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[PMID]: 28453858 [Au] Autor: McCormack SE; Li D; Kim YJ; Lee JY; Kim SH; Rapaport R; Levine MA [Ad] Endereço: Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104. [Ti] Título: Digenic Inheritance of PROKR2 and WDR11 Mutations in Pituitary Stalk Interruption Syndrome. [So] Source: J Clin Endocrinol Metab;102(7):2501-2507, 2017 Jul 01. [Is] ISSN: 1945-7197 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Context: Pituitary stalk interruption syndrome (PSIS, ORPHA95496) is a congenital defect of the pituitary gland characterized by the triad of a very thin/interrupted pituitary stalk, an ectopic (or absent) posterior pituitary gland, and hypoplasia or aplasia of the anterior pituitary gland. Complex genetic patterns of inheritance of this disorder are increasingly recognized. Objective: The objective of this study was to identify a genetic cause of PSIS in an affected child. Methods: Whole exome sequencing (WES) was performed by using standard techniques, with prioritized genetic variants confirmed via Sanger sequencing. To investigate the effects of one candidate variant on mutant WDR11 function, Western blotting and coimmunofluorescence were used to assess binding capacity, and leptomycin B exposure along with immunofluorescence was used to assess nuclear localization. Results: We describe a child who presented in infancy with combined pituitary hormone deficiencies and whose brain imaging demonstrated a small anterior pituitary, ectopic posterior pituitary, and a thin, interrupted stalk. WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (c.253C>T;p.R85C) inherited from an unaffected mother, and a WDR11 (c.1306A>G;p.I436V) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, EMX1, and to localize to the nucleus. Conclusions: WES in a child with PSIS and his unaffected family implicates a digenic mechanism of inheritance. In cases of hypopituitarism in which there is incomplete segregation of a monogenic genotype with the phenotype, the possibility that a second genetic locus is involved should be considered. [Mh] Termos MeSH primário: Predisposição Genética para Doença Hipopituitarismo/genética Proteínas de Membrana/genética Mutação Hipófise/anormalidades Proteínas Proto-Oncogênicas/genética Receptores Acoplados a Proteínas-G/genética Receptores de Peptídeos/genética [Mh] Termos MeSH secundário: Exoma/genética Genótipo Heterozigoto Seres Humanos Hipopituitarismo/congênito Hipopituitarismo/patologia Recém-Nascido Masculino Linhagem Síndrome [Pt] Tipo de publicação: CASE REPORTS; JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Membrane Proteins); 0 (PROKR2 protein, human); 0 (Proto-Oncogene Proteins); 0 (Receptors, G-Protein-Coupled); 0 (Receptors, Peptide); 0 (WDR11 protein, human) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 180308 [Lr] Data última revisão: 180308 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170429 [St] Status: MEDLINE [do] DOI: 10.1210/jc.2017-00332

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[PMID]: 29362361 [Au] Autor: Yousri NA; Fakhro KA; Robay A; Rodriguez-Flores JL; Mohney RP; Zeriri H; Odeh T; Kader SA; Aldous EK; Thareja G; Kumar M; Al-Shakaki A; Chidiac OM; Mohamoud YA; Mezey JG; Malek JA; Crystal RG; Suhre K [Ad] Endereço: Genetic Medicine, Weill Cornell Medicine-Qatar, PO Box 24144, Doha, Qatar. nay2005@qatar-med.cornell.edu. [Ti] Título: Whole-exome sequencing identifies common and rare variant metabolic QTLs in a Middle Eastern population. [So] Source: Nat Commun;9(1):333, 2018 01 23. [Is] ISSN: 2041-1723 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Metabolomics-genome-wide association studies (mGWAS) have uncovered many metabolic quantitative trait loci (mQTLs) influencing human metabolic individuality, though predominantly in European cohorts. By combining whole-exome sequencing with a high-resolution metabolomics profiling for a highly consanguineous Middle Eastern population, we discover 21 common variant and 12 functional rare variant mQTLs, of which 45% are novel altogether. We fine-map 10 common variant mQTLs to new metabolite ratio associations, and 11 common variant mQTLs to putative protein-altering variants. This is the first work to report common and rare variant mQTLs linked to diseases and/or pharmacological targets in a consanguineous Arab cohort, with wide implications for precision medicine in the Middle East. [Mh] Termos MeSH primário: Árabes Exoma Estudo de Associação Genômica Ampla Metaboloma Locos de Características Quantitativas [Mh] Termos MeSH secundário: Adulto Mapeamento Cromossômico Estudos de Coortes Consanguinidade Feminino Variação Genética Genótipo Sequenciamento de Nucleotídeos em Larga Escala Seres Humanos Masculino Meia-Idade Oriente Médio [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180222 [Lr] Data última revisão: 180222 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180125 [St] Status: MEDLINE [do] DOI: 10.1038/s41467-017-01972-9

