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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
Shanshan Han, Xiliang Liu, Shanglun Xie, Meng Gao, Fei Liu, Shanshan Yu, Peng Sun, Changquan Wang, Stephen Archacki, Zhaojing Lu, Xuebin Hu, Yayun Qin, Zhen Qu, Yuwen Huang, Yuexia Lv, Jiayi Tu, Jingzhen Li, Tinsae Assefa Yimer, Tao Jiang, Zhaohui Tang, Daji Luo, Fangyi Chen, Mugen Liu
Most cases of Usher syndrome type II (USH2) are due to mutations in the USH2A gene. There are no effective treatments or ideal animal models for this disease, and the pathological mechanisms of USH2 caused by USH2A mutations are still unknown. Here, we constructed a ush2a knockout (ush2a-/- ) zebrafish model using TALEN technology to investigate the molecular pathology of USH2. An early onset auditory disorder and abnormal morphology of inner ear stereocilia were identified in the ush2a-/- zebrafish. Consequently, the disruption of Ush2a in zebrafish led to a hearing impairment, like that in mammals...
September 21, 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
Toomas Kivisild
The following sentence on the 11th page of the article.
September 20, 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
Florencia Cavodeassi, Sophie Creuzet, Heather C Etchevers
Mutations in effectors of the hedgehog signaling pathway are responsible for a wide variety of ocular developmental anomalies. These range from massive malformations of the brain and ocular primordia, not always compatible with postnatal life, to subtle but damaging functional effects on specific eye components. This review will concentrate on the effects and effectors of the major vertebrate hedgehog ligand for eye and brain formation, Sonic hedgehog (SHH), in tissues that constitute the eye directly and also in those tissues that exert indirect influence on eye formation...
August 2, 2018: Human Genetics
Trevor J Pemberton, Paul Verdu, Noémie S Becker, Cristen J Willer, Barry S Hewlett, Sylvie Le Bomin, Alain Froment, Noah A Rosenberg, Evelyne Heyer
The evolutionary and biological bases of the Central African "pygmy" phenotype, a characteristic of rainforest hunter-gatherers defined by reduced body size compared with neighboring farmers, remain largely unknown. Here, we perform a joint investigation in Central African hunter-gatherers and farmers of adult standing height, sitting height, leg length, and body mass index (BMI), considering 358 hunter-gatherers and 169 farmers with genotypes for 153,798 SNPs. In addition to reduced standing heights, hunter-gatherers have shorter sitting heights and leg lengths and higher sitting/standing height ratios than farmers and lower BMI for males...
July 14, 2018: Human Genetics
Heather M Ochs-Balcom, Holly Shaw, Leah Preus, Julie R Palmer, Stephen A Haddad, Lynn Rosenberg, Edward A Ruiz-Narváez
Several genome-wide association studies (GWAS) have identified genetic variants associated with birth weight. To date, however, most GWAS of birth weight have focused primarily on European ancestry samples even though prevalence of low birth weight is higher among African-Americans. We conducted admixture mapping using 2918 ancestral informative markers in 2596 participants of the Black Women's Health Study, with the goal of identifying novel genomic regions where local African ancestry is associated with birth weight...
July 13, 2018: Human Genetics
Hildegard Kehrer-Sawatzki, Lan Kluwe, Reinhard E Friedrich, Anna Summerer, Eleonora Schäfer, Ute Wahlländer, Cordula Matthies, Isabel Gugel, Said Farschtschi, Christian Hagel, David N Cooper, Victor-Felix Mautner
Schwannomatosis and neurofibromatosis type 2 (NF2) are both characterized by the development of multiple schwannomas but represent different genetic entities. Whereas NF2 is caused by mutations of the NF2 gene, schwannomatosis is associated with germline mutations of SMARCB1 or LZTR1. Here, we studied 15 sporadic patients with multiple non-intradermal schwannomas, but lacking vestibular schwannomas and ophthalmological abnormalities, who fulfilled the clinical diagnostic criteria for schwannomatosis. None of them harboured germline NF2 or SMARCB1 mutations as determined by the analysis of blood samples but seven had germline LZTR1 variants predicted to be pathogenic...
