Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility

Abstract The COVID-19 pandemic has accounted for millions of infections and hundreds of thousand deaths worldwide in a short-time period. The patients demonstrate a great diversity in clinical and laboratory manifestations and disease severity. Nonetheless, little is known about the host genetic contribution to the observed interindividual phenotypic variability. Here, we report the first host genetic study in the Chinese population by deeply sequencing and analyzing 332 COVID-19 patients categorized by varying levels of severity from the Shenzhen Third People’s Hospital. Upon a total of 22.2 million genetic variants, we conducted both single-variant and gene-based association tests among five severity groups including asymptomatic, mild, moderate, severe, and critical ill patients after the correction of potential confounding factors. Pedigree analysis suggested a potential monogenic effect of loss of function variants in GOLGA3 and DPP7 for critically ill and asymptomatic disease demonstration. Genome-wide association study suggests the most significant gene locus associated with severity were located in TMEM189–UBE2V1 that involved in the IL-1 signaling pathway. The p.Val197Met missense variant that affects the stability of the TMPRSS2 protein displays a decreasing allele frequency among the severe patients compared to the mild and the general population. We identified that the HLA-A*11:01, B*51:01, and C*14:02 alleles significantly predispose the worst outcome of the patients. This initial genomic study of Chinese patients provides genetic insights into the phenotypic difference among the COVID-19 patient groups and highlighted genes and variants that may help guide targeted efforts in containing the outbreak. Limitations and advantages of the study were also reviewed to guide future international efforts on elucidating the genetic architecture of host–pathogen interaction for COVID-19 and other infectious and complex diseases.

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Initial Whole Genome Sequencing and Analysis of the Host Genetic Contribution to COVID-19 Severity and Susceptibility

10.1101/2020.06.09.20126607 ◽

2020 ◽

Cited By ~ 2

Author(s):

Fang Wang ◽

Shujia Huang ◽

Rongsui Gao ◽

Yuwen Zhou ◽

Changxiang Lai ◽

...

Keyword(s):

Genetic Difference ◽

Phenotypic Variability ◽

Missense Variant ◽

Initial Study ◽

Chinese Patients ◽

Genetic Contribution ◽

Significant Gene ◽

Patient Groups ◽

Host Genetic ◽

The Stability

AbstractThe COVID-19 pandemic has accounted for more than five million infections and hundreds of thousand deaths worldwide in the past six months. The patients demonstrate a great diversity in clinical and laboratory manifestations and disease severity. Nonetheless, little is known about the host genetic contribution to the observed inter-individual phenotypic variability. Here, we report the first host genetic study in China by deeply sequencing and analyzing 332 COVID-19 patients categorized by varying levels of severity from the Shenzhen Third People’s Hospital. Upon a total of 22.2 million genetic variants, we conducted both single-variant and gene-based association tests among five severity groups including asymptomatic, mild, moderate, severe and critical ill patients after the correction of potential confounding factors. The most significant gene locus associated with severity is located in TMEM189-UBE2V1 involved in the IL-1 signaling pathway. The p.Val197Met missense variant that affects the stability of the TMPRSS2 protein displays a decreasing allele frequency among the severe patients compared to the mild and the general population. We also identified that the HLA-A*11:01, B*51:01 and C*14:02 alleles significantly predispose the worst outcome of the patients. This initial study of Chinese patients provides a comprehensive view of the genetic difference among the COVID-19 patient groups and highlighted genes and variants that may help guide targeted efforts in containing the outbreak. Limitations and advantages of the study were also reviewed to guide future international efforts on elucidating the genetic architecture of host-pathogen interaction for COVID-19 and other infectious and complex diseases.

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Genetic and Phenotypic Variability in Chinese Patients With Branchio-Oto-Renal or Branchio-Oto Syndrome

Frontiers in Genetics ◽

10.3389/fgene.2021.765433 ◽

2021 ◽

Vol 12 ◽

Author(s):

Haifeng Feng ◽

Hongen Xu ◽

Bei Chen ◽

Shuping Sun ◽

Rongqun Zhai ◽

...

