medically actionable disease alleles in an outbred population of European descent. Our study shows that 1 in 38 healthy individuals (2.7%) has a (likely) pathogenic variant in one of 59 medically actionable dominant disease genes for which the American College of Medical Genetics and Genomics (ACMG) recommends disclosure. Additionally, we identified 36 individuals (2.2%) to be a carrier of a recessive pathogenic disease allele. Whereas these frequencies of secondary findings are in line with what has been reported in the East-Asian population, the pathogenic variants are differently distributed across the 59 ACMG genes. Our results contribute to the debate on genetic risk factor screening in healthy individuals and the discussion whether the potential benefits of this knowledge and related preventive options, outweigh the risk of the emotional impact of the test result and possible stigmatization.

4.
J Clin Sleep Med ; 14(8): 1427-1430, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30092902

RESUMO

ABSTRACT: We report an unusual case of an adult patient carrying a germline PHOX2B frameshift mutation and hence was diagnosed with congenital central hypoventilation syndrome. He came to medical attention after the mutation was identified in his daughter who presented with hypoventilation and a neuroblastoma. Although PHOX2B mutations are usually associated with a phenotype of congenital hypoventilation, severe autonomic dysfunction and neural crest tumors, our patient had no complaints at the time of presentation. At polysomnography we found severe positional hypercapnic central sleep apnea, partly responsive to positional therapy. Eventually, he was titrated to noninvasive ventilation with resolution of the central breathing events and, in hindsight, a more refreshing sleep than before. Clinicians working in sleep medicine need to be aware of the variable expression of this rare condition to prevent late cardiorespiratory and neurocognitive complications.

5.
Biol Psychiatry ; 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29724491

RESUMO

BACKGROUND: In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. METHODS: We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. RESULTS: We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. CONCLUSIONS: This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.

6.
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
7.
Hum Mutat ; 38(5): 594-599, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28074630

RESUMO

Next-generation sequencing led to the identification of many potential novel disease genes. The presence of mutations in the same gene in multiple unrelated patients is, however, a priori insufficient to establish that these genes are truly involved in the respective disease. Here, we show how phenotype information can be incorporated within statistical approaches to provide additional evidence for the causality of mutations. We developed a broadly applicable statistical model that integrates gene-specific mutation rates, cohort size, mutation type, and phenotype frequency information to assess the chance of identifying de novo mutations affecting the same gene in multiple patients with shared phenotype features. We demonstrate our approach based on the frequency of phenotype features present in a unique cohort of 6,149 patients with intellectual disability. We show that our combined approach can decrease the number of patients required to identify novel disease genes, especially for patients with combinations of rare phenotypes. In conclusion, we show how integrating genotype-phenotype information can aid significantly in the interpretation of de novo mutations in potential novel disease genes.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Fenótipo , Estudos de Associação Genética/métodos , Genótipo , Humanos , Modelos Genéticos , Modelos Estatísticos , Reprodutibilidade dos Testes
8.
Eur J Hum Genet ; 24(8): 1145-53, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26757981

RESUMO

Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Transporte/genética , Anormalidades Craniofaciais/genética , Proteínas de Drosophila/genética , Deficiência Intelectual/genética , Transtornos de Aprendizagem/genética , Mutação , Adolescente , Animais , Proteínas de Transporte/metabolismo , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Drosophila/genética , Drosophila/fisiologia , Proteínas de Drosophila/metabolismo , Feminino , Habituação Psicofisiológica , Humanos , Deficiência Intelectual/diagnóstico , Aprendizagem , Transtornos de Aprendizagem/diagnóstico , Masculino , Fenótipo , Síndrome , Adulto Jovem
9.
Am J Hum Genet ; 97(1): 99-110, 2015 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-26119818

RESUMO

Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades do Olho/genética , Doenças Palpebrais/genética , Hirsutismo/genética , Hipertelorismo/genética , Hipertricose/genética , Macrostomia/genética , Modelos Moleculares , Fenótipo , Proteínas Repressoras/genética , Anormalidades da Pele/genética , Proteína 1 Relacionada a Twist/genética , Anormalidades Múltiplas/patologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Imunoprecipitação da Cromatina , Exoma/genética , Anormalidades do Olho/patologia , Doenças Palpebrais/patologia , Células HeLa , Hirsutismo/patologia , Humanos , Hipertelorismo/patologia , Hipertricose/patologia , Macrostomia/patologia , Microscopia Eletrônica , Dados de Sequência Molecular , Mutação de Sentido Incorreto/genética , Conformação Proteica , Proteínas Repressoras/química , Análise de Sequência de DNA , Anormalidades da Pele/patologia , Proteína 1 Relacionada a Twist/química , Peixe-Zebra
10.
Am J Hum Genet ; 96(4): 612-22, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25817016

