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Human Genetics

J Plaisancié, F Ceroni, R Holt, C Zazo Seco, P Calvas, N Chassaing, Nicola K Ragge
Eye formation is the result of coordinated induction and differentiation processes during embryogenesis. Disruption of any one of these events has the potential to cause ocular growth and structural defects, such as anophthalmia and microphthalmia (A/M). A/M can be isolated or occur with systemic anomalies, when they may form part of a recognizable syndrome. Their etiology includes genetic and environmental factors; several hundred genes involved in ocular development have been identified in humans or animal models...
February 14, 2019: Human Genetics
Hanan E Shamseldin, Nawal Makhseed, Niema Ibrahim, Tarfa Al-Sheddi, Eman Alobeid, Firdous Abdulwahab, Fowzan S Alkuraya
Nuclear pore complex (NPC) is a fundamental component of the nuclear envelope and is key to the nucleocytoplasmic transport. Mutations in several NUP genes that encode individual components of NPC known as nucleoporins have been identified in recent years among patients with static encephalopathies characterized by developmental delay and microcephaly. We describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death...
February 13, 2019: Human Genetics
Peter P Nghiem, Joe N Kornegay
Therapies for Duchenne muscular dystrophy (DMD) must first be tested in animal models to determine proof-of-concept, efficacy, and importantly, safety. The murine and canine models for DMD are genetically homologous and most commonly used in pre-clinical testing. Although the mouse is a strong, proof-of-concept model, affected dogs show more analogous clinical and immunological disease progression compared to boys with DMD. As such, evaluating genetic therapies in the canine models may better predict response at the genetic, phenotypic, and immunological levels...
February 7, 2019: Human Genetics
Kathryn M Meurs, Steven G Friedenberg, Justin Kolb, Chandra Saripalli, Paola Tonino, Kathleen Woodruff, Natasha J Olby, Bruce W Keene, Darcy B Adin, Oriana L Yost, Teresa C DeFrancesco, Sunshine Lahmers, Sandra Tou, G Diane Shelton, Henk Granzier
The dog provides a large animal model of familial dilated cardiomyopathy for the study of important aspects of this common familial cardiovascular disease. We have previously demonstrated a form of canine dilated cardiomyopathy in the Doberman pinscher breed that is inherited as an autosomal dominant trait and is associated with a splice site variant in the pyruvate dehydrogenase kinase 4 (PDK4) gene, however, genetic heterogeneity exists in this species as well and not all affected dogs have the PDK4 variant...
February 4, 2019: Human Genetics
Jonas Carlsson Almlöf, Sara Nystedt, Dag Leonard, Maija-Leena Eloranta, Giorgia Grosso, Christopher Sjöwall, Anders A Bengtsson, Andreas Jönsen, Iva Gunnarsson, Elisabet Svenungsson, Lars Rönnblom, Johanna K Sandling, Ann-Christine Syvänen
Systemic lupus erythematosus (SLE, OMIM 152700) is a systemic autoimmune disease with a complex etiology. The mode of inheritance of the genetic risk beyond familial SLE cases is currently unknown. Additionally, the contribution of heterozygous variants in genes known to cause monogenic SLE is not fully understood. Whole-genome sequencing of DNA samples from 71 Swedish patients with SLE and their healthy biological parents was performed to investigate the general genetic risk of SLE using known SLE GWAS risk loci identified using the ImmunoChip, variants in genes associated to monogenic SLE, and the mode of inheritance of SLE risk alleles in these families...
February 1, 2019: Human Genetics
Karen Y He, Xiaoyin Li, Tanika N Kelly, Jingjing Liang, Brian E Cade, Themistocles L Assimes, Lewis C Becker, Amber L Beitelshees, Adam P Bress, Yen-Pei Christy Chang, Yii-Der Ida Chen, Paul S de Vries, Ervin R Fox, Nora Franceschini, Anna Furniss, Yan Gao, Xiuqing Guo, Jeffrey Haessler, Shih-Jen Hwang, Marguerite Ryan Irvin, Rita R Kalyani, Ching-Ti Liu, Chunyu Liu, Lisa Warsinger Martin, May E Montasser, Paul M Muntner, Stanford Mwasongwe, Walter Palmas, Alex P Reiner, Daichi Shimbo, Jennifer A Smith, Beverly M Snively, Lisa R Yanek, Eric Boerwinkle, Adolfo Correa, L Adrienne Cupples, Jiang He, Sharon L R Kardia, Charles Kooperberg, Rasika A Mathias, Braxton D Mitchell, Bruce M Psaty, Ramachandran S Vasan, D C Rao, Stephen S Rich, Jerome I Rotter, James G Wilson, Aravinda Chakravarti, Alanna C Morrison, Daniel Levy, Donna K Arnett, Susan Redline, Xiaofeng Zhu
In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0...