Keyword(s):

Genetic Testing ◽

Phenotypic Variability ◽

Bone Conduction ◽

Missense Variant ◽

Chinese Patients ◽

Renal Anomalies ◽

Auditory Rehabilitation ◽

Whole Exome ◽

Splicing Variants ◽

Feasible Option

Background: Branchio-oto-renal syndrome (BOR) and branchio-oto syndrome (BOS) are rare autosomal dominant disorders defined by varying combinations of branchial, otic, and renal anomalies. Here, we characterized the clinical features and genetic etiology of BOR/BOS in several Chinese families and then explored the genotypes and phenotypes of BOR/BOS-related genes, as well as the outcomes of auditory rehabilitation in different modalities.Materials and Methods: Probands and all affected family members underwent detailed clinical examinations. Their DNA was subjected to whole-exome sequencing to explore the underlying molecular etiology of BOR/BOS; candidate variants were validated using Sanger sequencing and interpreted in accordance with the American College of Medical Genetics guidelines. In addition, a literature review concerning EYA1 and SIX1 alterations was performed to explore the genotypes and phenotypes of BOR/BOS-related genes.Results: Genetic testing identified the novel deletion (c.1425delC, p(Asp476Thrfs*4); NM_000,503.6), a nonsense variant (c.889C > T, p(Arg297*)), and two splicing variants in the EYA1 gene (c.1050+1G > T and c.1140+1G > A); it also identified one novel missense variant in the SIX1 gene (c.316G > A, p(Val106Met); NM_005,982.4). All cases exhibited a degree of phenotypic variability between or within families. Middle ear surgeries for improving bone-conduction component hearing loss had unsuccessful outcomes; cochlear implantation (CI) contributed to hearing gains.Conclusion: This is the first report of BOR/BOS caused by the SIX1 variant in China. Our findings increase the numbers of known EYA1 and SIX1 variants. They also emphasize the usefulness of genetic testing in the diagnosis and prevention of BOR/BOS while demonstrating that CI for auditory rehabilitation is a feasible option in some BOR/BOS patients.

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YARS2 Missense Variant in Belgian Shepherd Dogs with Cardiomyopathy and Juvenile Mortality

Genes ◽

10.3390/genes11030313 ◽

2020 ◽

Vol 11 (3) ◽

pp. 313

Author(s):

Corinne Gurtner ◽

Petra Hug ◽

Miriam Kleiter ◽

Kernt Köhler ◽

Elisabeth Dietschi ◽

...

Keyword(s):

Genetic Defect ◽

Autosomal Recessive Inheritance ◽

Missense Variant ◽

Homozygosity Mapping ◽

Pedigree Analysis ◽

Trna Synthetase ◽

Loss Of Function ◽

Juvenile Mortality ◽

Abnormal Accumulation ◽

The Central Nervous System

Dog puppy loss by the age of six to eight weeks after normal development is relatively uncommon. Necropsy findings in two spontaneously deceased Belgian Shepherd puppies indicated an abnormal accumulation of material in several organs. A third deceased puppy exhibited mild signs of an inflammation in the central nervous system and an enteritis. The puppies were closely related, raising the suspicion of a genetic cause. Pedigree analysis suggested a monogenic autosomal recessive inheritance. Combined linkage and homozygosity mapping assigned the most likely position of a potential genetic defect to 13 genome segments totaling 82 Mb. The genome of an affected puppy was sequenced and compared to 645 control genomes. Three private protein changing variants were found in the linked and homozygous regions. Targeted genotyping in 96 Belgian Shepherd dogs excluded two of these variants. The remaining variant, YARS2:1054G>A or p.Glu352Lys, was perfectly associated with the phenotype in a cohort of 474 Belgian Shepherd dogs. YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase 2 and the predicted amino acid change replaces a negatively charged and evolutionary conserved glutamate at the surface of the tRNA binding domain of YARS2 with a positively charged lysine. Human patients with loss-of-function variants in YARS2 suffer from myopathy, lactic acidosis, and sideroblastic anemia 2, a disease with clinical similarities to the phenotype of the studied dogs. The carrier frequency was 27.2% in the tested Belgian Shepherd dogs. Our data suggest YARS2:1054G>A as the candidate causative variant for the observed juvenile mortality.