RESUMO

Robinow syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non-canonical signaling gene WNT5A underlie a subset of autosomal-dominant Robinow syndrome (DRS) cases, but most individuals with DRS remain without a molecular diagnosis. We performed whole-exome sequencing in four unrelated DRS-affected individuals without coding mutations in WNT5A and found heterozygous DVL1 exon 14 mutations in three of them. Targeted Sanger sequencing in additional subjects with DRS uncovered DVL1 exon 14 mutations in five individuals, including a pair of monozygotic twins. In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1. In five families in which samples from unaffected parents were available, the variants were demonstrated to represent de novo mutations. All variant alleles are predicted to result in a premature termination codon within the last exon, escape nonsense-mediated decay (NMD), and most likely generate a C-terminally truncated protein with a distinct -1 reading-frame terminus. Study of the transcripts extracted from affected subjects' leukocytes confirmed expression of both wild-type and variant alleles, supporting the hypothesis that mutant mRNA escapes NMD. Genomic variants identified in our study suggest that truncation of the C-terminal domain of DVL1, a protein hypothesized to have a downstream role in the Wnt-5a non-canonical pathway, is a common cause of DRS.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Anormalidades Craniofaciais/genética , Nanismo/genética , Mutação da Fase de Leitura/genética , Deformidades Congênitas dos Membros/genética , Fosfoproteínas/genética , Anormalidades Urogenitais/genética , Sequência de Aminoácidos , Sequência de Bases , Primers do DNA/genética , Proteínas Desgrenhadas , Exoma/genética , Éxons/genética , Componentes do Gene , Humanos , Dados de Sequência Molecular , Análise de Sequência de DNA
11.
Am J Hum Genet ; 96(3): 386-96, 2015 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-25704603

RESUMO

We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of neutral amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses.


Assuntos
Sistemas de Transporte de Aminoácidos/genética , Homozigoto , Deficiência Intelectual/genética , Transtornos Mentais/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Distúrbios da Fala/genética , Tremor/genética , Sequência de Aminoácidos , Animais , Mapeamento Cromossômico , Variações do Número de Cópias de DNA , Exoma , Feminino , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Linhagem , Fenótipo , Transfecção , Adulto Jovem
12.
Hum Mutat ; 36(1): 106-17, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25385192

RESUMO

Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating variants. Neuroimaging data, available for 15 patients, showed the presence of cerebral malformations in ten patients. The cerebral anomalies comprised malformations of cortical development (MCD), ventriculomegaly, and diminished white matter volume. The phenotypic heterogeneity of the cerebral malformations might result from the involvement of CUL-4B in various cellular pathways essential for normal brain development. Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD. This interaction might contribute to the development of cerebral malformations in patients with variants in CUL4B.


Assuntos
Encéfalo/patologia , Proteínas Culina/genética , Proteínas Culina/metabolismo , Malformações do Desenvolvimento Cortical/genética , Retardo Mental Ligado ao Cromossomo X/genética , Proteínas do Tecido Nervoso/metabolismo , Adolescente , Adulto , Células Cultivadas , Criança , Pré-Escolar , Estudos de Associação Genética , Células HEK293 , Humanos , Lactente , Masculino , Malformações do Desenvolvimento Cortical/metabolismo , Malformações do Desenvolvimento Cortical/patologia , Retardo Mental Ligado ao Cromossomo X/metabolismo , Retardo Mental Ligado ao Cromossomo X/patologia , Pessoa de Meia-Idade , Linhagem , Análise de Sequência de DNA , Adulto Jovem
13.
Nat Genet ; 46(10): 1063-71, 2014 10.
Artigo em Inglês | MEDLINE | ID: mdl-25217958

RESUMO

Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically large, and the underlying causative genes are unclear. We created an expanded CNV morbidity map from 29,085 children with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Follow-up of a subset of affected individuals identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. These genetic changes include haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and genes involved in neuropsychiatric disease despite extensive genetic heterogeneity.


