Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
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.

3.
Am J Hum Genet ; 102(6): 1195-1203, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29861108

RESUMO

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.

4.
Am J Hum Genet ; 102(5): 995-1007, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29656858

RESUMO

Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.

6.
Am J Med Genet A ; 176(1): 56-67, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29150892

RESUMO

PURA syndrome is a recently described developmental encephalopathy presenting with neonatal hypotonia, feeding difficulties, global developmental delay, severe intellectual disability, and frequent apnea and epilepsy. We describe 18 new individuals with heterozygous sequence variations in PURA. A neuromotor disorder starting with neonatal hyptonia, but ultimately allowing delayed progression to walking, was present in nearly all individuals. Congenital apnea was present in 56% during infancy, but all cases in this cohort resolved during the first year of life. Feeding difficulties were frequently reported, with gastrostomy tube placement required in 28%. Epilepsy was present in 50% of the subjects, including infantile spasms and Lennox-Gastaut syndrome. Skeletal complications were found in 39%. Disorders of gastrointestinal motility and nystagmus were also recurrent features. Autism was diagnosed in one individual, potentially expanding the neurodevelopmental phenotype associated with this syndrome. However, we did not find additional PURA sequence variations in a cohort of 120 subjects with autism. We also present the first neuropathologic studies of PURA syndrome, and describe chronic inflammatory changes around the arterioles within the deep white matter. We did not find significant correlations between mutational class and severity, nor between location of the sequence variation in PUR repeat domains. Further studies are required in larger cohorts of subjects with PURA syndrome to clarify these genotype-phenotype associations.


Assuntos
Encefalopatias/diagnóstico , Encefalopatias/genética , Proteínas de Ligação a DNA/genética , Estudos de Associação Genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Fenótipo , Fatores de Transcrição/genética , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 5 , Análise Mutacional de DNA , Gerenciamento Clínico , Epilepsia , Facies , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética/métodos , Masculino , Síndrome , Substância Branca/patologia , Sequenciamento Completo do Exoma , Adulto Jovem
7.
J Med Genet ; 55(2): 104-113, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29097605

RESUMO

BACKGROUND: De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. OBJECTIVES: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. METHODS: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes. RESULTS: We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. CONCLUSION: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.

8.
Am J Hum Genet ; 101(5): 716-724, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29100085

RESUMO

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.


Assuntos
Deficiências do Desenvolvimento/genética , Mutação de Sentido Incorreto/genética , RNA Helicases/genética , Adenosina Trifosfatases/genética , Adolescente , Aminoácidos/genética , Linhagem Celular , Linhagem Celular Tumoral , Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Feminino , Células HEK293 , Humanos , Deficiência Intelectual/genética , Masculino , RNA/genética
9.
Am J Hum Genet ; 101(5): 824-832, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29106825

RESUMO

The Rab GTPase family comprises ∼70 GTP-binding proteins, functioning in vesicle formation, transport and fusion. They are activated by a conformational change induced by GTP-binding, allowing interactions with downstream effectors. Here, we report five individuals with two recurrent de novo missense mutations in RAB11B; c.64G>A; p.Val22Met in three individuals and c.202G>A; p.Ala68Thr in two individuals. An overlapping neurodevelopmental phenotype, including severe intellectual disability with absent speech, epilepsy, and hypotonia was observed in all affected individuals. Additionally, visual problems, musculoskeletal abnormalities, and microcephaly were present in the majority of cases. Re-evaluation of brain MRI images of four individuals showed a shared distinct brain phenotype, consisting of abnormal white matter (severely decreased volume and abnormal signal), thin corpus callosum, cerebellar vermis hypoplasia, optic nerve hypoplasia and mild ventriculomegaly. To compare the effects of both variants with known inactive GDP- and active GTP-bound RAB11B mutants, we modeled the variants on the three-dimensional protein structure and performed subcellular localization studies. We predicted that both variants alter the GTP/GDP binding pocket and show that they both have localization patterns similar to inactive RAB11B. Evaluation of their influence on the affinity of RAB11B to a series of binary interactors, both effectors and guanine nucleotide exchange factors (GEFs), showed induction of RAB11B binding to the GEF SH3BP5, again similar to inactive RAB11B. In conclusion, we report two recurrent dominant mutations in RAB11B leading to a neurodevelopmental syndrome, likely caused by altered GDP/GTP binding that inactivate the protein and induce GEF binding and protein mislocalization.