January 22, 2019: Human Genetics
Jia Xu, Pengwei Yang, Shang Xue, Bhuvan Sharma, Marta Sanchez-Martin, Fang Wang, Kirk A Beaty, Elinor Dehan, Baiju Parikh
In the field of cancer genomics, the broad availability of genetic information offered by next-generation sequencing technologies and rapid growth in biomedical publication has led to the advent of the big-data era. Integration of artificial intelligence (AI) approaches such as machine learning, deep learning, and natural language processing (NLP) to tackle the challenges of scalability and high dimensionality of data and to transform big data into clinically actionable knowledge is expanding and becoming the foundation of precision medicine...
January 22, 2019: Human Genetics
Bing Mei, Ya Wang, Weiyuan Ye, Han Huang, Qian Zhou, Yuanyuan Chen, Yajing Niu, Manling Zhang, Qingyang Huang
Previous genome-wide linkage and association studies have identified an osteoporosis-associated locus at 1p36 that harbors SNPs rs34920465 and rs6426749. The 1p36 locus also comprises the WNT4 gene with known role in bone metabolism and functionally unknown ZBTB40/lncRNA ZBTB40-IT1 genes. How these might interact to contribute to osteoporosis susceptibility is not known. In this study, we show that lncRNA ZBTB40-IT1 is able to suppress osteogenesis and promote osteoclastogenesis by regulating the expression of WNT4, RUNX2, OSX, ALP, COL1A1, OPG and RANKL in U-2OS and hFOB1...
January 19, 2019: Human Genetics
Chuan Qiu, Hui Shen, Xiaoying Fu, Chao Xu, Qing Tian, Hongwen Deng
Osteoporosis is a skeletal disorder characterized by low bone mineral density (BMD) and deterioration of bone microarchitecture. To identify novel genetic loci underlying osteoporosis, an effective strategy is to focus on scanning of variants with high potential functional impacts. Enhancers play a crucial role in regulating cell-type-specific transcription. Therefore, single-nucleotide polymorphisms (SNPs) located in enhancers (enhancer-SNPs) may represent strong candidate functional variants. Here, we performed a targeted analysis for potential functional enhancer-SNPs that may affect gene expression and biological processes in bone-related cells, specifically, osteoblasts, and peripheral blood monocytes (PBMs), using five independent cohorts (n = 5905) and the genetics factors for osteoporosis summary statistics, followed by comprehensive integrative genomic analyses of chromatin states, transcription, and metabolites...
January 17, 2019: Human Genetics
Marco Fichera, Pinella Failla, Lucia Saccuzzo, Martina Miceli, Eliana Salvo, Lucia Castiglia, Ornella Galesi, Lucia Grillo, Francesco Calì, Donatella Greco, Carmelo Amato, Corrado Romano, Maurizio Elia
Developmental and epileptic encephalopathies (DEEs) are genetically heterogenous conditions, often characterized by early onset, EEG interictal epileptiform abnormalities, polymorphous and drug-resistant seizures, and neurodevelopmental impairments. In this study, we investigated the genetic defects in two siblings who presented with severe DEE, microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature, and kyphoscoliosis. Whole exome next-generation sequencing (WES) identified in both siblings a homozygous non-sense variant in the ACTL6B gene (NM_016188:c...
January 17, 2019: Human Genetics
Rossella Cannarella, Rosita A Condorelli, Ylenia Duca, Sandro La Vignera, Aldo E Calogero
Genetic anomalies are known to affect about 15% of infertile patients with azoospermia or severe oligozoospermia. Despite a throughout diagnostic work-up, in up to the 72% of the male partners of infertile couples, no etiological factor can be found; hence, the cause of infertility remains unclear. Recently, several novel genetic causes of spermatogenic failure (SPGF) have been described. The aim of this review was to collect all the available evidence of SPGF genetics, matching data from in-vitro and animal models with those in human beings to provide a comprehensive and updated overview of the genes capable of affecting spermatogenesis...
January 17, 2019: Human Genetics
Anelisa Gollo Dantas, Marcos Leite Santoro, Natalia Nunes, Claudia Berlim de Mello, Larissa Salustiano Evangelista Pimenta, Vera Ayres Meloni, Diogo Cordeiro Queiroz Soares, Sintia Nogueira Belangero, Gianna Carvalheira, Chong Ae Kim, Maria Isabel Melaragno
The 22q11.2 deletion syndrome (22q11.2DS) is caused by recurrent hemizygous deletions of chromosome 22q11.2. The phenotype of the syndrome is complex and varies widely among individuals. Little is known about the role of the different genes located in 22q11.2, and we hypothesized that genetic risk factors lying elsewhere in the genome might contribute to the phenotype. Here, we present the whole-genome gene expression data of 11 patients with approximately 3 Mb deletions. Apart from the hemizygous genes mapped to the 22q11...
January 9, 2019: Human Genetics
Cheryl Y Gregory-Evans, Xia Wang, Kevin Gregory-Evans
Over the last three decades, genetic studies have made great strides toward the identification of genes and genetic mechanisms underlying congenital disorders of the eye. However, despite the vast knowledge available this has not translated into treatments to prevent or repair the damage in the clinical setting. Recently, new research in technologies, such as tissue regeneration, next generation designer drugs, and genome editing, have become available for some genetic disorders that might be applicable to congenital ocular diseases in the near future...
