De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

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

Agricultura familiar e programas de desenvolvimento rural no Alto Jequitinhonha.

Os regimes agrários peculiares e os baixos níveis relativos dos indicadores sócio-econômicos fizeram com que a região do alto Jequitinhonha, nordeste de Minas Gerais, fosse considerada uma das mais complexas do Brasil. Por isso, vários governos orientaram para lá programas de desenvolvimento rural. Mas esses esforços não produziram bons resultados. Este artigo analisa as relações entre programas públicos e agricultura familiar, fazendo um balanço dos métodos e resultados das últimas três décadas. Conclui pela necessidade de incorporar as especificidades de história, ambientes e sociedade aos programas, que deveriam partir das experiências das organizações da região e se ajustar às ações e à cultura desses agricultores

Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

Genetics of disease, diagnosis and treatmen

Paralog Studies Augment Gene Discovery: DDX and DHX Genes

PubMedID: 31256877Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders. © 2019 American Society of Human GeneticsNational Heart, Lung, and Blood Institute Aicardi Syndrome Foundation: 2T32NS043124-16 National Institute on Drug Abuse National Institute of Diabetes and Digestive and Kidney Diseases: K12 DK083014 National Heart, Lung, and Blood Institute Fondazione Telethon National Institute of Neurological Disorders and Stroke: U54-HG003273 GSP15001 Deutsche Forschungsgemeinschaft California Department of Fish and Game: LE 4223/1 National Human Genome Research Institute National Institutes of Health: K08 HG008986, DK088767 National Cancer Institute R01 NS058529, R35 NS105078 National Institute of Mental Health National Institute of Neurological Disorders and StrokeThis work was supported in part by grants UM1 HG006542 (J.R.L) and UM1 HG006493 (M.B.) from the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI) to the Baylor Hopkins Center for Mendelian Genomics and the University of Washington Center for Mendelian Genomics, R01 NS058529 and R35 NS105078 (J.R.L.) from the National Institute of Neurological Disorders and Stroke (NINDS), U54-HG003273 (R.A.G.) from NHGRI , and Telethon Undiagnosed Diseases Program (TUDP) GSP15001 (N.B.-P.) from the Telethon Foundation , and also by the Aicardi Syndrome Foundation. I.P. was supported by 2T32NS043124-16 through the National Institutes of Health . J.E.P. was supported by NHGRI K08 HG008986 . F.H. was supported by the National Institutes of Health ( DK088767 ). M.R.B. was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) K12 DK083014 . D.L was supported by the Werner Otto Stiftung and the German Research Foundation ( DFG; LE 4223/1 ). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health , and by the National Cancer Institute , NHGRI , NHLBI , the National Institute on Drug Abuse , the National Institute of Mental Health , and NINDS . The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/29/18. The authors would like to thank Hans-Jurgen Kreienkamp for the help in identifying helicase core motifs and the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at https://gnomad.broadinstitute.org/about

Phenotypic expansion illuminates multilocus pathogenic variation

PubMedID: 29790871Purpose: Multilocus variation—pathogenic variants in two or more disease genes—can potentially explain the underlying genetic basis for apparent phenotypic expansion in cases for which the observed clinical features extend beyond those reported in association with a “known” disease gene. Methods: Analyses focused on 106 patients, 19 for whom apparent phenotypic expansion was previously attributed to variation at known disease genes. We performed a retrospective computational reanalysis of whole-exome sequencing data using stringent Variant Call File filtering criteria to determine whether molecular diagnoses involving additional disease loci might explain the observed expanded phenotypes. Results: Multilocus variation was identified in 31.6% (6/19) of families with phenotypic expansion and 2.3% (2/87) without phenotypic expansion. Intrafamilial clinical variability within two families was explained by multilocus variation identified in the more severely affected sibling. Conclusion: Our findings underscore the role of multiple rare variants at different loci in the etiology of genetically and clinically heterogeneous cohorts. Intrafamilial phenotypic and genotypic variability allowed a dissection of genotype–phenotype relationships in two families. Our data emphasize the critical role of the clinician in diagnostic genomic analyses and demonstrate that apparent phenotypic expansion may represent blended phenotypes resulting from pathogenic variation at more than one locus. © 2018, American College of Medical Genetics and Genomics.National Heart, Lung, and Blood Institute National Human Genome Research Institute: UM1 HG006542 R01 NS058529, R35 NS105078 K08 HG008986 National Institute of Neurological Disorders and Stroke: U54-HG003273J.E.P. was supported by a Chao Physician-Scientist Award through the Ting Tsung and Wei Fong Chao Foundation and K08 HG008986 through the National Human Genome Research Institute. This work was supported in part by grants UM1 HG006542 (J.R.L.) from the National Human Genome Research Institute/National Heart, Lung, and Blood Institute to the Baylor Hopkins Center for Mendelian Genomics, R01 NS058529 and R35 NS105078 (J.R.L.) from the National Institute of Neurological Disorders and Stroke, and U54-HG003273 (R.A.G.) from the National Human Genome Research Institute

Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease

Contains fulltext : 207316.pdf (Publisher’s version ) (Closed access

AHDC1 missense mutations in Xia-Gibbs syndrome

Xia-Gibbs syndrome (XGS; MIM: 615829) is a phenotypically heterogeneous neurodevelopmental disorder (NDD) caused by newly arising mutations in the AT-Hook DNA-Binding Motif-Containing 1 (AHDC1) gene that are predicted to lead to truncated AHDC1 protein synthesis. More than 270 individuals have been diagnosed with XGS worldwide. Despite the absence of an independent assay for AHDC1 protein function to corroborate potential functional consequences of rare variant genetic findings, there are also reports of individuals with XGS-like trait manifestations who have de novo missense AHDC1 mutations and who have been provided a molecular diagnosis of the disorder. To investigate a potential contribution of missense mutations to XGS, we mapped the missense mutations from 10 such individuals to the AHDC1 conserved protein domain structure and detailed the observed phenotypes. Five newly identified individuals were ascertained from a local XGS Registry, and an additional five were taken from external reports or databases, including one publication. Where clinical data were available, individuals with missense mutations all displayed phenotypes consistent with those observed in individuals with AHDC1 truncating mutations, including delayed motor milestones, intellectual disability (ID), hypotonia, and speech delay. A subset of the 10 reported missense mutations cluster in two regions of the AHDC1 protein with known conserved domains, likely representing functional motifs. Variants outside the clustered regions score lower for computational prediction of their likely damaging effects. Overall, de novo missense variants in AHDC1 are likely diagnostic of XGS when in silico analysis of their position relative to conserved regions is considered together with disease trait manifestations.Genetics of disease, diagnosis and treatmen