Burden of rare coding variants in an Italian cohort of familial multiple sclerosis

Mascia, Elisabetta; Clarelli, Ferdinando; Zauli, Andrea; Guaschino, Clara; Sorosina, Melissa; Barizzone, Nadia; Basagni, Chiara; Santoro, Silvia; Ferré, Laura; Bonfiglio, Silvia; Biancolini, Donatella; Pozzato, Mattia; Guerini, Franca Rosa; Protti, Alessandra; Liguori, Maria; Moiola, Lucia; Vecchio, Domizia; Bresolin, Nereo; Comi, Giancarlo; Filippi, Massimo; Esposito, Federica; D’Alfonso, Sandra; Boneschi, Filippo Martinelli

doi:10.1016/j.jneuroim.2021.577760

Cited by 4 publications

(3 citation statements)

References 50 publications

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“…However recent mapping of established MS susceptibility genes onto multiple single cell RNA sequencing datasets from MS brain tissue, has revealed enrichment of MS-susceptibility genes in astrocytes, vascular cells and excitatory neurons (Absinta et al, 2021). Additionally, family-based studies and a novel machine learning approach implicate variants in CNS related genes in affecting MS susceptibility and progression, respectively (Fazia et al, 2021;Jokubaitis et al, 2022;Mascia et al, 2022). This supports the idea that cells of the CNS, not only immune cells, are involved in MS development.…”

Section: Are Brain Cells Intrinsically Different Between People With ...mentioning

confidence: 62%

Using MS induced pluripotent stem cells to investigate MS aetiology

Fortune

Fletcher

Blackburn

et al. 2022

Multiple Sclerosis and Related Disorders

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Section: Are Brain Cells Intrinsically Different Between People With ...mentioning

confidence: 62%

Using MS induced pluripotent stem cells to investigate MS aetiology

Fortune

Fletcher

Blackburn

et al. 2022

Multiple Sclerosis and Related Disorders

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“…To assess the aggregate contribution of multiple rare genes in the disease processes studied, the authors performed burden testing analysis using high confidence variants and potentially pathogenic variants based on MAF or protein-prediction algorithms. Variants were identified by literature driven review in multiple sclerosis as other, more rare disorders, did not have sufficient genetic investigation to warrant phenotype/ genotype differentiation [11][12][13]. Variants meeting criteria were considered qualifying variants and were applied in Test Rare vAriants with Public Data (TRAPD) [14] as a pathogenicity filter and subsequently analyzed against the gnomeAD database.…”

Section: Burden Test Analysismentioning

confidence: 99%

Association of rare variants in genes of immune regulation with pediatric autoimmune CNS diseases

et al. 2022

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Background There is a gap in the literature regarding genetic underpinnings of pediatric autoimmune CNS diseases. This study explored rare gene variants implicated in immune dysregulation within these disorders. Methods This was a single-center observational study of children with inflammatory CNS disorder who had genetic testing through next generation focused exome sequencing targeting 155 genes associated with innate or adaptive immunity. For in silico prediction of functional effects of single-nucleotide variants, Polymorphism Phenotyping v2, and Sorting Intolerant from Tolerant were used, and Combined Annotation Dependent Depletion (CADD) scores were calculated. Identified genes were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Results Of 54 patients, 42 (77.8%) carried variant(s), among which 12 (22.2%) had 3-8 variants. Eighty-eight unique singlenucleotide variants of 55 genes were identified. The most variants were detected in UNC13D, LRBA, LYST, NOD2, DOCK8, RNASEH2A, STAT5B, and AIRE. The majority of variants (62, 70.4%) had CADD > 10. KEGG pathway analysis revealed seven genes associated with primary immunodeficiency (Benjamini 1.40E − 06), six genes with NOD-like receptor signaling (Benjamini 4.10E − 04), five genes with Inflammatory Bowel Disease (Benjamini 9.80E − 03), and five genes with NF-kappa B signaling pathway (Benjamini 1.90E − 02). Discussion We observed a high rate of identification of rare and low-frequency variants in immune regulatory genes in pediatric neuroinflammatory CNS disorders. We identified 88 unique single-nucleotide variants of 55 genes with pathway analysis revealing an enrichment of NOD2-receptor signaling, consistent with involvement of the pathway within other autoinflammatory conditions and warranting further investigation.

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“…Such a phenomenon can be explained in different ways, including a poor representation of rare variants in typed arrays, epigenetic mechanisms and interaction between genetic and environmental factors, whose role can be better explored in family-based studies that offer a privileged setting of higher prevalence of the disease. This strategy allowed the identification of several rare variants with a possible role in MS susceptibility [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], and several genes were implicated, such as TYK2 [ 15 ], also confirmed in sporadic case [ 4 ], UBR2 and DST [ 11 ], and more recently, among others, MBP, MECP2, and CPT1A [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

A Whole-Genome Sequencing Study Implicates GRAMD1B in Multiple Sclerosis Susceptibility

Esposito

Osiceanu

Sorosina

et al. 2022

Genes

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While the role of common genetic variants in multiple sclerosis (MS) has been elucidated in large genome-wide association studies, the contribution of rare variants to the disease remains unclear. Herein, a whole-genome sequencing study in four affected and four healthy relatives of a consanguineous Italian family identified a novel missense c.1801T > C (p.S601P) variant in the GRAMD1B gene that is shared within MS cases and resides under a linkage peak (LOD: 2.194). Sequencing GRAMD1B in 91 familial MS cases revealed two additional rare missense and two splice-site variants, two of which (rs755488531 and rs769527838) were not found in 1000 Italian healthy controls. Functional studies demonstrated that GRAMD1B, a gene with unknown function in the central nervous system (CNS), is expressed by several cell types, including astrocytes, microglia and neurons as well as by peripheral monocytes and macrophages. Notably, GRAMD1B was downregulated in vessel-associated astrocytes of active MS lesions in autopsied brains and by inflammatory stimuli in peripheral monocytes, suggesting a possible role in the modulation of inflammatory response and disease pathophysiology.

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Burden of rare coding variants in an Italian cohort of familial multiple sclerosis

Cited by 4 publications

References 50 publications

Using MS induced pluripotent stem cells to investigate MS aetiology

Using MS induced pluripotent stem cells to investigate MS aetiology

Association of rare variants in genes of immune regulation with pediatric autoimmune CNS diseases

A Whole-Genome Sequencing Study Implicates GRAMD1B in Multiple Sclerosis Susceptibility

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