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Human Genetics

Lisa G Shaffer, Kyle Sundin, Anja Geretschlaeger, Julia Segert, June E Swinburne, Ramon Royal, Robert Loechel, Christina J Ramirez, Blake C Ballif
This publication represents a proposed approach to quality standards and guidelines for canine clinical genetic testing laboratories. Currently, there are no guidelines for laboratories performing clinical testing on dogs. Thus, there is no consensus set of protocols that set the minimal standards of quality among these laboratories, potentially causing variable results between laboratories, inconsistencies in reporting, and the inability to share information that could impact testing among organizations. A minimal standard for quality in testing is needed as breeders use the information from genetic testing to make breeding choices and irreversible decisions regarding spay, neuter or euthanasia...
November 13, 2018: Human Genetics
Deepti Anand, Atul Kakrana, Archana D Siddam, Hongzhan Huang, Irfan Saadi, Salil A Lachke
Isolated or syndromic congenital cataracts are heterogeneous developmental defects, making the identification of the associated genes challenging. In the past, mouse lens expression microarrays have been successfully applied in bioinformatics tools (e.g., iSyTE) to facilitate human cataract-associated gene discovery. To develop a new resource for geneticists, we report high-throughput RNA sequencing (RNA-seq) profiles of mouse lens at key embryonic stages (E)10.5 (lens pit), E12.5 (primary fiber cell differentiation), E14...
November 11, 2018: Human Genetics
Ekaterina Orlova, Andrew Yeh, Min Shi, Brian Firek, Sarangarajan Ranganathan, David C Whitcomb, David N Finegold, Robert E Ferrell, M Michael Barmada, Mary L Marazita, David A Hinds, John R Shaffer, Michael J Morowitz
Appendicitis affects 9% of Americans and is the most common diagnosis requiring hospitalization of both children and adults. We performed a genome-wide association study of self-reported appendectomy with 18,773 affected adults and 114,907 unaffected adults of European American ancestry. A significant association with appendectomy was observed at 4q25 near the gene PITX2 (rs2129979, p value = 8.82 × 10-14 ) and was replicated in an independent sample of Caucasians (59 affected, 607 unaffected; p value = 0...
November 3, 2018: Human Genetics
Svetlana A Smirnikhina, Arina A Anuchina, Alexander V Lavrov
Despite the recent discover of genome-editing methods, today we can say these approaches have firmly entered our life. Two approaches-knocking out malfunctioning gene allele or correcting the mutation with precise knock-in-can be used in hereditary monogenic diseases treatment. The latter approach is relatively ineffective. Modern data about the ways of repair of double-strand DNA breaks formed by nucleases are presented in this review. The main part of the review is devoted to the ways of increasing precise and effective knock-in: inhibition of non-homologous end joining and stimulation of homology-directed repair key factors, use of small molecules with unknown mechanism of action, cell-cycle synchronization and cell-cycle-dependent activity of Cas9, donor molecule design, selection, alternative methods for insertion and other approaches...
November 2, 2018: Human Genetics
J C Gomez-Verjan, E R Vazquez-Martinez, N A Rivero-Segura, R H Medina-Campos
Ageing is one of the most complex processes in nature; how could we prevent the associated biological changes and chronic diseases that string along with this process, is a challenge in healthcare around the world. Recent advances in next-generation sequencing have reached a stage where it is possible to know from a specific tissue the most abundant transcripts, alternative splicing process and, non-coding RNA molecules (microRNA's, long non-coding RNA's, and circular RNAs). Moreover, our knowledge of several biological processes related to ageing such as senescence and autophagy have dramatically increased in the last years...
November 1, 2018: Human Genetics
Pedro Gaspar, Isabel Almudi, Maria D S Nunes, Alistair P McGregor
The fruit fly Drosophila melanogaster has served as an excellent model to study and understand the genetics of many human diseases from cancer to neurodegeneration. Studying the regulation of growth, determination and differentiation of the compound eyes of this fly, in particular, have provided key insights into a wide range of diseases. Here we review the regulation of the development of fly eyes in light of shared aspects with human eye development. We also show how understanding conserved regulatory pathways in eye development together with the application of tools for genetic screening and functional analyses makes Drosophila a powerful model to diagnose and characterize the genetics underlying many human eye conditions, such as aniridia and retinitis pigmentosa...
November 1, 2018: Human Genetics
Anne Slavotinek
As new genes for A/M are identified in the genomic era, the number of syndromes associated with A/M has greatly expanded. In this review, we provide a brief synopsis of the clinical presentation and molecular genetic etiology of previously characterized pathways involved in A/M, including the Sex-determining region Y-box 2 (SOX2), Orthodenticle Homeobox 2 (OTX2) and Paired box protein-6 (PAX6) genes, and the Stimulated by retinoic acid gene 6 homolog (STRA6), Aldehyde Dehydrogenase 1 Family Member A3 (ALDH1A3), and RA Receptor Beta (RARβ) genes that are involved in retinoic acid synthesis...
