Genomics of Immune Diseases and New Therapies

Lenardo, Michael J.; Lo, Bernice; Lucas, Carrie L.

doi:10.1146/annurev-immunol-041015-055620

Cited by 40 publications

(40 citation statements)

References 124 publications

(299 reference statements)

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“…When using diagnostic sequencing of ADA2 as the initial approach, caution is needed with interpretation of clinical significance of novel variants. The disease‐causing effect should not be extrapolated from variant‐level parameters, ie, allele frequency solely . Candidate variant segregation should comply with the disease recessive inheritance pattern.…”

Section: Diagnosismentioning

confidence: 99%

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

Moens

Hershfield

Arts

et al. 2018

Immunological Reviews

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Human adenosine deaminase 1 deficiency was described in the 1970s to cause severe combined immunodeficiency. The residual adenosine deaminase activity in these patients was attributed to adenosine deaminase 2. Human adenosine deaminase type 2 deficiency (DADA2), due to biallelic deleterious mutations in the ADA2 gene, is the first described monogenic type of small‐ and medium‐size vessel vasculitis. The phenotype of DADA2 also includes lymphoproliferation, cytopenia, and variable degrees of immunodeficiency. The physiological role of ADA2 is still enigmatic hence the pathophysiology of the condition is unclear. Preliminary data showed that in the absence of ADA2, macrophage differentiation is skewed to a pro‐inflammatory M1 subset, which is detrimental for endothelial integrity. The inflammatory phenotype responds well to anti‐TNF therapy with etanercept and that is the first‐line treatment for prevention of severe vascular events including strokes. The classic immunosuppressive drugs are not successful in controlling the disease activity. However, hematopoietic stem cell transplantation (HSCT) has been shown to be a definitive cure in DADA2 patients who present with a severe cytopenia. HSCT can also cure the vascular phenotype and is the treatment modality for patients’ refractory to anti‐cytokine therapies. In this review, we describe what is currently known about the molecular mechanisms of DADA2. Further research on the pathophysiology of this multifaceted condition is needed to fine‐tune and steer future therapeutic strategies.

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Section: Diagnosismentioning

confidence: 99%

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

Moens

Hershfield

Arts

et al. 2018

Immunological Reviews

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“…A causal relationship between a candidate genotype and a relevant phenotype requires an experimentally proven thread of causes and consequences. This step may be straightforward (the exception) or may necessitate substantial investigation (the rule), accounting for the lion’s share of time from sequencing to final validation (48). Solid knowledge of physiology and pathology is essential for the design of optimal ways to test candidate variants experimentally (38).…”

Section: Validating Genetic Findings Experimentallymentioning

confidence: 99%

“…NGS has also boosted new insights into disease mechanisms leading to new therapies, e.g. magnesium treatment in MAGT1 deficiency (48). The genetic dissection of PIDs identified by NGS has also demonstrated new functions for known proteins.…”

Section: Discoveries Of Pid-causing Mutations By Ngsmentioning

confidence: 99%

Exome and genome sequencing for inborn errors of immunity

Meyts

Bosch

Bolze

et al. 2016

Journal of Allergy and Clinical Immunology

167

148

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The advent of next generation sequencing (NGS) in 2010 has transformed medicine and particularly the growing field of monogenic inborn errors of immunity, including primary immunodeficiencies (PID). NGS has facilitated the discovery of novel disease-causing genes and the genetic diagnosis of patients with PID. Whole-exome sequencing (WES) is presently the most cost-effective approach for PID research and diagnostics, though whole genome sequencing (WGS) offers several advantages. The scientific or diagnostic challenge consists in selecting one or two candidate variants among thousands of NGS calls. Variant- and gene-level computational methods as well as immunological hypotheses can help to narrow down this genome-wide search. The key to success is a well-informed genetic hypothesis on three key aspects: mode of inheritance, clinical penetrance, and genetic heterogeneity of the condition. This determines the search strategy and the frequency cut-offs for candidate alleles. Subsequent functional validation of the disease-causing effect of the candidate variant is critical. Even the most up-to-date dry lab cannot clinch this validation without a seasoned wet lab. The multifariousness of variations entails an experimental rigor even greater than traditional Sanger sequencing-based approaches, in order not to assign PID to false positives. Finding the needle in the haystack takes patience, prudence, and discernment.

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“…Knowledge of the aberrant molecular pathways in cases of PID is even more apparent now as the field of precision medicine expands within the discipline [2]. We highlight the utility of a non-bias investigational approach using whole exome sequencing to reach a genetic diagnosis in a case activated phosphoinositide 3-kinase δ syndrome (APDS) (OMIM 615513) that led to long-term clinical stability with a precision medicine approach.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%