Showing papers by "Stylianos E. Antonarakis published in 2021"
National Institutes of Health1, University of California, San Diego2, Saint Petersburg State University3, University of Washington4, University of California, Berkeley5, Johns Hopkins University6, University of Connecticut7, University of California, Santa Cruz8, University of Geneva9, Stowers Institute for Medical Research10, Harvard University11, Wellcome Trust Sanger Institute12, University of Cambridge13, Howard Hughes Medical Institute14, Washington University in St. Louis15, University of Tennessee Health Science Center16, Yale University17, Pacific Biosciences18, University of Düsseldorf19, National Institute of Standards and Technology20, Max Planck Society21, Baylor College of Medicine22, University of California, Davis23, Institute for Systems Biology24, Duke University25, University of Pittsburgh26, Russian Academy of Sciences27
TL;DR: The T2T-CHM13 reference as mentioned in this paper contains gapless assemblies for all 22 autosomes plus Chromosome X, corrected numerous errors, and introduced nearly 200 million bp of novel sequence containing 2,226 paralogous gene copies, 115 of which are predicted to be protein coding.
Abstract: In 2001, Celera Genomics and the International Human Genome Sequencing Consortium published their initial drafts of the human genome, which revolutionized the field of genomics. While these drafts and the updates that followed effectively covered the euchromatic fraction of the genome, the heterochromatin and many other complex regions were left unfinished or erroneous. Addressing this remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium has finished the first truly complete 3.055 billion base pair (bp) sequence of a human genome, representing the largest improvement to the human reference genome since its initial release. The new T2T-CHM13 reference includes gapless assemblies for all 22 autosomes plus Chromosome X, corrects numerous errors, and introduces nearly 200 million bp of novel sequence containing 2,226 paralogous gene copies, 115 of which are predicted to be protein coding. The newly completed regions include all centromeric satellite arrays and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies for the first time.
108 citations
Peking Union Medical College Hospital1, Baylor College of Medicine2, Shandong University3, Shenzhen University4, Wenzhou Medical College5, Guangxi Medical University6, University of Tübingen7, Fudan University8, Peking Union Medical College9, Baylor University10, National and Kapodistrian University of Athens11, University of Paris12, University of São Paulo13, University of Bern14, University of Geneva15, Boston Children's Hospital16
TL;DR: In this paper, the authors performed exome sequencing on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe).
Abstract: Mayer-Rokitansky-Kuster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Mullerian ducts (MD)/Wolffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.
37 citations
Bar-Ilan University1, Laboratory of Molecular Biology2, Tel Aviv University3, McGill University4, Pompeu Fabra University5, University of Geneva6, University at Buffalo7, Roswell Park Cancer Institute8, University of Strasbourg9, Allen Institute for Brain Science10, Indiana University – Purdue University Indianapolis11, University of Paris12, University of California, San Diego13, South London and Maudsley NHS Foundation Trust14, King's College London15
TL;DR: In this paper, the authors provide a biological overview with regard to specific susceptibility of individuals with DS to SARS-CoV-2 infection as well as data from a recent survey on the prevalence of COVID-19 among them.
Abstract: The current SARS-CoV-2 outbreak, which causes COVID-19, is particularly devastating for individuals with chronic medical conditions, in particular those with Down Syndrome (DS) who often exhibit a higher prevalence of respiratory tract infections, immune dysregulation and potential complications. The incidence of Alzheimer's disease (AD) is much higher in DS than in the general population, possibly increasing further the risk of COVID-19 infection and its complications. Here we provide a biological overview with regard to specific susceptibility of individuals with DS to SARS-CoV-2 infection as well as data from a recent survey on the prevalence of COVID-19 among them. We see an urgent need to protect people with DS, especially those with AD, from COVID-19 and future pandemics and focus on developing protective measures, which also include interventions by health systems worldwide for reducing the negative social effects of long-term isolation and increased periods of hospitalization.
22 citations
Bar-Ilan University1, Laboratory of Molecular Biology2, Autonomous University of Barcelona3, McGill University4, Pompeu Fabra University5, University of Geneva6, University at Buffalo7, Roswell Park Cancer Institute8, University of Strasbourg9, Allen Institute for Brain Science10, Indiana University – Purdue University Indianapolis11, University of Paris12, University of California, San Diego13, King's College London14, South London and Maudsley NHS Foundation Trust15
TL;DR: In this article, the authors comprehensively review the immunobiology of Down Syndrome and its contribution to higher susceptibility to severe illness and mortality from respiratory tract infections, such as the influenza virus, respiratory syncytial virus, SARS-CoV-2 (COVID-19), and bacterial pneumonias.