October 30, 2018: Human Genetics
Ikumi Umeki, Tetsuya Niihori, Taiki Abe, Shin-Ichiro Kanno, Nobuhiko Okamoto, Seiji Mizuno, Kenji Kurosawa, Keisuke Nagasaki, Makoto Yoshida, Hirofumi Ohashi, Shin-Ichi Inoue, Yoichi Matsubara, Ikuma Fujiwara, Shigeo Kure, Yoko Aoki
RASopathies are a group of developmental disorders caused by mutations in genes that regulate the RAS/MAPK pathway and include Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome and other related disorders. Whole exome sequencing studies recently identified LZTR1, PPP1CB and MRAS as new causative genes in RASopathies. However, information on the phenotypes of LZTR1 mutation-positive patients and functional properties of the mutations are limited. To identify variants of LZTR1, PPP1CB, and MRAS, we performed a targeted next-generation sequencing and reexamined previously analyzed exome data in 166 patients with suspected RASopathies...
October 27, 2018: Human Genetics
Ivan Shelihan, Sophie Ehresmann, Cinzia Magnani, Francesca Forzano, Chiara Baldo, Nicola Brunetti-Pierri, Philippe M Campeau
Lowry-Wood syndrome (LWS) is a skeletal dysplasia characterized by multiple epiphyseal dysplasia associated with microcephaly, developmental delay and intellectual disability, and eye involvement. Pathogenic variants in RNU4ATAC, an RNA of the minor spliceosome important for the excision of U12-dependent introns, have been recently associated with LWS. This gene had previously also been associated with microcephalic osteodysplastic primordial dwarfism (MOPD) and Roifman syndrome (RS), two distinct conditions which share with LWS some skeletal and neurological anomalies...
October 27, 2018: Human Genetics
Xiaoning Yu, Xiyuan Ping, Xin Zhang, Yilei Cui, Hao Yang, Xiajing Tang, Yelei Tang, Xingchao Shentu
The gap junction protein alpha 8 (GJA8) gene has been widely studied in human congenital cataracts. However, little is known about its relationship with age-related cataract (ARC). In this study, three GJA8-tagged single nucleotide polymorphisms related to an increased ARC risk were identified: rs2132397 for general ARC under both dominant and additive models; rs7541950 for general ARC under both recessive and additive models; and rs6657114 for cortical cataract under the recessive model. To uncover the underlying mechanisms, this study also sought to explore whether GJA8 is involved in the autophagy process in human lens epithelial cells...
October 22, 2018: Human Genetics
Rupal L Shah, Jeremy A Guggenheim
Previous studies have suggested that naturally occurring genetic variation contributes to the risk of astigmatism. The purpose of this investigation was to identify genetic markers associated with corneal and refractive astigmatism in a large-scale European ancestry cohort (UK Biobank) who underwent keratometry and autorefraction at an assessment centre. Genome-wide association studies for corneal and refractive astigmatism were performed in individuals of European ancestry (N = 86,335 and 88,005 respectively), with the mean corneal astigmatism or refractive astigmatism in fellow eyes analysed as a quantitative trait (dependent variable)...
October 10, 2018: Human Genetics
Hildegard Nikki Hall, Kathleen A Williamson, David R FitzPatrick
Absence of part or all of the iris, aniridia, is a feature of several genetically distinct conditions. This review focuses on iris development and then the clinical features and molecular genetics of these iris malformations. Classical aniridia, a panocular eye malformation including foveal hypoplasia, is the archetypal phenotype associated with heterozygous PAX6 loss-of-function mutations. Since this was identified in 1991, many genetic mechanisms of PAX6 inactivation have been elucidated, the commonest alleles being intragenic mutations causing premature stop codons, followed by those causing C-terminal extensions...
September 22, 2018: Human Genetics
A S Ma, J R Grigg, R V Jamieson
Disorders of the anterior segment of the eye encompass a variety of clinical presentations including aniridia, Axenfeld and Rieger anomalies, primary congenital glaucoma, Peters anomaly, as well as syndromal associations. These conditions have a significant impact on vision due to disruption of the visual axis, and also secondary glaucoma which occurs in over 50% of patients. Ocular anterior segment disorders occur due to a complex interplay of developmental, embryological and genetic factors, and often have phenotypic overlaps and genetic heterogeneity...
September 21, 2018: Human Genetics
Linda M Reis, Elena V Semina
Pediatric cataract represents an important cause of pediatric visual impairment. While both genetic and environmental causes for pediatric cataract are known, a large proportion remains idiopathic. The purpose of this review is to discuss genes involved in isolated pediatric cataract, with a focus on variable inheritance patterns within genes. Mutations in over 52 genes are known to cause isolated pediatric cataract, with a major contribution from genes encoding for crystallins, transcription factors, membrane proteins, and cytoskeletal proteins...
