Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Remote control of gene function by local translation

The subcellular position of a protein is a key determinant of its function. Mounting evidence indicates that RNA localization, where specific mRNAs are transported subcellularly and subsequently translated in response to localized signals, is an evolutionarily conserved mechanism to control protein localization. On-site synthesis confers novel signaling properties to a protein and helps to maintain local proteome homeostasis. Local translation plays particularly important roles in distal neuronal compartments, and dysregulated RNA localization and translation cause defects in neuronal wiring and survival. Here, we discuss key findings in this area and possible implications of this adaptable and swift mechanism for spatial control of gene function

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Local adaptation in populations of Mycobacterium tuberculosis endemic to the Indian Ocean Rim

This work was supported by the Swiss National Science Foundation (grants 310030_188888, CRSII5_177163, IZRJZ3_164171 and IZLSZ3_170834) and the European Research Council (309540‑EVODRTB and 883582-ECOEVODRTB)Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Institute of Biomedicine of Valencia. Valencia, Spain.Universidade Federal do Rio de Janeiro. Instituto de Microbiologia. Laboratório de Micobactérias. Rio de Janeiro, RJ, Brazil / Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Programa de Pós-graduação em Pesquisa Clínica e Doenças Infecciosas. Rio de Janeiro, RJ, Brazil.University of Valencia- joint Unit. I2SysBio,Valencia, Spain.University of Cape Town. Wellcome Centre for Infectious Diseases Research in Africa. Institute of Infectious Diseases and Molecular Medicine. Cape Town, South Africa.Makerere University. Department of Medical Microbiology. Kampala, Uganda.National Health Research Institutes. National Institute of Infectious Diseases and Vaccinology. Zhunan, Taiwan.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland / University of Bern. Institute for Social and Preventive Medicine. Switzerland.Victorian Infectious Diseases Reference Laboratory. Victoria, Australia.Fudan University. School of Basic Medical Science. Institutes of Biomedical Sciences and Institute of Medical Microbiology. The Key Laboratory of Medical Molecular Virology of Ministries of Education and Health. Shanghai, China.Instituto de Investigación Sanitaria Gregorio Marañón. Hospital General Universitario Gregorio Marañón. Madrid, Spain / CIBER Enfermedades Respiratorias. Spain.Universitat de Barcelona. Hospital Clínic. Barcelona Institute for Global Health. Barcelona, Spain / Centro de Investigação em Saúde de Manhiça. Maputo, Mozambique.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland / United Republic of Tanzania. Ifakara Health Institute, Bagamoyo, Bagamoyo District Hospital. Bagamoyo, Tanzania.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland / United Republic of Tanzania. Ifakara Health Institute. Bagamoyo District Hospital. Bagamoyo, Tanzania.University of California. School of Medicine. San Francisco, USA.Fudan University. School of Basic Medical Science. Institutes of Biomedical Sciences and Institute of Medical Microbiology. The Key Laboratory of Medical Molecular Virology of Ministries of Education and Health. Shanghai, China.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland / Papua New Guinea Institute of Medical Research. Goroka, Papua New Guinea.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Mahidol University. Faculty of Science. Department of Microbiology. Pornchai Matangkasombut Center for Microbial Genomics / National Science and Technology Development Agency. Bangkok, Thailand.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Mahidol University. Faculty of Science. Department of Microbiology. Pornchai Matangkasombut Center for Microbial Genomics / National Science and Technology Development Agency. Bangkok, Thailand.Institut Pasteur de Madagascar. Mycobacteriology Unit. Antananarivo, Madagascar.Institut Pasteur de Madagascar. Mycobacteriology Unit. Antananarivo, Madagascar.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.University of Basel. Basel, Switzerland / Swiss Tropical and Public Health Institute. Department of Medicine. Basel, Switzerland.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland / United Republic of Tanzania. Ifakara Health Institute. Bagamoyo District Hospital. Bagamoyo, Tanzania.Universidade Federal do Rio de Janeiro. Instituto de Microbiologia. Laboratório de Micobactérias. Rio de Janeiro, RJ, Brazil.Université Paris-Saclay. Paris, France / Paris Diderot University. Sorbonne Paris Cité. Paris, France.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular Aplicada a Micobactérias. Rio de Janeiro, RJ, Brazil.Universidade do Estado do Pará. Centro de Ciências Biológicas e da Saúde. Programa de Pós-graduação em Biologia Parasitária na Amazônia. Belém, PA, Brazil / Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.University of Ghana. Noguchi Memorial Institute for Medical Research. Accra, Ghana.ETH Zürich. Department of Biosystems Science and Engineering. Basel, Switzerland.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Swiss Tropical and Public Health Institute. Department of Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Lineage 1 (L1) and 3 (L3) are two lineages of the Mycobacterium tuberculosis complex (MTBC), causing tuberculosis (TB) in humans. L1 and L3 are endemic to the Rim of the Indian Ocean, the region that accounts for most of the world’s new TB cases. Despite their relevance for this region, L1 and L3 remain understudied. Here we analyzed 2,938 L1 and 2,030 L3 whole genome sequences originating from 69 countries. We show that South Asia played a central role in the dispersion of these two lineages to neighboring regions. Moreover, we found that L1 exhibits signatures of local adaptation at the esxH locus, a gene coding for a secreted effector that targets the human endosomal sorting complex, and is included in several vaccine candidates. Our study highlights the importance of genetic diversity in the MTBC, and sheds new light on two of the most important MTBC lineages affecting humans