Genetic determinants of severe COVID-19 in young Asian and Middle Eastern patients

Badla, Beshr; Hanifa, Mohamed; Jain, Ruchi; Naofal, Maha El; Halabi, Nour; Yaslam, Sawsan; Ramaswamy, Sathishkumar; Taylor, Alan; Falasi, Roudha Al; Shenbagam, Shruti; Khansaheb, Hamda; Suwaidi, Hanan Al; Nowotny, Norbert; Popatia, Rizwana; Alsheikh-Ali, Alawi; Khayat, Abdulla Al; Loney, Tom; Dabal, Laila Al; Tayoun, Ahmad Abou

doi:10.1101/2023.01.11.23284427

Cited by 4 publications

(2 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Patients presenting with recurrent infections and/or inflammatory disease were found, by clinical genomic testing, to carry loss‐of‐function variants in the IFIH1 gene were included in this study ( N = 5). In addition, patients meeting criteria for severe COVID‐19 23 or MIS‐C 24 and subsequently determined to have loss‐of‐function IFIH1 variants by whole‐exome sequencing were also included ( N = 4). This study was approved by the Dubai Scientific Research Ethics Committee, Dubai Health Authority (study numbers: DSREC‐07/2023_06, DSREC‐SR‐03/2023_08 and DSREC‐07/2021_05).…”

Section: Methodsmentioning

confidence: 99%

IFIH1 loss of function predisposes to inflammatory and SARS‐CoV‐2‐related infectious diseases

Najm,

Yavuz,

Jain

et al. 2024

Scand J Immunol

Self Cite

View full text Add to dashboard Cite

The IFIH1 gene, encoding melanoma differentiation‐associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation in weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain‐of‐function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi–Goutieres and Singleton–Merten syndromes, while biallelic loss causes immunodeficiency. In this study, nine patients suffering from recurrent infections, inflammatory diseases, severe COVID‐19 or multisystem inflammatory syndrome in children (MIS‐C) were identified with putative loss‐of‐function IFIH1 variants by whole‐exome sequencing. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL‐6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID‐19 or MIS‐C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS‐C. There was a significant association between IFIH1 monoallelic loss of function and susceptibility to infections in males. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with Poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss‐of‐function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS‐CoV‐2‐related disorders.

show abstract

Section: Methodsmentioning

confidence: 99%

IFIH1 loss of function predisposes to inflammatory and SARS‐CoV‐2‐related infectious diseases

Najm,

Yavuz,

Jain

et al. 2024

Scand J Immunol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Patients presenting with recurrent infections and/or in ammatory disease were found, by clinical genomic testing, to carry loss-of-function variants in the IFIH1 gene were included in this study (N = 5). In addition, patients meeting criteria for severe COVID-19 23 or MIS-C 24…”

Section: Study Cohortmentioning

confidence: 99%

IFIH1 loss-of-function predisposes to inflammatory and SARS-CoV-2-related infectious diseases

Najm,

Yavuz,

Jain

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

The IFIH1 gene, encoding melanoma differentiation-associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation linking it to weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain-of-function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi-Goutieres and Singleton-Merten syndromes, while biallelic loss of this gene causes immunodeficiency. In this study, nine patients suffering from different cases of recurrent infections, inflammatory diseases, severe COVID-19, or multisystem inflammatory syndrome in children (MIS-C) were identified with putative loss-of-function IFIH1 variants by whole exome sequencing. All patients revealed signs of lymphopenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin, and IL-6. One patient with a pathogenic homozygous variant c.2807 + 1G > A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641 + 1G > C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19, or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with Poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss-of-function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS-CoV-2 related disorders.

show abstract

IFIH1loss-of-function predisposes to inflammatory and SARS-CoV-2-related infectious diseases

Najm,

Yavuz,

Jain

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

The IFIH1 gene, encoding melanoma differentiation-associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation linking it to weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain-of-function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi-Goutieres and Singleton-Merten syndromes, while biallelic loss of this gene causes immunodeficiency. In this study, nine patients suffering from different cases of recurrent infections, inflammatory diseases, severe COVID-19, or multisystem inflammatory syndrome in children (MIS-C) were identified with putative loss-of-function IFIH1 variants by whole exome sequencing. All patients revealed signs of lymphopenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin, and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19, or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss-of-function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS-CoV-2 related disorders.

show abstract

Genetic determinants of severe COVID-19 in young Asian and Middle Eastern patients

Cited by 4 publications

References 23 publications

IFIH1 loss of function predisposes to inflammatory and SARS‐CoV‐2‐related infectious diseases

IFIH1 loss of function predisposes to inflammatory and SARS‐CoV‐2‐related infectious diseases

IFIH1 loss-of-function predisposes to inflammatory and SARS-CoV-2-related infectious diseases

IFIH1loss-of-function predisposes to inflammatory and SARS-CoV-2-related infectious diseases

Contact Info

Product

Resources

About