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[PMID]: 29193015 [Au] Autor: Zamò A; Pischimarov J; Horn H; Ott G; Rosenwald A; Leich E [Ad] Endereço: Department of Diagnostics and Public Health, University of Verona, Verona, Italy. [Ti] Título: The exomic landscape of t(14;18)-negative diffuse follicular lymphoma with 1p36 deletion. [So] Source: Br J Haematol;180(3):391-394, 2018 02. [Is] ISSN: 1365-2141 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Predominantly diffuse t(14;18) negative follicular lymphoma (FL) with 1p36 deletion shows distinctive clinical, morphological and molecular features that distinguish it from classical FL. In order to investigate whether it possesses a unique mutation profile, we performed whole exome sequencing of six well-characterised cases. Our analysis showed that the mutational landscape of this subtype is largely distinct from classical FL. It appears to harbour several recurrent mutations, affecting STAT6, CREBBP and basal membrane protein genes with high frequency. Our data support the view that this FL subtype should be considered a separate entity from classical FL. [Mh] Termos MeSH primário: Deleção Cromossômica Cromossomos Humanos Par 1 Exoma Predisposição Genética para Doença Linfoma Folicular/genética Linfoma Folicular/patologia Translocação Genética [Mh] Termos MeSH secundário: Cromossomos Humanos Par 14 Cromossomos Humanos Par 18 Seres Humanos Mutação Polimorfismo de Nucleotídeo Único Sequenciamento Completo do Exoma [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180222 [Lr] Data última revisão: 180222 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171202 [St] Status: MEDLINE [do] DOI: 10.1111/bjh.15041

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[PMID]: 28470529 [Au] Autor: Thormählen AS; Runz H [Ad] Endereço: Institute of Human Genetics, University of Heidelberg, Heidelberg, 69120, Germany. [Ti] Título: Systematic Cell-Based Phenotyping of Missense Alleles. [So] Source: Methods Mol Biol;1601:215-228, 2017. [Is] ISSN: 1940-6029 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Sequencing of the protein-coding genome, the exome, has proven powerful to unravel links between genetic variation and disease for both Mendelian and complex conditions. Importantly, however, the increasing number of sequenced human exomes and mapping of disease-associated alleles is accompanied by a simultaneous, yet exponential increase in the overall number of rare and low frequency alleles identified. For most of these novel alleles, biological consequences remain unknown since reliable experimental approaches to better characterize their impact on protein function are only slowly emerging.Here we review a scalable, cell-based strategy that we have recently established to systematically profile the biological impact of rare and low frequency missense variants in vitro. By applying this approach to missense alleles identified through cohort-level exome sequencing in the low-density lipoprotein receptor (LDLR) we are able to distinguish rare alleles that predispose to familial hypercholesterolemia and myocardial infarction from alleles without obvious impact on LDLR levels or functions. We propose that systematic implementation of such and similar strategies will significantly advance our understanding of the protein-coding human genome and how rare and low frequency genetic variation impacts on health and disease. [Mh] Termos MeSH primário: Alelos Hiperlipoproteinemia Tipo II/genética Mutação de Sentido Incorreto Infarto do Miocárdio/genética Receptores de LDL/genética Receptores de LDL/metabolismo [Mh] Termos MeSH secundário: DNA Complementar/química Exoma/genética Predisposição Genética para Doença Proteínas de Fluorescência Verde/química Células HeLa Seres Humanos Fenótipo RNA Interferente Pequeno Análise de Sequência de DNA [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (DNA, Complementary); 0 (LDLR protein, human); 0 (RNA, Small Interfering); 0 (Receptors, LDL); 147336-22-9 (Green Fluorescent Proteins) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180219 [Lr] Data última revisão: 180219 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170505 [St] Status: MEDLINE [do] DOI: 10.1007/978-1-4939-6960-9_17

