Whole-Exome Sequencing of Patients With Recurrent HSV-2 Lymphocytic Mollaret Meningitis

Abstract Recurrent lymphocytic meningitis, also referred to as Mollaret meningitis, is a rare neurological disease characterized mainly by reactivation of herpes simplex virus 2 (HSV-2) from sensory ganglia. However, the underlying host immune determinants and viral factors rendering some individuals unable to maintain HSV-2 latency are largely unknown. We collected a cohort of 15 patients diagnosed with Mollaret meningitis. By whole-exome sequencing we identified rare host genetic variants predicted to be deleterious in molecules involved in (1) ubiquitin-proteasome pathways, (2) the autophagy machinery, and (3) cell proliferation/apoptosis. Moreover, infection of patient cells with HSV-2 or stimulation by virus-derived double-stranded DNA ligands revealed reduced antiviral interferon responses in most patients. These findings may contribute to a better understanding of disease pathogenesis and protective immunity to HSV in the central nervous system, and may ultimately be of importance for identification of targets for development of improved prophylaxis and treatment of this disease.

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The mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing

Leukemia ◽

10.1038/leu.2014.264 ◽

2014 ◽

Vol 29 (3) ◽

pp. 677-685 ◽

Cited By ~ 81

Author(s):

I Vater ◽

M Montesinos-Rongen ◽

M Schlesner ◽

A Haake ◽

F Purschke ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Primary Lymphoma ◽

Whole Exome ◽

Mutational Pattern ◽

The Central Nervous System

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DOP36 Family-specific host genetic and gut microbial signatures have a beneficial role in early identification of familial inflammatory bowel diseases

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.075 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S073-S074

Author(s):

G Y SHIN ◽

Y M Park ◽

E Ha ◽

K N Gu ◽

K Kim ◽

...

Keyword(s):

Ulcerative Colitis ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Identification ◽

Beneficial Role ◽

Specific Host ◽

Whole Exome ◽

Host Genetic

Abstract Background Familial IBD may have its own signatures with respect to host genetic variants and/or gut microbiome. However, available data focussing on this topic is still limited, particularly for Asian patients with familial IBD. We aimed to investigate the possible host genetic and gut microbial signatures in familial IBD through a combined analysis of genomic and metagenomic profiles. Methods All patients were affiliated with a prospectively recruited cohort of patients with IBD (NCT03589183) and met the diagnostic criteria of Crohn’s disease (CD) or ulcerative colitis (UC). We constructed a unique family cohort comprising ≥2 affected individuals with familial IBD and ≥1 their unaffected, healthy first-degree relative (FDR) in each family. Whole-exome sequencing for rare variants followed by a genome-wide single-nucleotide polymorphism analysis for common variants was performed. A polygenic risk score (PRS) was calculated separately in Crohn’s disease (CD), ulcerative colitis (UC) or IBD. Gut microbial community was analysed by 16s rRNA sequencing of stool samples. Results Eight Korean families comprising 16 with familial IBD (12 concordant IBD, 4 discordant IBD) and 9 FDRs were included for analysis. Whole-exome sequencing identified four family-specific candidate genes (LAMA5, MYO15B, TTN, and WDR66) with rare missense variants that were transmitted preferentially to the affected FDRs in at least ≥3 families (Figure 1). An in silico analysis identified the deleterious effect of the identified variants on the gene products including LAMA5 (SIFT = 0, PolyPhen-2 = 0.72). The patients with CD, but not those with UC, had a significantly higher mean PRS than controls (PRS = 2.137 vs. 0.742, p-value = 0.030). Metagenomic sequencing revealed significant differences in α- and β-diversity of gut microbiota among the patients with CD, those with UC, and unaffected FDRs (all p < 0.05), showing lower microbial richness in the patients with familial IBD (p = 0.02). In various taxonomic levels, compared with unaffected FDRs, the patients with familial IBD showed the significantly differential abundance of several gut bacteria (all corrected p < 0.05; Figure 2). Conclusion Family-specific host genetic and gut microbial signatures have a beneficial role in early-identification of familial IBD (NCT03515070).

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