Assuntos
Epilepsia/genética , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Mutação , Doenças do Nervo Óptico/congênito , Proteínas rab de Ligação ao GTP/genética , Adolescente , Sequência de Aminoácidos , Sítios de Ligação , Vermis Cerebelar/diagnóstico por imagem , Vermis Cerebelar/metabolismo , Vermis Cerebelar/patologia , Criança , Pré-Escolar , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Epilepsia/diagnóstico por imagem , Epilepsia/patologia , Feminino , Expressão Gênica , Guanosina Difosfato/química , Guanosina Difosfato/metabolismo , Guanosina Trifosfato/química , Guanosina Trifosfato/metabolismo , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Imagem por Ressonância Magnética , Masculino , Modelos Moleculares , Hipotonia Muscular/diagnóstico por imagem , Hipotonia Muscular/patologia , Doenças do Nervo Óptico/diagnóstico por imagem , Doenças do Nervo Óptico/genética , Doenças do Nervo Óptico/patologia , Fenótipo , Ligação Proteica , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo , Substância Branca/patologia , Proteínas rab de Ligação ao GTP/química , Proteínas rab de Ligação ao GTP/deficiência
10.
PLoS Genet ; 13(10): e1006864, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29069077

RESUMO

Kleefstra syndrome, caused by haploinsufficiency of euchromatin histone methyltransferase 1 (EHMT1), is characterized by intellectual disability (ID), autism spectrum disorder (ASD), characteristic facial dysmorphisms, and other variable clinical features. In addition to EHMT1 mutations, de novo variants were reported in four additional genes (MBD5, SMARCB1, NR1I3, and KMT2C), in single individuals with clinical characteristics overlapping Kleefstra syndrome. Here, we present a novel cohort of five patients with de novo loss of function mutations affecting the histone methyltransferase KMT2C. Our clinical data delineates the KMT2C phenotypic spectrum and reinforces the phenotypic overlap with Kleefstra syndrome and other related ID disorders. To elucidate the common molecular basis of the neuropathology associated with mutations in KMT2C and EHMT1, we characterized the role of the Drosophila KMT2C ortholog, trithorax related (trr), in the nervous system. Similar to the Drosophila EHMT1 ortholog, G9a, trr is required in the mushroom body for short term memory. Trr ChIP-seq identified 3371 binding sites, mainly in the promoter of genes involved in neuronal processes. Transcriptional profiling of pan-neuronal trr knockdown and G9a null mutant fly heads identified 613 and 1123 misregulated genes, respectively. These gene sets show a significant overlap and are associated with nearly identical gene ontology enrichments. The majority of the observed biological convergence is derived from predicted indirect target genes. However, trr and G9a also have common direct targets, including the Drosophila ortholog of Arc (Arc1), a key regulator of synaptic plasticity. Our data highlight the clinical and molecular convergence between the KMT2 and EHMT protein families, which may contribute to a molecular network underlying a larger group of ID/ASD-related disorders.


Assuntos
Transtorno do Espectro Autista/genética , Anormalidades Craniofaciais/genética , Proteínas do Citoesqueleto/genética , Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/genética , Cardiopatias Congênitas/genética , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Adolescente , Adulto , Animais , Transtorno do Espectro Autista/fisiopatologia , Sítios de Ligação/genética , Criança , Deleção Cromossômica , Cromossomos Humanos Par 9/genética , Anormalidades Craniofaciais/fisiopatologia , Drosophila melanogaster/genética , Feminino , Regulação da Expressão Gênica , Haploinsuficiência , Cardiopatias Congênitas/fisiopatologia , Histonas/genética , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Mutação , Plasticidade Neuronal/genética , Regiões Promotoras Genéticas
11.
Am J Hum Genet ; 101(3): 466-477, 2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28886345

RESUMO

RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between -2.5 to -5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of ∼10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.


Assuntos
Encefalopatias/genética , Deficiências do Desenvolvimento/genética , Microcefalia/genética , Mutação de Sentido Incorreto , Proteínas rac1 de Ligação ao GTP/genética , Adolescente , Sequência de Aminoácidos , Animais , Encefalopatias/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Feminino , Humanos , Lactente , Masculino , Camundongos , Microcefalia/patologia , Linhagem , Fenótipo , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
12.
Am J Hum Genet ; 99(3): 711-719, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27545680

RESUMO

The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.