Abstract: The risk of severe outcomes following respiratory tract infections is significantly increased in individuals over 60 years, especially in those with chronic medical conditions, i.e., hypertension, diabetes, cardiovascular disease, dementia, chronic respiratory disease, and cancer. Down Syndrome (DS), the most prevalent intellectual disability, is caused by trisomy-21 in ~1:750 live births worldwide. Over the past few decades, a substantial body of evidence has accumulated, pointing at the occurrence of alterations, impairments, and subsequently dysfunction of the various components of the immune system in individuals with DS. This associates with increased vulnerability to respiratory tract infections in this population, such as the influenza virus, respiratory syncytial virus, SARS-CoV-2 (COVID-19), and bacterial pneumonias. To emphasize this link, here we comprehensively review the immunobiology of DS and its contribution to higher susceptibility to severe illness and mortality from respiratory tract infections.
21 citations
TL;DR: The findings indicate that CELF2 variants that disrupt its nuclear localization are associated with DEE, and it is demonstrated the extranuclear mislocalization of mutant CELF1 protein in cells transfected with mutant Celf2 complementary DNA plasmids.
Abstract: We report heterozygous CELF2 (NM_006561.3) variants in five unrelated individuals: Individuals 1-4 exhibited developmental and epileptic encephalopathy (DEE) and Individual 5 had intellectual disability and autistic features. CELF2 encodes a nucleocytoplasmic shuttling RNA-binding protein that has multiple roles in RNA processing and is involved in the embryonic development of the central nervous system and heart. Whole-exome sequencing identified the following CELF2 variants: two missense variants [c.1558C>T:p.(Pro520Ser) in unrelated Individuals 1 and 2, and c.1516C>G:p.(Arg506Gly) in Individual 3], one frameshift variant in Individual 4 that removed the last amino acid of CELF2 c.1562dup:p.(Tyr521Ter), possibly resulting in escape from nonsense-mediated mRNA decay (NMD), and one canonical splice site variant, c.272-1G>C in Individual 5, also probably leading to NMD. The identified variants in Individuals 1, 2, 4, and 5 were de novo, while the variant in Individual 3 was inherited from her mosaic mother. Notably, all identified variants, except for c.272-1G>C, were clustered within 20 amino acid residues of the C-terminus, which might be a nuclear localization signal. We demonstrated the extranuclear mislocalization of mutant CELF2 protein in cells transfected with mutant CELF2 complementary DNA plasmids. Our findings indicate that CELF2 variants that disrupt its nuclear localization are associated with DEE.
10 citations
TL;DR: The authors identified two consanguineous families with homozygous variants predicted to alter the splicing of ATP9A which encodes a transmembrane lipid flippase of the class II P4-ATPases.
Abstract: Intellectual disability (ID) is a highly heterogeneous disorder with hundreds of associated genes. Despite progress in the identification of the genetic causes of ID following the introduction of high-throughput sequencing, about half of affected individuals still remain without a molecular diagnosis. Consanguineous families with affected individuals provide a unique opportunity to identify novel recessive causative genes. In this report, we describe a novel autosomal recessive neurodevelopmental disorder. We identified two consanguineous families with homozygous variants predicted to alter the splicing of ATP9A which encodes a transmembrane lipid flippase of the class II P4-ATPases. The three individuals homozygous for these putatively truncating variants presented with severe ID, motor and speech impairment, and behavioral anomalies. Consistent with a causative role of ATP9A in these patients, a previously described Atp9a-/- mouse model showed behavioral changes.
9 citations
Boston Children's Hospital1, Durham University2, University of Alberta3, Leipzig University4, Columbia University Medical Center5, University of Lausanne6, Sheba Medical Center7, Tel Aviv University8, Oslo University Hospital9, Baylor College of Medicine10, University of Cape Town11, Washington University in St. Louis12, University of Rennes13, Children's Mercy Hospital14, Utrecht University15, Broad Institute16, Children's Hospital of Philadelphia17, Hospital Universitario La Paz18, Cincinnati Children's Hospital Medical Center19, University of Cincinnati Academic Health Center20, University of Basel21, University of Pennsylvania22, University of Nantes23, Cornell University24, University of Missouri–Kansas City25, University of Kansas26, Alberta Children's Hospital27
TL;DR: In this article, the authors describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations, including developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy.
7 citations
Centre Hospitalier Universitaire Sainte-Justine1, UCL Institute of Neurology2, St George's Hospital3, Aga Khan University4, Mashhad University of Medical Sciences5, Boston Children's Hospital6, Penn State Milton S. Hershey Medical Center7, Kennedy Krieger Institute8, Johns Hopkins University School of Medicine9, United Arab Emirates University10, University of British Columbia11, Children's Hospital of Philadelphia12, Harvard University13, University of Toronto14, Alberta Health Services15, Osaka University16, University of New South Wales17, Erasmus University Rotterdam18, University of Zurich19, Technische Universität München20, University of Oxford21, Northwick Park Hospital22, University of Exeter23, University of California, San Francisco24, Baylor College of Medicine25, University of Geneva26
TL;DR: In this article, the authors describe 22 individuals from 19 unrelated families with biallelic variants in PIGG, and demonstrate enzymatic activity defects for these variants in vitro in a double knockout system, showing cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction.