July 13, 2018: Human Genetics
Yumi Yamaguchi-Kabata, Takashi Morihara, Tomoyuki Ohara, Toshiharu Ninomiya, Atsushi Takahashi, Hiroyasu Akatsu, Yoshio Hashizume, Noriyuki Hayashi, Daichi Shigemizu, Keith A Boroevich, Manabu Ikeda, Michiaki Kubo, Masatoshi Takeda, Tatsuhiko Tsunoda
Alzheimer's disease (AD) is a common neurological disease that causes dementia in humans. Although the reports of associated pathological genes have been increasing, the molecular mechanism leading to the accumulation of amyloid-β (Aβ) in human brain is still not well understood. To identify novel genes that cause accumulation of Aβ in AD patients, we conducted an integrative analysis by combining a human genetic association study and transcriptome analysis in mouse brain. First, we examined genome-wide gene expression levels in the hippocampus, comparing them to amyloid Aβ level in mice with mixed genetic backgrounds...
July 13, 2018: Human Genetics
Anna Summerer, Victor-Felix Mautner, Meena Upadhyaya, Kathleen B M Claes, Josef Högel, David N Cooper, Ludwine Messiaen, Hildegard Kehrer-Sawatzki
The breakpoints of type-1 NF1 deletions encompassing 1.4-Mb are located within NF1-REPa and NF1-REPc, which exhibit a complex structure comprising different segmental duplications in direct and inverted orientation. Here, we systematically assessed the proportion of type-1 NF1 deletions caused by nonallelic homologous recombination (NAHR) and those mediated by other mutational mechanisms. To this end, we analyzed 236 unselected type-1 deletions and observed that 179 of them (75.8%) had breakpoints located within the NAHR hotspot PRS2, whereas 39 deletions (16...
July 10, 2018: Human Genetics
Paola Bovolenta, Juan-Ramón Martinez-Morales
Embryological manipulations in chick embryos have been pivotal in our understanding of many aspects of vertebrate eye formation. This research was particularly important in uncovering the role of tissue interactions as drivers of eye morphogenesis and to dissect the function of critical genes. Here, we have highlighted a few of these past experiments to endorse their value in searching for hitherto unknown causes of rare congenital eye anomalies, such as microphthalmia, anophthalmia and coloboma. We have also highlighted a number of similarities between the chicken and human eye, which might be exploited to address other eye pathologies, including degenerative ocular diseases...
July 6, 2018: Human Genetics
Nicola Ragge, Bertrand Isidor, Pierre Bitoun, Sylvie Odent, Irina Giurgea, Benjamin Cogné, Wallid Deb, Marie Vincent, Jessica Le Gall, Jenny Morton, Derek Lim, Guylène Le Meur, Celia Zazo Seco, Dimitra Zafeiropoulou, Dorine Bax, Petra Zwijnenburg, Anara Arteche, Saoud Tahsin Swafiri, Ruth Cleaver, Meriel McEntagart, Usha Kini, William Newman, Carmen Ayuso, Marta Corton, Yvan Herenger, Médéric Jeanne, Patrick Calvas, Nicolas Chassaing
Two distinct syndromes arise from pathogenic variants in the X-linked gene BCOR (BCL-6 corepressor): oculofaciocardiodental (OFCD) syndrome, which affects females, and a severe microphthalmia ('Lenz'-type) syndrome affecting males. OFCD is an X-linked dominant syndrome caused by a variety of BCOR null mutations. As it manifests only in females, it is presumed to be lethal in males. The severe male X-linked recessive microphthalmia syndrome ('Lenz') usually includes developmental delay in addition to the eye findings and is caused by hypomorphic BCOR variants, mainly by a specific missense variant c...
July 4, 2018: Human Genetics
Bincui Cai, Shuo Sun, Zhiqing Li, Xiaomin Zhang, Yifeng Ke, Jin Yang, Xiaorong Li
Retinal degeneration diseases, such as age-related macular degeneration and retinitis pigmentosa, affect millions of people worldwide and are major causes of irreversible blindness. Effective treatments for retinal degeneration, including drug therapy, gene augmentation or transplantation approaches, have been widely investigated. Nevertheless, more research should be dedicated to therapeutic methods to improve future clinical treatments. Recently, with the rapid development of genome-editing technology, gene therapy has become a potentially effective treatment for retinal degeneration diseases...
