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J Genet Couns ; 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31553108


In hereditary cancer, multigene panel testing is currently replacing older single-gene approaches. Patients whose tests were previously uninformative could benefit from updated testing. Research suggests that patients desire to be recontacted about updated genetic testing, but few studies have tested the efficacy of recontact efforts. This study investigated the outcomes of a recontact effort in a hereditary cancer clinic and explored the impact of four different recontact letters, randomized in a 2X2 factorial design. Patients who had negative genetic testing for single genes or conditions were mailed letters inviting them to schedule an appointment to discuss updated testing. Patients were randomized to receive one of four letters and each letter emphasized different implications of updated multigene genetic testing: (a) personal medical management implications, (b) implications for family members, (c) both personal and family implications or (d) a control letter. The proportion of patients who arrived for appointments was assessed approximately 7 months after mailing along with associations with patient demographics and type of letter received. Letters were mailed to 586 patients who had initial testing between 2001 and 2015. Most patients were white (78%) and female (97%) with private insurance (65%). At 7 months, 25 patients (4.3%, 95% CI: 2.6% to 5.9%) had arrived for an appointment. Older age was significantly associated with response rate (p = .01), while type of recontact letter was not (p = .54). This study suggests that recontacting patients about updated genetic testing by mail does not yield a large response. It also suggests that personal and/or familial implications do not seem to be significant factors that determine response rate. Nevertheless, results provide meaningful information for cancer clinics about the outcomes of recontact efforts via informational letter.

Nat Commun ; 9(1): 4619, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30397230


Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

Am J Hum Genet ; 101(4): 503-515, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28942966


Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.

Anormalidades Múltiplas/genética , Antígenos Nucleares/genética , Anormalidades Craniofaciais/genética , Regulação da Expressão Gênica no Desenvolvimento , Haploinsuficiência/genética , Transtornos do Desenvolvimento da Linguagem/genética , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/patologia , Adolescente , Animais , Antígenos Nucleares/metabolismo , Sistemas CRISPR-Cas , Proliferação de Células , Células Cultivadas , Criança , Pré-Escolar , Montagem e Desmontagem da Cromatina , Estudos de Coortes , Anormalidades Craniofaciais/patologia , Feminino , Edição de Genes , Haploinsuficiência/fisiologia , Humanos , Transtornos do Desenvolvimento da Linguagem/patologia , Larva/genética , Larva/crescimento & desenvolvimento , Masculino , Microcefalia/patologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Fenótipo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
Biomacromolecules ; 6(3): 1769-81, 2005 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15877404


A new series of linear and permanently charged poly(amidoammonium) salts were synthesized in order to investigate the influence of their ionic and hydrophobic contents on both the cytotoxicity and the transfection mediated by polycation-DNA complexes. The poly(amidoammonium) salts were prepared by chemical modification of a parent poly(amidoamine) containing two tertiary amino groups per structural unit: one incorporated into the main chain and the other fixed at the end of a short bismethylene spacer. The permanent charges were introduced through a quaternization reaction involving iodomethane or 1-iodododecane as an alkylating agent. Under appropriate conditions, the methylation reaction was found to be regioselective, allowing the quaternization of either the side chains or both the side chains and the backbone. Under physiological salt conditions (150 mM NaCl), all of the poly(amidoammonium) salts self-assembled with DNA to form complexes. High proportions of highly quaternized polycation provided better defined morphology to the polycation-DNA complexes. Complexes formed from unquaternized polycation were less cytotoxic than branched poly(ethyleneimine) (25 kDa). At high polycation-DNA weight ratios, the introduction of permanent charges generated a significant increase in the cytotoxicity, but no patent correlation could be established with the amount and the position of the permanent charges. Only complexes formed from polycations with quaternized backbone were able to generate significant gene expression, which was putatively attributed to a better defined toroidal-like morphology together with a higher stability, as suggested by zeta potential measurements. The incorporation of dodecane side chains on highly charged polycations severely amplified the cytotoxicity so that, in return, the transfection level was dramatically affected.

DNA/síntese química , DNA/genética , Técnicas de Transferência de Genes , Compostos de Amônio Quaternário/síntese química , Transfecção/métodos , Animais , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/genética , Células COS , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Cercopithecus aethiops , Avaliação Pré-Clínica de Medicamentos/métodos , Compostos de Amônio Quaternário/farmacologia , Sais