5 citations
Radboud University Nijmegen1, Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior2, Shiraz University of Medical Sciences3, University of Geneva4, Academy of Athens5, Hannover Medical School6, Pasteur Institute of Iran7, University of Health Sciences Lahore8, University of Maryland, Baltimore9, Center for Excellence in Education10, Erasmus University Rotterdam11, Medical University of Silesia12, University of Jordan13, University of Lausanne14, Seattle Children's Research Institute15, University of Washington16, University of Miami17
TL;DR: In this article, a combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in lower extremities, and mild hypotonia.
4 citations
TL;DR: The Human Genome Organization (HUGO) as discussed by the authors was initially established to help integrate international scientific genomic activity and to accelerate the diffusion of knowledge from the efforts of the human genome project.
Abstract: The Human Genome Organization (HUGO) was initially established in 1988 to help integrate international scientific genomic activity and to accelerate the diffusion of knowledge from the efforts of the human genome project. Its founding President was Victor McKusick. During the late 1980s and 1990s, HUGO organized lively gene mapping meetings to accurately place genes on the genome as chromosomes were being sequenced. With the completion of the Human Genome Project, HUGO went through some transitions and self-reflection. In 2020, HUGO (which hosts a large annual scientific meeting and comprises the renowned HUGO Gene Nomenclature Committee [HGNC], responsible for naming genes, and an outstanding Ethics Committee) was merged with the Human Genome Variation Society (HGVS; which defines the correct nomenclature for variation description) and the Human Variome Project (HVP; championed by the late Richard Cotton) into a single organization that is committed to assembling human genomic variation from all over the world. This consolidated effort, under a new Executive Board and seven focused committees, will facilitate efficient and effective communication and action to bring the benefits of increasing knowledge of genome diversity and biology to people all over the world.
3 citations
TL;DR: The past 45 years have witnessed a triumph in the discovery of genes and genetic variation that cause Mendelian disorders due to high impact variants as discussed by the authors, however, much more work is needed to identify all the high impact genomic variation that substantially contributes to the phenotypic variation.
Abstract: The past 45 years have witnessed a triumph in the discovery of genes and genetic variation that cause Mendelian disorders due to high impact variants. Important discoveries and organized projects have provided the necessary tools and infrastructure for the identification of gene defects leading to thousands of monogenic phenotypes. This endeavor can be divided in three phases in which different laboratory strategies were employed for the discovery of disease-related genes: (i) the biochemical phase, (ii) the genetic linkage followed by positional cloning phase, and (iii) the sequence identification phase. However, much more work is needed to identify all the high impact genomic variation that substantially contributes to the phenotypic variation.
Bar-Ilan University1, Laboratory of Molecular Biology2, Tel Aviv University3, McGill University4, Pompeu Fabra University5, University of Geneva6, Roswell Park Cancer Institute7, University at Buffalo8, University of Strasbourg9, Allen Institute for Brain Science10, Indiana University – Purdue University Indianapolis11, University of Paris12, University of California, San Diego13, South London and Maudsley NHS Foundation Trust14, King's College London15
TL;DR: This paper identified two consanguineous families with homozygous variants predicted to alter the splicing of Atp9A, which encodes a transmembrane lipid flippase of the class II P4-ATPases.
Abstract: Intellectual disability (ID) is a highly heterogeneous disorder with hundreds of associated genes. Despite progress in the identification of the genetic causes of ID following the introduction of high-throughput sequencing, about half of affected individuals still remain without a molecular diagnosis. Consanguineous families with affected individuals provide a unique opportunity to identify novel recessive causative genes.
In this report we describe a novel autosomal recessive neurodevelopmental disorder. We identified two consanguineous families with homozygous variants predicted to alter the splicing of ATP9A
which encodes a transmembrane lipid flippase of the class II P4-ATPases. The three individuals homozygous for these putatively truncating variants presented with severe ID, motor and speech impairment, and behavioral anomalies. Consistent with a causative role of ATP9A in these patients, a previously described Atp9a-/- mouse model showed behavioral changes.
TL;DR: CoverageMaster (CoM) as discussed by the authors is a copy number variation (CNV) calling algorithm based on depth-of-coverage maps designed to detect CNVs of any size in exome (WES) and genome (WGS) data.
Abstract: CoverageMaster (CoM) is a Copy Number Variation (CNV) calling algorithm based on depth-of-coverage maps designed to detect CNVs of any size in exome (WES) and genome (WGS) data. The core of the algorithm is the compression of sequencing coverage data in a multiscale Wavelet space and the analysis through an iterative Hidden Markov Model (HMM). CoM processes WES and WGS data at nucleotide scale resolution and accurately detect and visualize full size range CNVs, including single or partial exon deletions and duplications. The results obtained with this approach support the possibility for coverage-based CNV callers to replace probe-based methods such array CGH and MLPA in the near future.