COVID-19 and TLR7 gene

Severe coronavirus disease 2019 (COVID-19) usually occurs in individuals with chronic conditions like diabetes and hypertension. It can also occur in younger, predominantly male, individuals  without preexisting chronic conditions.

Genetic immunodeficiencies may predispose to severe disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: 

 The 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. 

Hospitalization with COVID-19: 

The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). 

Mortality: One patient died out of 4 men.

Genetic features: Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. 

Loss-of-function of TLR7 leads to lack of type I and II IFN (interferon) responses. 

Relevance: 

TLR-3, -7, and -8 are essential in the recognition of single-stranded RNA viruses. TLR7 senses single-stranded RNA oligonucleotides containing guanosine- and uridine-rich sequences from RNA viruses, a recognition occuring in the endosomes of plasmacytoid dendritic cells and B cells. This gene is predominantly expressed in lung, placenta, and spleen. Knowing the status of this gene can help in individualization and prioritization of care and therapy.

My Point: 

Emerging approaches in clinical molecular diagnostics and genomics can be used to improve treatment of viral and bacterial infections.

Clinical genetic testing methodologies:

CGH, comparative genomic hybridization; FISH, fluorescent in situ hybridization; MLPA, multiplex ligation-dependent probe amplification; SNP, single-nucleotide polymorphism; STR, short tandem repeat; WES, whole-exome sequencing; WGS, whole-genome sequencing.

*Familial mutations or genomic rearrangements can be assayed.

‡Categorical assignments in these columns are subjective and vary according to context of the tests being ordered and the laboratory conducting the tests. The ‘low’, ‘average’ and ‘high’ are presented to simplify and to compare platforms generally.

§Low, <80%; average, 80–98%; high, >98%.

||Low, <80%; average, 80–98%; high, >98%.

¶Low, <1 week; average, 1 week 1 month; high, >1 month.

#Costs of the testing will widely vary from one laboratory to the next; however, these estimates are based on the charge of the test from a sampling of laboratories, not on the costs of consumables or the reimbursed amount. Low, less than US$400; average, $400–$2,000; high, >$2,000.

**Uniparental disomy can be detected by any method if both parents are genotyped. However, only the indicated approaches will detect uniparental disomy in absence of the parental genetic samples.

‡‡Copy number variant detections are improving in next-generation sequencing applications but are more efficient in WGS than WES, although they are of limited reliability for clinical diagnostics.

References:

1. van der Made CI, Simons A, Schuurs-Hoeijmakers J, et al. Presence of Genetic Variants Among Young Men With Severe COVID-19. JAMA. 2020;324(7):663–673.
2. Katsanis SH, Katsanis N. Molecular genetic testing and the future of clinical genomics. Nat Rev Genet. 2013;14(6):415-426.