September 5, 2018: Human Genetics
Marianthi Karali, Sandro Banfi
Accumulating evidence on the role of non-protein-coding RNA sequences in the regulation of gene expression is greatly expanding our understanding of the flow of genetic information within biological systems. The interplay between protein-coding and non-coding RNAs (ncRNAs) is essential for tissue development, homeostasis, and function. NcRNAs can be divided in short ncRNAs, whose main subtype is represented by microRNAs, and long ncRNAs, which constitute a more heterogeneous class. The retina is a light-sensitive tissue consisting of highly interconnected cell types and is the primary target of many genetic diseases...
September 5, 2018: Human Genetics
Steven A Narod
It has been suggested that a personalised approach to cancer prevention and screening might lead to a new paradigm for cancer control. Various aspects include testing for high-penetrance cancer susceptibility genes and generating personal risks scores, based on panels of single nucleotide polymorphisms. These tests can categorize women into various groupings of risk for cancer prevention (surgery and chemoprevention) cancer screening and prevention of cancer recurrence. In this review, I investigate various claims and come to the conclusion that the approach may be beneficial for the occasional patient but is unlikely to have any impact on reducing the burden of cancer incidence and mortality as whole...
October 2018: Human Genetics
Pieter W M Bonnemaijer, Adriana I Iglesias, Girish N Nadkarni, Anna J Sanyiwa, Hassan G Hassan, Colin Cook, Mark Simcoe, Kent D Taylor, Claudia Schurmann, Gillian M Belbin, Eimear E Kenny, Erwin P Bottinger, Suzanne van de Laar, Susan E I Wiliams, Stephen K Akafo, Adeyinka O Ashaye, Linda M Zangwill, Christopher A Girkin, Maggie C Y Ng, Jerome I Rotter, Robert N Weinreb, Zheng Li, R Rand Allingham, Abhishek Nag, Pirro G Hysi, Magda A Meester-Smoor, Janey L Wiggs, Michael A Hauser, Christopher J Hammond, Hans G Lemij, Ruth J F Loos, Cornelia M van Duijn, Alberta A H J Thiadens, Caroline C W Klaver
Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1...
October 2018: Human Genetics
Julie Plaisancié, M Tarilonte, P Ramos, C Jeanton-Scaramouche, V Gaston, H Dollfus, D Aguilera, J Kaplan, L Fares-Taie, F Blanco-Kelly, C Villaverde, C Francannet, A Goldenberg, I Arroyo, J M Rozet, C Ayuso, N Chassaing, P Calvas, M Corton
There is an increasing implication of non-coding regions in pathological processes of genetic origin. This is partly due to the emergence of sophisticated techniques that have transformed research into gene expression by allowing a more global understanding of the genome, both at the genomic, epigenomic and chromatin levels. Here, we implemented the analysis of PAX6, whose coding loss-of-function variants are mainly implied in aniridia, by studying its non-coding regions (untranslated regions, introns and cis-regulatory sequences)...
October 2018: Human Genetics
Maria Clara Bonaglia, Nehir Edibe Kurtas, Edoardo Errichiello, Sara Bertuzzo, Silvana Beri, Mana M Mehrjouy, Aldesia Provenzano, Debora Vergani, Vanna Pecile, Francesca Novara, Paolo Reho, Marilena Carmela Di Giacomo, Giancarlo Discepoli, Roberto Giorda, Micheala A Aldred, Cíntia Barros Santos-Rebouças, Andressa Pereira Goncalves, Diane N Abuelo, Sabrina Giglio, Ivana Ricca, Fabrizia Franchi, Philippos Patsalis, Carolina Sismani, María Angeles Morí, Julián Nevado, Niels Tommerup, Orsetta Zuffardi
We investigated 52 cases of de novo unbalanced translocations, consisting in a terminally deleted or inverted-duplicated deleted (inv-dup del) 46th chromosome to which the distal portion of another chromosome or its opposite end was transposed. Array CGH, whole-genome sequencing, qPCR, FISH, and trio genotyping were applied. A biparental origin of the deletion and duplication was detected in 6 cases, whereas in 46, both imbalances have the same parental origin. Moreover, the duplicated region was of maternal origin in more than half of the cases, with 25% of them showing two maternal and one paternal haplotype...
October 2018: Human Genetics
N H Chapman, R A Bernier, S J Webb, J Munson, E M Blue, D-H Chen, E Heigham, W H Raskind, Ellen M Wijsman
Hundreds of genes have been implicated in autism spectrum disorders (ASDs). In genetically heterogeneous conditions, large families with multiple affected individuals provide strong evidence implicating a rare variant, and replication of the same variant in multiple families is unusual. We previously published linkage analyses and follow-up exome sequencing in seven large families with ASDs, implicating 14 rare exome variants. These included rs200195897, which was transmitted to four affected individuals in one family...
October 2018: Human Genetics
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