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Autosomal Recessive Non-syndromic Keratoconus: Homozygous Frameshift Variant in the Candidate Novel Gene GALNT14

Current Molecular Medicine ◽

10.2174/1566524019666190730095630 ◽

2019 ◽

Vol 19 (9) ◽

pp. 683-687 ◽

Cited By ~ 3

Author(s):

Tawfiq Froukh ◽

Ammar Hawwari

Keyword(s):

Strong Evidence ◽

Autosomal Recessive ◽

Eye Diseases ◽

Initial Reaction ◽

Genetic Contribution ◽

Loss Of Function ◽

Consanguineous Family ◽

Truncated Protein ◽

Threonine Residue ◽

Whole Exome

Background: Keratoconus (KC) is usually bilateral, noninflammatory progressive corneal ectasia in which the cornea becomes progressively thin and conical. Despite the strong evidence of genetic contribution in KC, the etiology of KC is not understood in most cases. Methods: In this study, we used whole-exome sequencing to identify the genetic cause of KC in two sibs in a consanguineous family. The Homozygous frameshift variant NM_001253826.1:c.60delC;p.Leu21Cysfs*6 was identified in the gene Nacetylgalactosaminyltransferase 14 (GALNT14). The variant does not exist in all public databases neither in our internal exome database. Moreover, no database harbours homozygous loss of function variants in the candidate gene. Result: GALNT14 catalyses the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D- galactosamine residue to a serine or threonine residue on target proteins especially Mucins. Conclusion: As alterations of mucin’s glycosylation are linked to a number of eye diseases, we demonstrate in this study an association between the truncated protein GALNT14 and KC.

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GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms

Nature Communications ◽

10.1038/s41467-021-24563-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Lucas D. Ward ◽

Ho-Chou Tu ◽

Chelsea B. Quenneville ◽

Shira Tsour ◽

Alexander O. Flynn-Carroll ◽

...

Keyword(s):

Bile Duct ◽

Extrahepatic Bile Duct ◽

Association Studies ◽

Missense Variant ◽

Deficiency Anemia ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Extrahepatic Bile Duct Cancer ◽

Hepatocellular Damage ◽

Increased Risk

AbstractUnderstanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These results suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.

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Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development

Genes ◽

10.3390/genes12040470 ◽

2021 ◽

Vol 12 (4) ◽

pp. 470

Author(s):

Jeremy W. Prokop ◽

Caleb P. Bupp ◽

Austin Frisch ◽

Stephanie M. Bilinovich ◽

Daniel B. Campbell ◽

...

Keyword(s):

Brain Development ◽

Neural Progenitor Cells ◽

Neurodevelopmental Disorder ◽

Fetal Brain ◽

Missense Variant ◽

Neural Progenitor ◽

Loss Of Function ◽

Gain Of Function ◽

Systematic Analysis ◽

Function Expression

Ornithine decarboxylase 1 (ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributions to schizophrenia, mood disorders, anxiety, epilepsy, learning, and suicidal behavior. The evidence of ODC1 connection to neural disorders highlights the need for a systematic analysis of ODC1 genotype-to-phenotype associations. An analysis of variants from ClinVar, Geno2MP, TOPMed, gnomAD, and COSMIC revealed an intellectual disability and seizure connected loss-of-function variant, ODC G84R (rs138359527, NC_000002.12:g.10444500C > T). The missense variant is found in ~1% of South Asian individuals and results in 2.5-fold decrease in enzyme function. Expression quantitative trait loci (eQTLs) reveal multiple functionally annotated, non-coding variants regulating ODC1 that associate with psychiatric/neurological phenotypes. Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion. The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene.

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Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility

Cancers ◽

10.3390/cancers13112704 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2704

Author(s):

Sally Yepes ◽

Nirav N. Shah ◽

Jiwei Bai ◽

Hela Koka ◽

Chuzhong Li ◽

...

Keyword(s):

Internal Control ◽

Susceptibility Gene ◽

Copy Number Variants ◽

Bone Cancer ◽

Chinese Patients ◽

European Ancestry ◽

Unknown Etiology ◽

Loss Of Function ◽

Single Nucleotide Variants ◽

Pathogenic Variants

Background: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China. Methods: We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma. Results: Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients. Conclusion: We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies.