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[PMID]: 25816005 [Au] Autor: Azaiez H; Decker AR; Booth KT; Simpson AC; Shearer AE; Huygen PL; Bu F; Hildebrand MS; Ranum PT; Shibata SB; Turner A; Zhang Y; Kimberling WJ; Cornell RA; Smith RJ [Ad] Endereço: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America. [Ti] Título: HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice. [So] Source: PLoS Genet;11(3):e1005137, 2015 Mar. [Is] ISSN: 1553-7404 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Hereditary hearing loss is a clinically and genetically heterogeneous disorder. More than 80 genes have been implicated to date, and with the advent of targeted genomic enrichment and massively parallel sequencing (TGE+MPS) the rate of novel deafness-gene identification has accelerated. Here we report a family segregating post-lingual progressive autosomal dominant non-syndromic hearing loss (ADNSHL). After first excluding plausible variants in known deafness-causing genes using TGE+MPS, we completed whole exome sequencing in three hearing-impaired family members. Only a single variant, p.Arg185Pro in HOMER2, segregated with the hearing-loss phenotype in the extended family. This amino acid change alters a highly conserved residue in the coiled-coil domain of HOMER2 that is essential for protein multimerization and the HOMER2-CDC42 interaction. As a scaffolding protein, HOMER2 is involved in intracellular calcium homeostasis and cytoskeletal organization. Consistent with this function, we found robust expression in stereocilia of hair cells in the murine inner ear and observed that over-expression of mutant p.Pro185 HOMER2 mRNA causes anatomical changes of the inner ear and neuromasts in zebrafish embryos. Furthermore, mouse mutants homozygous for the targeted deletion of Homer2 present with early-onset rapidly progressive hearing loss. These data provide compelling evidence that HOMER2 is required for normal hearing and that its sequence alteration in humans leads to ADNSHL through a dominant-negative mode of action. [Mh] Termos MeSH primário: Proteínas de Transporte/genética Orelha Interna/metabolismo Exoma/genética Perda Auditiva Neurossensorial/genética [Mh] Termos MeSH secundário: Animais Proteínas de Transporte/biossíntese Cóclea/metabolismo Cóclea/patologia Orelha Interna/patologia Regulação da Expressão Gênica Perda Auditiva Neurossensorial/patologia Sequenciamento de Nucleotídeos em Larga Escala Proteínas de Arcabouço Homer Seres Humanos Camundongos RNA Mensageiro/biossíntese RNA Mensageiro/genética Estereocílios/genética Estereocílios/patologia Peixe-Zebra Proteína cdc42 de Ligação ao GTP/genética Proteína cdc42 de Ligação ao GTP/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S. [Nm] Nome de substância: 0 (Carrier Proteins); 0 (Homer Scaffolding Proteins); 0 (Homer2 protein, mouse); 0 (RNA, Messenger); EC 3.6.5.2 (cdc42 GTP-Binding Protein) [Em] Mês de entrada: 1512 [Cu] Atualização por classe: 180216 [Lr] Data última revisão: 180216 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150328 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pgen.1005137

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[PMID]: 29331481 [Au] Autor: Sha YW; Xu X; Ji ZY; Lin SB; Wang X; Qiu PP; Zhou Y; Mei LB; Su ZY; Li L; Li P [Ad] Endereço: Department of Reproductive Medicine, Xiamen Maternity and Child Care Hospital, Xiamen, Fujian 361005, China. [Ti] Título: Genetic contribution of SUN5 mutations to acephalic spermatozoa in Fujian China. [So] Source: Gene;647:221-225, 2018 Mar 20. [Is] ISSN: 1879-0038 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Acephalic spermatozoa is an extremely rare disease associated with primary infertility. A recent study showed that genetic alterations in the SUN5 gene lead to this disease, and SUN5 mutations could explain the disease in about half of the patients. Therefore, in the present study, to re-visit the genetic contribution of SUN5 mutations to acephalic spermatozoa, we recruited 15 unrelated affected individuals and screened the SUN5 gene for mutations by whole-exome sequencing (WES) and Sanger sequencing. Five of the 15 (33.33%) subjects were found to carry the same homozygous mutation in the SUN5 gene c.381delA (p.V128Sfs*7). Neither homozygous nor compound heterozygous mutations in SUN5 were found in the other 10 patients. The c.381delA mutation resulted in the truncation of the SUN5 protein and decreased the expression and altered the distribution of the outer dense fiber 1 (ODF1) protein. Thus, in our study SUN5 mutations accounted for only one-third of the patients in our cohort, which is lower than the percentage reported previously. Thus, our study suggests that the contribution of SUN5 mutations to acephalic spermatozoa might not be as high as described previously. These results will help in the genetic counseling of patients with acephalic spermatozoa. [Mh] Termos MeSH primário: Mutação/genética Proteínas/genética Espermatozoides/metabolismo [Mh] Termos MeSH secundário: Adulto China Estudos de Coortes Exoma/genética Proteínas de Choque Térmico/genética Heterozigoto Homozigoto Seres Humanos Infertilidade Masculina/genética Masculino Análise de Sequência de DNA/métodos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Heat-Shock Proteins); 0 (Proteins); 0 (SUN5 protein, human) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180209 [Lr] Data última revisão: 180209 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180115 [St] Status: MEDLINE