January 2, 2019: Human Genetics
Dayana A Delgado, Chenan Zhang, Kevin Gleason, Kathryn Demanelis, Lin S Chen, Jianjun Gao, Shantanu Roy, Justin Shinkle, Mekala Sabarinathan, Maria Argos, Lin Tong, Alauddin Ahmed, Tariqul Islam, Muhammad Rakibuz-Zaman, Golam Sarwar, Hasan Shahriar, Mahfuzar Rahman, Muhammad Yunus, Jennifer A Doherty, Farzana Jasmine, Muhammad G Kibriya, Habibul Ahsan, Brandon L Pierce
Leukocyte telomere length (LTL) is a heritable trait with two potential sources of heritability (h2 ): inherited variation in non-telomeric regions (e.g., SNPs that influence telomere maintenance) and variability in the lengths of telomeres in gametes that produce offspring zygotes (i.e., "direct" inheritance). Prior studies of LTL h2 have not attempted to disentangle these two sources. Here, we use a novel approach for detecting the direct inheritance of telomeres by studying the association between identity-by-descent (IBD) sharing at chromosome ends and phenotypic similarity in LTL...
December 10, 2018: Human Genetics
Jeroen J Smits, Jaap Oostrik, Andy J Beynon, Sarina G Kant, Pia A M de Koning Gans, Liselotte J C Rotteveel, Jolien S Klein Wassink-Ruiter, Rolien H Free, Saskia M Maas, Jiddeke van de Kamp, Paul Merkus, Wouter Koole, Ilse Feenstra, Ronald J C Admiraal, Cornelis P Lanting, Margit Schraders, Helger G Yntema, Ronald J E Pennings, Hannie Kremer
ATP2B2 encodes the PMCA2 Ca2+ pump that plays an important role in maintaining ion homeostasis in hair cells among others by extrusion of Ca2+ from the stereocilia to the endolymph. Several mouse models have been described for this gene; mice heterozygous for loss-of-function defects display a rapidly progressive high-frequency hearing impairment. Up to now ATP2B2 has only been reported as a modifier, or in a digenic mechanism with CDH23 for hearing impairment in humans. Whole exome sequencing in hearing impaired index cases of Dutch and Polish origins revealed five novel heterozygous (predicted to be) loss-of-function variants of ATP2B2...
December 8, 2018: Human Genetics
Anas M Alazami, Sateesh Maddirevula, Mohamed Zain Seidahmed, Lulu A Albhlal, Fowzan S Alkuraya
ISLR2 (immunoglobulin superfamily containing leucine-rich repeat 2), encodes a protein involved in axon guidance in brain development (hence the other name leucine-rich repeat domain- and immunoglobulin domain-containing axon extension proteins; LINX). A recently described mouse knockout displays hydrocephalus. However, the corresponding phenotype in humans is unknown. Here, we describe a multiplex consanguineous family in which a homozygous truncating variant in ISLR2 segregates with severe congenital hydrocephalus, arthrogryposis multiplex congenita and abdominal distension...
November 27, 2018: Human Genetics
Anna Summerer, Eleonora Schäfer, Victor-Felix Mautner, Ludwine Messiaen, David N Cooper, Hildegard Kehrer-Sawatzki
Different types of large NF1 deletion are distinguishable by breakpoint location and potentially also by the frequency of mosaicism with normal cells lacking the deletion. However, low-grade mosaicism with fewer than 10% normal cells has not yet been excluded for all NF1 deletion types since it is impossible to assess by the standard techniques used to identify such deletions, including MLPA and array analysis. Here, we used ultra-deep amplicon sequencing to investigate the presence of normal cells in the blood of 20 patients with type-1 NF1 deletions lacking mosaicism according to MLPA...
November 26, 2018: Human Genetics
Qiqi Wang, Da Li, Baozhu Cai, Qing Chen, Caihua Li, Yanhua Wu, Li Jin, Xiuxia Wang, Xiaojin Zhang, Feng Zhang
Premature ovarian insufficiency (POI) is a severe female disorder characterized by primary or secondary amenorrhea before 40 years of age. Genetic factors have been implicated in the pathogenesis of POI, but known POI-associated genes account for only a small fraction of heritability. Here, we performed whole-exome sequencing (WES) to explore pathogenic genes in Han Chinese subjects with POI. Intriguingly, we identified novel or rare heterozygous missense variants of SALL4 (spalt-like transcription factor 4) in 3 (6%) of 50 POI subjects...
January 2019: 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...
January 2019: Human Genetics
Qizong Lao, Marcia Des Jardin, Rahul Jayakrishnan, Monique Ernst, Deborah P Merke
CYP21A2 defects result in congenital adrenal hyperplasia (CAH), an autosomal recessive disorder characterized by impaired adrenal steroidogenesis. CYP21A2 lies within the major histocompatibility complex in an area of the genome highly susceptible to genetic variation. Alterations in the neighboring complement component 4 isotypes C4A and C4B have been associated with psychiatric and autoimmune disease. The purpose of this study was to evaluate C4A and C4B in patients with CAH in relation to CYP21A2 genotype and psychiatric and autoimmune comorbidity...
December 2018: Human Genetics
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