September 2018: Human Genetics
Nuria C Bramswig, Aida M Bertoli-Avella, Beate Albrecht, Aida I Al Aqeel, Amal Alhashem, Nouriya Al-Sannaa, Maissa Bah, Katharina Bröhl, Christel Depienne, Nathalie Dorison, Diane Doummar, Nadja Ehmke, Hasnaa M Elbendary, Svetlana Gorokhova, Delphine Héron, Denise Horn, Kiely James, Boris Keren, Alma Kuechler, Samira Ismail, Mahmoud Y Issa, Isabelle Marey, Michèle Mayer, Jennifer McEvoy-Venneri, Andre Megarbane, Cyril Mignot, Sarar Mohamed, Caroline Nava, Nicole Philip, Cecile Ravix, Arndt Rolfs, Abdelrahim Abdrabou Sadek, Lara Segebrecht, Valentina Stanley, Camille Trautman, Stephanie Valence, Laurent Villard, Thomas Wieland, Hartmut Engels, Tim M Strom, Maha S Zaki, Joseph G Gleeson, Hermann-Josef Lüdecke, Peter Bauer, Dagmar Wieczorek
NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively...
September 2018: Human Genetics
Regie Lyn P Santos-Cortez, Valeed Khan, Falak Sher Khan, Zaib-Un-Nisa Mughal, Imen Chakchouk, Kwanghyuk Lee, Memoona Rasheed, Rifat Hamza, Anushree Acharya, Ehsan Ullah, Muhammad Arif Nadeem Saqib, Izoduwa Abbe, Ghazanfar Ali, Muhammad Jawad Hassan, Saadullah Khan, Zahid Azeem, Irfan Ullah, Michael J Bamshad, Deborah A Nickerson, Isabelle Schrauwen, Wasim Ahmad, Muhammad Ansar, Suzanne M Leal
Identification of Mendelian genes for neurodevelopmental disorders using exome sequencing to study autosomal recessive (AR) consanguineous pedigrees has been highly successful. To identify causal variants for syndromic and non-syndromic intellectual disability (ID), exome sequencing was performed using DNA samples from 22 consanguineous Pakistani families with ARID, of which 21 have additional phenotypes including microcephaly. To aid in variant identification, homozygosity mapping and linkage analysis were performed...
September 2018: Human Genetics
E R Schiff, M Frampton, N Ben-Yosef, B E Avila, F Semplici, N Pontikos, S L Bloom, S A McCartney, R Vega, L B Lovat, E Wood, A Hart, E Israeli, D Crespi, M A Furman, S Mann, C D Murray, A W Segal, A P Levine
Rare variants are thought to contribute to the genetics of inflammatory bowel disease (IBD), which is more common amongst the Ashkenazi Jewish (AJ) population. A family-based approach using exome sequencing of AJ individuals with IBD was employed with a view to identify novel rare genetic variants for this disease. Exome sequencing was performed on 960 Jewish individuals including 513 from 199 multiplex families with up to eight cases. Rare, damaging variants in loci prioritized by linkage analysis and those shared by multiple affected individuals within the same family were identified...
September 2018: Human Genetics
Paolo Devanna, Maartje van de Vorst, Rolph Pfundt, Christian Gilissen, Sonja C Vernes
Intellectual disability (ID) is a severe neurodevelopmental disorder with genetically heterogeneous causes. Large-scale sequencing has led to the identification of many gene-disrupting mutations; however, a substantial proportion of cases lack a molecular diagnosis. As such, there remains much to uncover for a complete understanding of the genetic underpinnings of ID. Genetic variants present in non-coding regions of the genome have been highlighted as potential contributors to neurodevelopmental disorders given their role in regulating gene expression...
September 2018: Human Genetics
Jochen Weile, Frederick P Roth
Given the constantly improving cost and speed of genome sequencing, it is reasonable to expect that personal genomes will soon be known for many millions of humans. This stands in stark contrast with our limited ability to interpret the sequence variants which we find. Although it is, perhaps, easiest to interpret variants in coding regions, knowledge of functional impact is unknown for the vast majority of missense variants. While many computational approaches can predict the impact of coding variants, they are given a little weight in the current guidelines for interpreting clinical variants...
September 2018: Human Genetics
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