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[PMID]: 28748566 [Au] Autor: Leinøe E; Zetterberg E; Kinalis S; Østrup O; Kampmann P; Norström E; Andersson N; Klintman J; Qvortrup K; Nielsen FC; Rossing M [Ad] Endereço: Department of Haematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. [Ti] Título: Application of whole-exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia. [So] Source: Br J Haematol;179(2):308-322, 2017 10. [Is] ISSN: 1365-2141 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Rare inherited bleeding disorders (IBD) are a common cause of bleeding tendency. To ensure a correct diagnosis, specialized laboratory analyses are necessary. This study reports the results of an upfront diagnostic strategy using targeted whole exome sequencing. In total, 156 patients with a significant bleeding assessment tool score participated in the study, of which a third had thrombocytopenia. Eighty-seven genes specifically associated with genetic predisposition to bleeding were analysed by whole exome sequencing. Variants were classified according to the five-tier scheme. We identified 353 germline variants. Eight patients (5%) harboured a known pathogenic variant. Of the 345 previously unknown variants, computational analyses predicted 99 to be significant. Further filtration according to the Mendelian inheritance pattern, resulted in 59 variants being predicted to be clinically significant. Moreover, 34% (20/59) were assigned as novel class 4 or 5 variants upon targeted functional testing. A class 4 or 5 variant was identified in 30% of patients with thrombocytopenia (14/47) versus 11% of patients with a normal platelet count (12/109) (P < 0·01). An IBD diagnosis has a major clinical impact. The genetic investigations detailed here extricated our patients from a diagnostic conundrum, thus demonstrating that continuous optimization of the diagnostic work-up of IBD is of great benefit. [Mh] Termos MeSH primário: Transtornos Herdados da Coagulação Sanguínea/diagnóstico Transtornos Herdados da Coagulação Sanguínea/genética Exoma Mutação em Linhagem Germinativa [Mh] Termos MeSH secundário: Transtornos Herdados da Coagulação Sanguínea/epidemiologia Dinamarca/epidemiologia Feminino Estudo de Associação Genômica Ampla Seres Humanos Masculino Suécia/epidemiologia [Pt] Tipo de publicação: CLINICAL TRIAL; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 180209 [Lr] Data última revisão: 180209 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170728 [St] Status: MEDLINE [do] DOI: 10.1111/bjh.14863

