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1.
Eur J Hum Genet ; 27(5): 738-746, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30679813

RESUMO

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.

3.
Asia Pac J Ophthalmol (Phila) ; 6(2): 197-207, 2017 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28399338

RESUMO

Retinoblastoma is the prototype genetic cancer: in one or both eyes of young children, most retinoblastomas are initiated by biallelic mutation of the retinoblastoma tumor suppressor gene, RB1, in a developing retinal cell. All those with bilateral retinoblastoma have heritable cancer, although 95% have not inherited the RB1 mutation. Non-heritable retinoblastoma is always unilateral, with 98% caused by loss of both RB1 alleles from the tumor, whereas 2% have normal RB1 in tumors initiated by amplification of the MYCN oncogene. Good understanding of retinoblastoma genetics supports optimal care for retinoblastoma children and their families. Retinoblastoma is the first cancer to officially acknowledge the seminal role of genetics in cancer, by incorporating "H" into the eighth edition of cancer staging (2017): those who carry the RB1 cancer-predisposing gene are H1; those proven to not carry the familial RB1 mutation are H0; and those at unknown risk are HX. We suggest H0* be used for those with residual <1% risk to carry a RB1 mutation due to undetectable mosaicism. Loss of RB1 from a susceptible developing retinal cell initiates the benign precursor, retinoma. Progressive genomic changes result in retinoblastoma, and cancer progression ensues with increasing genomic disarray. Looking forward, novel therapies are anticipated from studies of retinoblastoma and metastatic tumor cells and the second primary cancers that the carriers of RB1 mutations are at high risk to develop. Here, we summarize the concepts of retinoblastoma genetics for ophthalmologists in a question/answer format to assist in the care of patients and their families.


Assuntos
DNA de Neoplasias/análise , Genes do Retinoblastoma/genética , Técnicas de Diagnóstico Molecular/métodos , Mutação , Neoplasias da Retina , Retinoblastoma , Biomarcadores Tumorais/metabolismo , Análise Mutacional de DNA/métodos , Humanos , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/genética , Neoplasias da Retina/metabolismo , Retinoblastoma/diagnóstico , Retinoblastoma/genética , Retinoblastoma/metabolismo
4.
Cancer Genet ; 209(7-8): 359-63, 2016 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27318443

RESUMO

The pediatric ocular tumor retinoblastoma readily metastasizes, but these lesions can masquerade as histologically similar pediatric small round blue cell tumors. Since 98% of retinoblastomas have RB1 mutations and a characteristic genomic copy number "signature", genetic analysis is an appealing adjunct to histopathology to distinguish retinoblastoma metastasis from second primary cancer in retinoblastoma patients. Here, we describe such an approach in two retinoblastoma cases. In patient one, allele-specific (AS)-PCR for a somatic nonsense mutation confirmed that a temple mass was metastatic retinoblastoma. In a second patient, a rib mass shared somatic copy number gains and losses with the primary tumor. For definitive diagnosis, however, an RB1 mutation was needed, but heterozygous promoter→exon 11 deletion was the only RB1 mutation detected in the primary tumor. We used a novel application of inverse PCR to identify the deletion breakpoint. Subsequently, AS-PCR designed for the breakpoint confirmed that the rib mass was metastatic retinoblastoma. These cases demonstrate that personalized molecular testing can confirm retinoblastoma metastases and rule out a second primary cancer, thereby helping to direct the clinical management.


Assuntos
Segunda Neoplasia Primária/genética , Reação em Cadeia da Polimerase/métodos , Neoplasias da Retina/genética , Proteínas de Ligação a Retinoblastoma/genética , Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética , Pré-Escolar , Quebra Cromossômica , Códon sem Sentido , Diagnóstico Diferencial , Evolução Fatal , Feminino , Dosagem de Genes , Humanos , Lactente , Masculino , Metástase Neoplásica
5.
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
6.
Nat Cell Biol ; 17(8): 1074-1087, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26167768

RESUMO

Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localize to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1, also known as CEP90, and C21orf2, also known as LRRC76, as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2 variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease.


Assuntos
Cílios/genética , Transtornos da Motilidade Ciliar/genética , Marcadores Genéticos , Testes Genéticos/métodos , Genômica/métodos , Células Fotorreceptoras , Interferência de RNA , Anormalidades Múltiplas , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/ultraestrutura , Doenças Cerebelares/genética , Cerebelo/anormalidades , Cílios/metabolismo , Cílios/patologia , Transtornos da Motilidade Ciliar/metabolismo , Transtornos da Motilidade Ciliar/patologia , Bases de Dados Genéticas , Síndrome de Ellis-Van Creveld/genética , Anormalidades do Olho/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças Renais Císticas/genética , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Fenótipo , Células Fotorreceptoras/metabolismo , Células Fotorreceptoras/ultraestrutura , Proteínas da Gravidez/genética , Proteínas da Gravidez/metabolismo , Proteínas/genética , Proteínas/metabolismo , Reprodutibilidade dos Testes , Retina/anormalidades , Fatores Supressores Imunológicos/genética , Fatores Supressores Imunológicos/metabolismo , Transfecção , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
7.
Am J Med Genet A ; 164A(3): 676-84, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24357594

RESUMO

Shprintzen-Goldberg syndrome (OMIM #182212) is a connective tissue disorder characterized by craniosynostosis, distinctive craniofacial features, skeletal abnormalities, marfanoid body habitus, aortic dilatation, and intellectual disability. Mutations in exon 1 of SKI have recently been identified as being responsible for approximately 90% of reported individuals diagnosed clinically with Shprintzen-Goldberg syndrome. SKI is a known regulator of TGFß signaling. Therefore, like Marfan syndrome and Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome is likely caused by deregulated TGFß signals, explaining the considerable phenotypic overlap between these three disorders. We describe two additional patients with exon 1 SKI mutations and review the clinical features and literature of Shprintzen-Goldberg syndrome.