Assuntos
Transtorno Autístico/genética , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença/genética , Sequência de Bases , Proteínas de Transporte/genética , Criança , Mapeamento Cromossômico , Hibridização Genômica Comparativa , Feminino , Estudos de Associação Genética , Haploinsuficiência/genética , Humanos , Deficiência Intelectual/genética , Masculino , Dados de Sequência Molecular , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
14.
Am J Med Genet C Semin Med Genet ; 166C(3): 315-26, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25169753

RESUMO

Mutations in ADNP were recently identified as a frequent cause of syndromic autism, characterized by deficits in social communication and interaction and restricted, repetitive behavioral patterns. Based on its functional domains, ADNP is a presumed transcription factor. The gene interacts closely with the SWI/SNF complex by direct and experimentally verified binding of its C-terminus to three of its core components. A detailed and systematic clinical assessment of the symptoms observed in our patients allows a detailed comparison with the symptoms observed in other SWI/SNF disorders. While the mutational mechanism of the first 10 patients identified suggested a gain of function mechanism, an 11th patient reported here is predicted haploinsufficient. The latter observation may raise hope for therapy, as addition of NAP, a neuroprotective octapeptide named after the first three amino acids of the sequence NAPVSPIQ, has been reported by others to ameliorate some of the cognitive abnormalities observed in a knockout mouse model. It is concluded that detailed clinical and molecular studies on larger cohorts of patients are necessary to establish a better insight in the genotype phenotype correlation and in the mutational mechanism.


Assuntos
Transtorno Autístico/genética , Proteínas de Homeodomínio/genética , Mutação , Proteínas do Tecido Nervoso/genética , Anormalidades Múltiplas/genética , Animais , Transtorno Autístico/etiologia , Pré-Escolar , DNA Helicases/genética , DNA Helicases/metabolismo , Face/anormalidades , Deformidades Congênitas da Mão/genética , Haploinsuficiência/genética , Humanos , Lactente , Deficiência Intelectual/genética , Camundongos Knockout , Micrognatismo/genética , Pescoço/anormalidades , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Oligopeptídeos/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
15.
Cell ; 158(2): 263-276, 2014 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-24998929

RESUMO

Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behaviorally have met with limited success. Hypothesizing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in postmitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Transtornos Globais do Desenvolvimento Infantil/fisiopatologia , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Adolescente , Sequência de Aminoácidos , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Criança , Transtornos Globais do Desenvolvimento Infantil/classificação , Transtornos Globais do Desenvolvimento Infantil/patologia , Pré-Escolar , Proteínas de Ligação a DNA/metabolismo , Feminino , Trato Gastrointestinal/inervação , Trato Gastrointestinal/fisiopatologia , Humanos , Macaca mulatta , Masculino , Megalencefalia/patologia , Dados de Sequência Molecular , Mutação , Alinhamento de Sequência , Fatores de Transcrição/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
16.
Am J Hum Genet ; 94(5): 649-61, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24726472

RESUMO

Recently, we identified in two individuals with intellectual disability (ID) different de novo mutations in DEAF1, which encodes a transcription factor with an important role in embryonic development. To ascertain whether these mutations in DEAF1 are causative for the ID phenotype, we performed targeted resequencing of DEAF1 in an additional cohort of over 2,300 individuals with unexplained ID and identified two additional individuals with de novo mutations in this gene. All four individuals had severe ID with severely affected speech development, and three showed severe behavioral problems. DEAF1 is highly expressed in the CNS, especially during early embryonic development. All four mutations were missense mutations affecting the SAND domain of DEAF1. Altered DEAF1 harboring any of the four amino acid changes showed impaired transcriptional regulation of the DEAF1 promoter. Moreover, behavioral studies in mice with a conditional knockout of Deaf1 in the brain showed memory deficits and increased anxiety-like behavior. Our results demonstrate that mutations in DEAF1 cause ID and behavioral problems, most likely as a result of impaired transcriptional regulation by DEAF1.


Assuntos
Deficiência Intelectual/genética , Transtornos Mentais/genética , Proteínas Nucleares/genética , Distúrbios da Fala/genética , Sequência de Aminoácidos , Animais , Criança , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Mutação , Estrutura Terciária de Proteína/genética , Fatores de Transcrição
17.
Orphanet J Rare Dis ; 9: 43, 2014 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-24674232