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A Nonsense Variant in Hephaestin Like 1 (HEPHL1) Is Responsible for Congenital Hypotrichosis in Belted Galloway Cattle

Genes ◽

10.3390/genes12050643 ◽

2021 ◽

Vol 12 (5) ◽

pp. 643

Author(s):

Thibaud Kuca ◽

Brandy M. Marron ◽

Joana G. P. Jacinto ◽

Julia M. Paris ◽

Christian Gerspach ◽

...

Keyword(s):

Genome Wide Association Study ◽

Homozygosity Mapping ◽

Mendelian Inheritance ◽

Large Animal Model ◽

Large Animal ◽

Loss Of Function ◽

Protein Coding ◽

Positional Candidate ◽

Genome Wide ◽

A Genome

Genodermatosis such as hair disorders mostly follow a monogenic mode of inheritance. Congenital hypotrichosis (HY) belong to this group of disorders and is characterized by abnormally reduced hair since birth. The purpose of this study was to characterize the clinical phenotype of a breed-specific non-syndromic form of HY in Belted Galloway cattle and to identify the causative genetic variant for this recessive disorder. An affected calf born in Switzerland presented with multiple small to large areas of alopecia on the limbs and on the dorsal part of the head, neck, and back. A genome-wide association study using Swiss and US Belted Galloway cattle encompassing 12 cases and 61 controls revealed an association signal on chromosome 29. Homozygosity mapping in a subset of cases refined the HY locus to a 1.5 Mb critical interval and subsequent Sanger sequencing of protein-coding exons of positional candidate genes revealed a stop gain variant in the HEPHL1 gene that encodes a multi-copper ferroxidase protein so-called hephaestin like 1 (c.1684A>T; p.Lys562*). A perfect concordance between the homozygous presence of this most likely pathogenic loss-of-function variant and the HY phenotype was found. Genotyping of more than 700 purebred Swiss and US Belted Galloway cattle showed the global spread of the mutation. This study provides a molecular test that will permit the avoidance of risk matings by systematic genotyping of relevant breeding animals. This rare recessive HEPHL1-related form of hypotrichosis provides a novel large animal model for similar human conditions. The results have been incorporated in the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002230-9913).

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Variable Expressivity of the Beckwith-Wiedemann Syndrome in Four Pedigrees Segregating Loss-of-Function Variants of CDKN1C

Genes ◽

10.3390/genes12050706 ◽

2021 ◽

Vol 12 (5) ◽

pp. 706

Author(s):

Angela Sparago ◽

Flavia Cerrato ◽

Laura Pignata ◽

Francisco Cammarata-Scalisi ◽

Livia Garavelli ◽

...

Keyword(s):

Cellular Proliferation ◽

Missense Variant ◽

Abdominal Wall Defects ◽

Loss Of Function ◽

Nonsense Mutations ◽

Molecular Defects ◽

Variable Expressivity ◽

Imprinting Disorder ◽

Perinatal Lethality ◽

Intrafamilial Variability

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by prenatal and/or postnatal overgrowth, organomegaly, abdominal wall defects and tumor predisposition. CDKN1C is a maternally expressed gene of the 11p15.5 chromosomal region and is regulated by the imprinting control region IC2. It negatively controls cellular proliferation, and its expression or activity are frequently reduced in BWS. In particular, loss of IC2 methylation is associated with CDKN1C silencing in the majority of sporadic BWS cases, and maternally inherited loss-of-function variants of CDKN1C are the most frequent molecular defects of familial BWS. We have identified, using Sanger sequencing, novel CDKN1C variants in three families with recurrent cases of BWS, and a previously reported variant in a woman with recurrent miscarriages with exomphalos. Clinical evaluation of the patients showed variable manifestation of the disease. The frameshift and nonsense variants were consistently associated with exomphalos, while the missense variant caused a less severe phenotype. Pregnancy loss and perinatal lethality were found in the families segregating nonsense mutations. Intrafamilial variability of the clinical BWS features was observed, even between siblings. Our data are indicative of severe BWS phenotypes that, with variable expressivity, may be associated with both frameshift and nonsense variants of CDKN1C.

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