Assuntos
Encéfalo/embriologia , Encéfalo/metabolismo , Proteínas de Ligação a DNA/genética , Genes Essenciais/genética , Deficiência Intelectual/genética , Antígenos de Histocompatibilidade Menor/genética , Mutação/genética , Processamento de RNA/genética , Animais , Encéfalo/anormalidades , Encéfalo/patologia , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/metabolismo , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Deficiências do Desenvolvimento/fisiopatologia , Anormalidades do Olho/genética , Feminino , Haploinsuficiência/genética , Cabeça/anormalidades , Heterozigoto , Humanos , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Antígenos de Histocompatibilidade Menor/análise , Antígenos de Histocompatibilidade Menor/metabolismo , Linhagem , RNA Mensageiro/análise , Coluna Vertebral/anormalidades , Síndrome , Peixe-Zebra/anormalidades , Peixe-Zebra/embriologia , Peixe-Zebra/genética
13.
Nat Neurosci ; 19(9): 1194-6, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27479843

RESUMO

To identify candidate genes for intellectual disability, we performed a meta-analysis on 2,637 de novo mutations, identified from the exomes of 2,104 patient-parent trios. Statistical analyses identified 10 new candidate ID genes: DLG4, PPM1D, RAC1, SMAD6, SON, SOX5, SYNCRIP, TCF20, TLK2 and TRIP12. In addition, we show that these genes are intolerant to nonsynonymous variation and that mutations in these genes are associated with specific clinical ID phenotypes.


Assuntos
Deficiência Intelectual/genética , Mutação/genética , Proteínas de Transporte/genética , Proteínas de Ligação a DNA/genética , Proteína 4 Homóloga a Disks-Large , Exoma/genética , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Antígenos de Histocompatibilidade Menor/genética , Fenótipo , Proteínas Quinases/genética , Proteína Fosfatase 2C/genética , Fatores de Transcrição SOXD/genética , Proteína Smad6/genética , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/genética , Proteínas rac1 de Ligação ao GTP/genética
14.
Am J Hum Genet ; 98(2): 373-81, 2016 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-26833328

RESUMO

Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function.


Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Mutação , Ubiquitina Tiolesterase/genética , Adolescente , Sequência de Bases , Criança , Pré-Escolar , Atresia das Cóanas/diagnóstico , Atresia das Cóanas/genética , Deficiências do Desenvolvimento/diagnóstico , Feminino , Genes Ligados ao Cromossomo X , Testes Genéticos , Humanos , Deficiência Intelectual/diagnóstico , Dados de Sequência Molecular , Fenótipo , Ubiquitina Tiolesterase/metabolismo , Inativação do Cromossomo X , Adulto Jovem
15.
Hum Mol Genet ; 25(5): 892-902, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26721934

RESUMO

Recently, we marked TRIO for the first time as a candidate gene for intellectual disability (ID). Across diverse vertebrate species, TRIO is a well-conserved Rho GTPase regulator that is highly expressed in the developing brain. However, little is known about the specific events regulated by TRIO during brain development and its clinical impact in humans when mutated. Routine clinical diagnostic testing identified an intragenic de novo deletion of TRIO in a boy with ID. Targeted sequencing of this gene in over 2300 individuals with ID, identified three additional truncating mutations. All index cases had mild to borderline ID combined with behavioral problems consisting of autistic, hyperactive and/or aggressive behavior. Studies in dissociated rat hippocampal neurons demonstrated the enhancement of dendritic formation by suppressing endogenous TRIO, and similarly decreasing endogenous TRIO in organotypic hippocampal brain slices significantly increased synaptic strength by increasing functional synapses. Together, our findings provide new mechanistic insight into how genetic deficits in TRIO can lead to early neuronal network formation by directly affecting both neurite outgrowth and synapse development.


Assuntos
Transtorno Autístico/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Deficiência Intelectual/genética , Mutação , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases/genética , Agitação Psicomotora/genética , Sinapses/metabolismo , Adulto , Animais , Transtorno Autístico/metabolismo , Transtorno Autístico/patologia , Criança , Feminino , Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/deficiência , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Neurogênese , Neurônios/patologia , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/deficiência , Agitação Psicomotora/metabolismo , Agitação Psicomotora/patologia , Ratos , Análise de Sequência de DNA , Índice de Gravidade de Doença , Sinapses/patologia
16.
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
17.
Am J Hum Genet ; 97(2): 343-52, 2015 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-26235985

RESUMO

Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.