RESUMO

BACKGROUND: Mutations in genes encoding components of the Brahma-associated factor (BAF) chromatin remodeling complex have recently been shown to contribute to multiple syndromes characterised by developmental delay and intellectual disability. ARID1B mutations have been identified as the predominant cause of Coffin-Siris syndrome and have also been shown to be a frequent cause of nonsyndromic intellectual disability. Here, we investigate the molecular basis of a patient with an overlapping but distinctive phenotype of intellectual disability, plantar fat pads and facial dysmorphism. METHODS/RESULTS: High density microarray analysis of the patient demonstrated a heterozygous deletion at 6q25.3, which resulted in the loss of four genes including AT Rich Interactive Domain 1B (ARID1B). Subsequent quantitative real-time PCR analysis revealed ARID1B haploinsufficiency in the patient. Analysis of both patient-derived and ARID1B knockdown fibroblasts after serum starvation demonstrated delayed cell cycle re-entry associated with reduced cell number in the S1 phase. Based on the patient's distinctive phenotype, we ascertained four additional patients and identified heterozygous de novo ARID1B frameshift or nonsense mutations in all of them. CONCLUSIONS: This study broadens the spectrum of ARID1B associated phenotypes by describing a distinctive phenotype including plantar fat pads but lacking the hypertrichosis or fifth nail hypoplasia associated with Coffin-Siris syndrome. We present the first direct evidence in patient-derived cells that alterations in cell cycle contribute to the underlying pathogenesis of syndromes associated with ARID1B haploinsufficiency.


Assuntos
Anormalidades Múltiplas/genética , Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Deformidades Congênitas da Mão/genética , Haploinsuficiência/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Fatores de Transcrição/genética , Montagem e Desmontagem da Cromatina , Feminino , Humanos , Masculino
18.
J Clin Invest ; 124(4): 1468-82, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24614104

RESUMO

The recent identification of multiple dominant mutations in the gene encoding ß-catenin in both humans and mice has enabled exploration of the molecular and cellular basis of ß-catenin function in cognitive impairment. In humans, ß-catenin mutations that cause a spectrum of neurodevelopmental disorders have been identified. We identified de novo ß-catenin mutations in patients with intellectual disability, carefully characterized their phenotypes, and were able to define a recognizable intellectual disability syndrome. In parallel, characterization of a chemically mutagenized mouse line that displays features similar to those of human patients with ß-catenin mutations enabled us to investigate the consequences of ß-catenin dysfunction through development and into adulthood. The mouse mutant, designated batface (Bfc), carries a Thr653Lys substitution in the C-terminal armadillo repeat of ß-catenin and displayed a reduced affinity for membrane-associated cadherins. In association with this decreased cadherin interaction, we found that the mutation results in decreased intrahemispheric connections, with deficits in dendritic branching, long-term potentiation, and cognitive function. Our study provides in vivo evidence that dominant mutations in ß-catenin underlie losses in its adhesion-related functions, which leads to severe consequences, including intellectual disability, childhood hypotonia, progressive spasticity of lower limbs, and abnormal craniofacial features in adults.


Assuntos
Anormalidades Craniofaciais/genética , Deficiência Intelectual/genética , Mutação , beta Catenina/genética , Adolescente , Adulto , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Sequência de Bases , Encéfalo/patologia , Caderinas/química , Pré-Escolar , Anormalidades Craniofaciais/patologia , DNA/genética , Modelos Animais de Doenças , Feminino , Genes Dominantes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Complexos Multiproteicos/química , Complexos Multiproteicos/genética , Fenótipo , Homologia de Sequência de Aminoácidos , Síndrome , Adulto Jovem , beta Catenina/química , beta Catenina/metabolismo
19.
Nat Genet ; 46(4): 380-4, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24531329

RESUMO

Despite the high heritability of autism spectrum disorders (ASD), characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests or activities, a genetic diagnosis can be established in only a minority of patients. Known genetic causes include chromosomal aberrations, such as the duplication of the 15q11-13 region, and monogenic causes, as in Rett and fragile-X syndromes. The genetic heterogeneity within ASD is striking, with even the most frequent causes responsible for only 1% of cases at the most. Even with the recent developments in next-generation sequencing, for the large majority of cases no molecular diagnosis can be established. Here, we report ten patients with ASD and other shared clinical characteristics, including intellectual disability and facial dysmorphisms caused by a mutation in ADNP, a transcription factor involved in the SWI/SNF remodeling complex. We estimate this gene to be mutated in at least 0.17% of ASD cases, making it one of the most frequent ASD-associated genes known to date.


Assuntos
Anormalidades Múltiplas/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Homeodomínio/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Sequência de Bases , Códon sem Sentido/genética , Exoma/genética , Mutação da Fase de Leitura/genética , Componentes do Gene , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA
20.
Nucleic Acids Res ; 42(Database issue): D966-74, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24217912

RESUMO

The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.


Assuntos
Ontologias Biológicas , Bases de Dados Factuais , Doenças Genéticas Inatas/genética , Fenótipo , Animais , Doenças Genéticas Inatas/diagnóstico , Genômica , Humanos , Internet , Camundongos
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