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[PMID]: 28742274 [Au] Autor: Ma D; Yang J; Wang Y; Huang X; Du G; Zhou L [Ad] Endereço: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China. [Ti] Título: Whole exome sequencing identified genetic variations in Chinese hemangioblastoma patients. [So] Source: Am J Med Genet A;173(10):2605-2613, 2017 Oct. [Is] ISSN: 1552-4833 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Hemangioblastomas (HBs) are uncommon tumors characterized by the presence of inactivating alterations in the von Hippel-Lindau (VHL) gene in inherited cases and by infrequent somatic mutation in sporadic entities. We performed whole exome sequencing on 11 HB patients to further elucidate the genetics of HBs. A total of 270 somatic variations in 219 genes, of which there were 86 mutations in 67 genes, were found in sporadic HBs, and 184 mutations were found in 154 genes in familial HBs. C: G>T: A and T: A>C: G mutations are relatively common in most HB patients. Genes harboring the most significant mutations include PCDH9, KLHL12, DCAF4L1, and VHL in sporadic HBs, and ZNF814, DLG2, RIMS1, PNN, and MUC7 in familial HBs. The frequency of CNV varied considerably within sporadic HBs but was relatively similar within familial HBs. Five genes, including OTOGL, PLCB4, SCEL, THSD4, and WWOX, have CNVs in the six patients with sporadic HBs, and three genes, including ABCA6, CWC27, and LAMA2, have CNVs in the five patients with familial HBs. We found new genetic mutations and CNVs that might be involved in HBs; these findings highlight the complexity of the tumorigenesis of HBs and pinpoint potential therapeutic targets for the treatment of HBs. [Mh] Termos MeSH primário: Grupo com Ancestrais do Continente Asiático/genética Biomarcadores Tumorais/genética Neoplasias Cerebelares/genética Exoma/genética Hemangioblastoma/genética Mutação Sequenciamento Completo do Exoma/métodos [Mh] Termos MeSH secundário: Adulto Feminino Predisposição Genética para Doença Seres Humanos Masculino Meia-Idade Prognóstico [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Biomarkers, Tumor) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180207 [Lr] Data última revisão: 180207 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170726 [St] Status: MEDLINE [do] DOI: 10.1002/ajmg.a.38350

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[PMID]: 27776519 [Au] Autor: Roszik J; Haydu LE; Hess KR; Oba J; Joon AY; Siroy AE; Karpinets TV; Stingo FC; Baladandayuthapani V; Tetzlaff MT; Wargo JA; Chen K; Forget MA; Haymaker CL; Chen JQ; Meric-Bernstam F; Eterovic AK; Shaw KR; Mills GB; Gershenwald JE; Radvanyi LG; Hwu P; Futreal PA; Gibbons DL; Lazar AJ; Bernatchez C; Davies MA; Woodman SE [Ad] Endereço: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 904, Houston, TX, 77030, USA. jroszik@mdanderson.org. [Ti] Título: Novel algorithmic approach predicts tumor mutation load and correlates with immunotherapy clinical outcomes using a defined gene mutation set. [So] Source: BMC Med;14(1):168, 2016 10 25. [Is] ISSN: 1741-7015 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: While clinical outcomes following immunotherapy have shown an association with tumor mutation load using whole exome sequencing (WES), its clinical applicability is currently limited by cost and bioinformatics requirements. METHODS: We developed a method to accurately derive the predicted total mutation load (PTML) within individual tumors from a small set of genes that can be used in clinical next generation sequencing (NGS) panels. PTML was derived from the actual total mutation load (ATML) of 575 distinct melanoma and lung cancer samples and validated using independent melanoma (n = 312) and lung cancer (n = 217) cohorts. The correlation of PTML status with clinical outcome, following distinct immunotherapies, was assessed using the Kaplan-Meier method. RESULTS: PTML (derived from 170 genes) was highly correlated with ATML in cutaneous melanoma and lung adenocarcinoma validation cohorts (R = 0.73 and R = 0.82, respectively). PTML was strongly associated with clinical outcome to ipilimumab (anti-CTLA-4, three cohorts) and adoptive T-cell therapy (1 cohort) clinical outcome in melanoma. Clinical benefit from pembrolizumab (anti-PD-1) in lung cancer was also shown to significantly correlate with PTML status (log rank P value < 0.05 in all cohorts). CONCLUSIONS: The approach of using small NGS gene panels, already applied to guide employment of targeted therapies, may have utility in the personalized use of immunotherapy in cancer. [Mh] Termos MeSH primário: Adenocarcinoma/genética Adenocarcinoma/terapia Imunoterapia/métodos Neoplasias Pulmonares/genética Neoplasias Pulmonares/terapia Melanoma/genética Melanoma/terapia Mutação Neoplasias Cutâneas/genética Neoplasias Cutâneas/terapia [Mh] Termos MeSH secundário: Adenocarcinoma/imunologia Algoritmos Anticorpos Monoclonais/uso terapêutico Antígeno CTLA-4/antagonistas & inibidores Antígeno CTLA-4/imunologia Estudos de Coortes Exoma Feminino Seres Humanos Imunoterapia Adotiva/métodos Ipilimumab Neoplasias Pulmonares/imunologia Masculino Melanoma/imunologia Meia-Idade Neoplasias Cutâneas/imunologia Linfócitos T/imunologia Linfócitos T/transplante Carga Tumoral/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antibodies, Monoclonal); 0 (CTLA-4 Antigen); 0 (CTLA4 protein, human); 0 (Ipilimumab) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 180127 [Lr] Data última revisão: 180127 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161026 [St] Status: MEDLINE

