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Eur J Hum Genet ; 27(5): 738-746, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30679813


Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.

Hum Mutat ; 38(11): 1592-1605, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28801929


Microdeletions of the Y chromosome (YCMs), Klinefelter syndrome (47,XXY), and CFTR mutations are known genetic causes of severe male infertility, but the majority of cases remain idiopathic. Here, we describe a novel method using single molecule Molecular Inversion Probes (smMIPs), to screen infertile men for mutations and copy number variations affecting known disease genes. We designed a set of 4,525 smMIPs targeting the coding regions of causal (n = 6) and candidate (n = 101) male infertility genes. After extensive validation, we screened 1,112 idiopathic infertile men with non-obstructive azoospermia or severe oligozoospermia. In addition to five chromosome YCMs and six other sex chromosomal anomalies, we identified five patients with rare recessive mutations in CFTR as well as a patient with a rare heterozygous frameshift mutation in SYCP3 that may be of clinical relevance. This results in a genetic diagnosis in 11-17 patients (1%-1.5%), a yield that may increase significantly when more genes are confidently linked to male infertility. In conclusion, we developed a flexible and scalable method to reliably detect genetic causes of male infertility. The assay consolidates the detection of different types of genetic variation while increasing the diagnostic yield and detection precision at the same or lower price compared with currently used methods.

Azoospermia/diagnóstico , Azoospermia/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Oligospermia/diagnóstico , Oligospermia/genética , Aberrações Cromossômicas , Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Estudos de Associação Genética/métodos , Estudos de Associação Genética/normas , Testes Genéticos/métodos , Testes Genéticos/normas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Fenótipo , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Aberrações dos Cromossomos Sexuais , Contagem de Espermatozoides
Hum Mol Genet ; 25(5): 892-902, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26721934


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.

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
Eur J Hum Genet ; 24(8): 1145-53, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26757981


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.

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
Am J Hum Genet ; 94(5): 649-61, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24726472


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.

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