Assuntos
Aracnodactilia/diagnóstico , Aracnodactilia/genética , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Proteínas de Ligação a DNA/genética , Éxons , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas/genética , Encéfalo/patologia , Pré-Escolar , Facies , Feminino , Humanos , Imagem por Ressonância Magnética , Fenótipo , Medula Espinal/patologia , Tomografia Computadorizada por Raios X
8.
G3 (Bethesda) ; 2(10): 1197-205, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23050230

RESUMO

Stem cell populations are maintained by keeping a balance between self-renewal (proliferation) and differentiation of dividing stem cells. Within the Caenorhabditis elegans germline, the key regulator maintaining this balance is the canonical Notch signaling pathway, with GLP-1/Notch activity promoting the proliferative fate. We identified the Pumilio homolog, PUF-8, as an inhibitor of the proliferative fate of stem cells in the C. elegans germline. puf-8(0) strongly enhances overproliferation of glp-1(gf) mutants and partially suppresses underproliferation of a weak glp-1(lf) mutant. The germline tumor that is formed in a puf-8(0); glp-1(gf) double mutant is due to a failure of germ cells to enter meiotic prophase. puf-8 likely inhibits the proliferative fate through negatively regulating GLP-1/Notch signaling or by functioning parallel to it.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Células Germinativas/metabolismo , Proteínas de Ligação a RNA/genética , Alelos , Animais , Proteínas de Caenorhabditis elegans/metabolismo , Proliferação de Células , Mapeamento Cromossômico , Regulação da Expressão Gênica , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Mitose , Modelos Biológicos , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteínas de Ligação a RNA/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Células-Tronco/metabolismo
9.
Am J Hum Genet ; 90(5): 925-33, 2012 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-22541558

RESUMO

Nager syndrome, first described more than 60 years ago, is the archetype of a class of disorders called the acrofacial dysostoses, which are characterized by craniofacial and limb malformations. Despite intensive efforts, no gene for Nager syndrome has yet been identified. In an international collaboration, FORGE Canada and the National Institutes of Health Centers for Mendelian Genomics used exome sequencing as a discovery tool and found that mutations in SF3B4, a component of the U2 pre-mRNA spliceosomal complex, cause Nager syndrome. After Sanger sequencing of SF3B4 in a validation cohort, 20 of 35 (57%) families affected by Nager syndrome had 1 of 18 different mutations, nearly all of which were frameshifts. These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4. Our findings add Nager syndrome to a growing list of disorders caused by mutations in genes that encode major components of the spliceosome and also highlight the synergistic potential of international collaboration when exome sequencing is applied in the search for genes responsible for rare Mendelian phenotypes.


Assuntos
Disostose Mandibulofacial/genética , Precursores de RNA/genética , Proteínas de Ligação a RNA/genética , Spliceossomos/genética , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Exoma , Feminino , Haploinsuficiência , Humanos , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Disostose Mandibulofacial/fisiopatologia , Mutação , Precursores de RNA/metabolismo , Fatores de Processamento de RNA , Proteínas de Ligação a RNA/metabolismo , Reprodutibilidade dos Testes , Adulto Jovem
10.
Genome ; 53(2): 83-102, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20140027

RESUMO

The formation of a fully developed gamete from an undifferentiated germ cell requires progression through numerous developmental stages and cell fate decisions. The precise timing and level of gene expression guides cells through these stages. Translational regulation is highly utilized in the germ line of many species, including Caenorhabditis elegans, to regulate gene expression and ensure the proper formation of gametes. In this review, we discuss some of the developmental stages and cell fate decisions involved in the formation of functional gametes in the C. elegans germ line in which translational control has been implicated. These stages include the mitosis versus meiosis decision, the sperm/oocyte decision, and gamete maturation. We also discuss some of the techniques used to identify mRNA targets; the identification of these targets is necessary to clearly understand the role each RNA-binding protein plays in these decisions. Relatively few mRNA targets have been identified, thus providing a major focus for future research. Finally, we propose some reasons why translational control may be utilized so heavily in the germ line. Given that many species have this substantial reliance on translational regulation for the control of gene expression in the germ line, an understanding of translational regulation in the C. elegans germ line is likely to increase our understanding of gamete formation in general.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Células Germinativas/metabolismo , Biossíntese de Proteínas , Regiões 3' não Traduzidas/genética , Animais , Proteínas de Caenorhabditis elegans/genética , Transtornos do Desenvolvimento Sexual/genética , Genes de Helmintos , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética
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