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[PMID]: 28453600 [Au] Autor: Jinda W; Taylor TD; Suzuki Y; Thongnoppakhun W; Limwongse C; Lertrit P; Trinavarat A; Atchaneeyasakul LO [Ad] Endereço: Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. [Ti] Título: Whole Exome Sequencing in Eight Thai Patients With Leber Congenital Amaurosis Reveals Mutations in the CTNNA1 and CYP4V2 Genes. [So] Source: Invest Ophthalmol Vis Sci;58(4):2413-2420, 2017 04 01. [Is] ISSN: 1552-5783 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Purpose: Our goal was to describe the clinical and molecular genetic findings in Thai patients with Leber congenital amaurosis (LCA). Methods: Whole exome sequencing (WES) was performed in eight unrelated patients. All genes responsible for inherited retinal diseases (IRDs) based on RetNet were selected for analysis. Potentially causative variants were filtered through a bioinformatics pipeline and validated using Sanger sequencing. Segregation analysis of the causative genes was performed in family members when available. Results: Eleven deleterious variants, six nonsense and five missense, were identified in seven genes: four LCA-associated genes (CEP290, IQCB1, NMNAT1, and RPGRIP1), one gene responsible for syndromic LCA (ALMS1), and two IRDs-related genes (CTNNA1 and CYP4V2). Clinical reassessment supported the diagnosis of syndromic LCA in those patients harboring potentially pathogenic variants in the ALMS1. Interestingly, two causative genes, CTNNA1 and CYP4V2, previously reported to cause butterfly-shaped pigment dystrophy (BSPD) and Bietti's crystalline dystrophy (BCD), respectively, were detected in two other patients. These two patients developed rapid and severe visual loss in contrast to BSPD and BCD patients in previous studies. The results of this study demonstrate that causative variants identified in the CTNNA1 and CYP4V2 genes are also associated with LCA. Conclusions: This is the first report describing the molecular genetics and clinical manifestations of Thai patients with LCA. The present study expands the spectrum of LCA-associated genes, which is a benefit for molecular diagnosis. The identification of mutations in the CTNNA1 and CYP4V2 genes requires further elucidation in larger cohorts with LCA. [Mh] Termos MeSH primário: Grupo com Ancestrais do Continente Asiático/genética Família 4 do Citocromo P450/genética Predisposição Genética para Doença Amaurose Congênita de Leber/genética Mutação alfa Catenina/genética [Mh] Termos MeSH secundário: Criança Pré-Escolar Códon sem Sentido Análise Mutacional de DNA Exoma Feminino Seres Humanos Lactente Masculino Mutação de Sentido Incorreto Tailândia [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (CTNNA1 protein, human); 0 (Codon, Nonsense); 0 (alpha Catenin); EC 1.14.13.- (CYP4V2 protein, human); EC 1.14.14.1 (Cytochrome P450 Family 4) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 180118 [Lr] Data última revisão: 180118 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170429 [St] Status: MEDLINE [do] DOI: 10.1167/iovs.16-21322

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2	and or and not		PalavrasDescritor de assuntoDescritor de assunto primárioLimitesAutorPalavras do títuloPalavras do resumoIdiomaPaís de publicaçãoNome de substânciaNome de pessoa como assuntoRevistaAssunto de RevistaISSNTipo de publicaçãoIdentificador únicoMês de entradaAno de publicaçãoTexto completoAtualização por classeCategoria DeCSCategoria DeCS explodidaCategoria CID-10SubSetsPais de AfiliaçãoAfiliaçãoAfiliação 2
3	and or and not		PalavrasDescritor de assuntoDescritor de assunto primárioLimitesAutorPalavras do títuloPalavras do resumoIdiomaPaís de publicaçãoNome de substânciaNome de pessoa como assuntoRevistaAssunto de RevistaISSNTipo de publicaçãoIdentificador únicoMês de entradaAno de publicaçãoTexto completoAtualização por classeCategoria DeCSCategoria DeCS explodidaCategoria CID-10SubSetsPais de AfiliaçãoAfiliaçãoAfiliação 2

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