Assuntos
RNA Helicases DEAD-box/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Caracteres Sexuais , Via de Sinalização Wnt/genética , Substituição de Aminoácidos/genética , Animais , Sequência de Bases , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Exoma/genética , Feminino , Dosagem de Genes/genética , Humanos , Deficiência Intelectual/patologia , Masculino , Dados de Sequência Molecular , Análise de Sequência de DNA , Peixe-Zebra
18.
J Clin Invest ; 125(8): 3051-62, 2015 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-26168268

RESUMO

Here we report inherited dysregulation of protein phosphatase activity as a cause of intellectual disability (ID). De novo missense mutations in 2 subunits of serine/threonine (Ser/Thr) protein phosphatase 2A (PP2A) were identified in 16 individuals with mild to severe ID, long-lasting hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and downslanting palpebral fissures. PP2A comprises catalytic (C), scaffolding (A), and regulatory (B) subunits that determine subcellular anchoring, substrate specificity, and physiological function. Ten patients had mutations within a highly conserved acidic loop of the PPP2R5D-encoded B56δ regulatory subunit, with the same E198K mutation present in 6 individuals. Five patients had mutations in the PPP2R1A-encoded scaffolding Aα subunit, with the same R182W mutation in 3 individuals. Some Aα cases presented with large ventricles, causing macrocephaly and hydrocephalus suspicion, and all cases exhibited partial or complete corpus callosum agenesis. Functional evaluation revealed that mutant A and B subunits were stable and uncoupled from phosphatase activity. Mutant B56δ was A and C binding-deficient, while mutant Aα subunits bound B56δ well but were unable to bind C or bound a catalytically impaired C, suggesting a dominant-negative effect where mutant subunits hinder dephosphorylation of B56δ-anchored substrates. Moreover, mutant subunit overexpression resulted in hyperphosphorylation of GSK3ß, a B56δ-regulated substrate. This effect was in line with clinical observations, supporting a correlation between the ID degree and biochemical disturbance.


Assuntos
Agenesia do Corpo Caloso , Corpo Caloso , Transtornos Mentais , Mutação de Sentido Incorreto , Proteína Fosfatase 2 , Adolescente , Adulto , Agenesia do Corpo Caloso/enzimologia , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/patologia , Substituição de Aminoácidos , Criança , Pré-Escolar , Corpo Caloso/enzimologia , Corpo Caloso/patologia , Feminino , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Lactente , Masculino , Transtornos Mentais/enzimologia , Transtornos Mentais/genética , Transtornos Mentais/patologia , Pessoa de Meia-Idade , Fosforilação/genética , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína
19.
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
20.
Eur J Paediatr Neurol ; 18(6): 677-84, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24912731

RESUMO

BACKGROUND: Cerebral visual impairment (CVI) is a disorder in projection and/or interpretation of the visual input in the brain and accounts for 27% of the visually impaired children. AIM: A large cohort of patients with CVI was investigated in order to ascertain the relevance of chromosomal aberrations in the etiology of this disorder. METHODS: 607 patients with CVI and a visual acuity ≤0.3 were assessed for the presence of a chromosomal aberration retrospectively. The observed aberrations were classified for pathogenicity. RESULTS: A total of 98 chromosomal aberrations were found in 79 persons (13%) of the cohort. In nine persons it was not possible to classify the clinical implication of the aberration, due to lack of detailed information. In 70 persons it was possible to classify the aberration for causality: in 41 patients the aberration was associated with CVI, in 16 it was unknown and in 13 the aberration was unlikely to be associated with CVI. For four aberrations, present in 26 patients, the association with CVI has been reported before: trisomy 21, 1p36 deletion syndrome, 17p13.3 deletion syndrome (Miller-Dieker syndrome) and 22q13.3 deletion syndrome (Phelan-McDermid syndrome). The chromosomal aberrations in another 15 patients were for the first time associated with CVI. CONCLUSIONS: Chromosomal aberrations associated with CVI were found in 7% (41/607) of patients, of which 37% (15/41) have not been reported before in association with CVI. Therefore, in patients with CVI chromosomal investigations should be routinely performed to warrant a good clinical diagnosis and counseling.


Assuntos
Cegueira Cortical/genética , Aberrações Cromossômicas , Predisposição Genética para Doença , Pessoas com Deficiência Visual , Cegueira Cortical/epidemiologia , Cegueira Cortical/fisiopatologia , Criança , Pré-Escolar , Mapeamento Cromossômico , Estudos de Coortes , Síndrome de Down/complicações , Feminino , Humanos , Masculino , Acuidade Visual/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA