Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes

Wang, Qingbo; Pierce‐Hoffman, Emma; Cummings, Beryl B.; Alföldi, Jessica; Francioli, Laurent C.; Gauthier, Laura D.; Hill, Andrew J.; O’Donnell-Luria, Anne; Team, Genome Aggregation Database Production; Karczewski, Konrad J.; MacArthur, Daniel G.

doi:10.1038/s41467-019-12438-5

Cited by 109 publications

(99 citation statements)

References 64 publications

(75 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By combining the gnomAD dataset with a large collection of RNA sequencing data from adult human tissues 14 , the value of tissue expression data in the interpretation of genetic variation across a range of human diseases is reported 15 . Finally, the effect of two understudied classes of human variation-multi-nucleotide variants 16 and variants that create or disrupt open-reading frames in the 5′ untranslated region of human genes-is characterized and investigated 17 .…”

mentioning

confidence: 99%

The mutational constraint spectrum quantified from variation in 141,456 humans

Karczewski¹,

Francioli²,

Tiao³

et al. 2020

Nature

Self Cite

6,603

111

6,214

View full text Add to dashboard Cite

show abstract

mentioning

confidence: 99%

The mutational constraint spectrum quantified from variation in 141,456 humans

Karczewski¹,

Francioli²,

Tiao³

et al. 2020

Nature

Self Cite

6,603

111

6,214

View full text Add to dashboard Cite

show abstract

“…Frequency and type of variants in the UNC13D gene. A, Reported missense and loss of function variants in the general populations according to gnomAD database 56 . B, Distribution of mutations reported in FHL3 patients within exons and introns of the UNC13D gene.…”

Section: Resultsmentioning

confidence: 99%

Clinical, immunological and genetic findings in patients with UNC13D deficiency (FHL3): A systematic review

Amirifar

Ranjouri

Abolhassani

et al. 2020

Pediatric Allergy Immunology

View full text Add to dashboard Cite

Background: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive immune disorder that is caused by mutations in 6 different genes related to the formation and function of secretory lysosomes within cytotoxic T lymphocytes and natural killer (NK) cells. Thus, defect in these genes is associated with the accumulation of antigens due to defective cytotoxic function. FHL type 3 (FHL3) accounts for nearly 30-40% of FHL, and its underlying reason is mutation in UNC13D gene which encodes Munc13-4 protein. Methods: For the first time, we aimed to systematically review clinical features, immunologic data, and genetic findings of patients with FHL3. We conducted electronic searches for English-language articles in PubMed, Web of Science, EMBASE, and Scopus databases to collect comprehensive records related to patients with UNC13D mutations. Results: A total of 279 abstracts were initially reviewed for inclusion. Among them, 57 articles corresponding to 322 individual FHL3 patients fulfilled our selection criteria. Finally, 73 and 249 patients were considered as severe and mild feature groups, respectively. Our results confirmed that fever, hepatosplenomegaly, and hemophagocytosis are common clinical features in the disease. Moreover, reduced fibrinogen and NK cell activity, as well as increased ferritin and triglycerides, are important markers for early diagnosis of the FHL3 disease. Investigation of genotype showed that the most prevalent type and zygosity of UNC13D are splice-site errors and compound heterozygous, respectively. Conclusion: FHL3 patients have a wide range of clinical manifestations, which makes it difficult to diagnose. Therefore, it seems that the sequencing of the entire UNC13D gene (coding and non-coding regions) is the most appropriate way to accurate diagnosis of FHL3 patients. | 187 AMIRIFAR et Al.

show abstract

“…Data were collected from the genotyping pipelines of the 1000 Genomes (1000G) project ( http://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/ ), 41 the US National Heart, Lung, and Blood Institute (NHLBI) ( http://www.nhlbi.nih.gov/ ), 42 gnomAD ( https://gnomad.broadinstitute.org/ ), 43 Tohoku Medical Megabank Organization (ToMMo) ( https://www.megabank.tohoku.ac.jp/english/ ) 44 45 and UK10K ( https://www.uk10k.org/ ), 46 which consisted of high-coverage whole-genome/whole-exome sequence data from various ethnic groups. The data set consisted of 156 513 individuals from various countries ( online supplementary table S1 ; it should be noted that gnomAD includes the 1000G data set, but not other projects).…”

Section: Methodsmentioning

confidence: 99%

Genetic variations in the human severe acute respiratory syndrome coronavirus receptorACE2and serine proteaseTMPRSS2

Fujikura

Uesaka

2020

J Clin Pathol

View full text Add to dashboard Cite

AimsThe recent emergence of novel, pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global health emergency. The coronaviral entry requires the spike (S)-protein for attachment to the host cell surface, and employs human angiotensin-converting enzyme 2 (hACE2) for entry and transmembrane protease serine 2 (TMPRSS2) for S-protein priming. Although coronaviruses undergo evolution by mutating themselves, it is also essential to know the host genetic factors. Here, we describe the single nucleotide variations (SNVs) in human ACE2 and TMPRSS2.MethodsThe genetic variants derived from five population-sequencing projects were classified by variant type, allele frequency (AF), ethnic group and estimated pathogenicity. The SNVs in SARS-CoV-2/hACE2 contact residues were investigated. The genetic variability was normalised using non-linear regression and the total number of SNVs was estimated by the derived formulas.ResultsWe detected 349 and 551 SNVs in ACE2 and TMPRSS2, respectively, in a total of 156 513 individuals. The vast majority (>97%) of the SNVs were very rare (AF <0.1%) and population-specific, and were computationally estimated to be more frequently deleterious than the SNVs with high AF. These SNVs were distributed throughout the coding regions; some ACE2 variants were located in the SARS-CoV-2/hACE2 contact residues, with a hemizygous state occurring in males. Using regression analysis, the total numbers of genetic variations in ACE2 and TMPRSS2 were 1.1×103 and 1.5×103, respectively, for a population of one million people.ConclusionThe majority of SNVs in ACE2 and TMPRSS2 are rare, population-specific and deleterious, and a multitude of very rare SNVs may explain different susceptibility to SARS-CoV-2.

show abstract

Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes

Cited by 109 publications

References 64 publications

The mutational constraint spectrum quantified from variation in 141,456 humans

The mutational constraint spectrum quantified from variation in 141,456 humans

Clinical, immunological and genetic findings in patients with UNC13D deficiency (FHL3): A systematic review

Genetic variations in the human severe acute respiratory syndrome coronavirus receptorACE2and serine proteaseTMPRSS2

Contact Info

Product

Resources

About