Exome and genome sequencing for inborn errors of immunity

Meyts, Isabelle; Bosch, Barbara; Bolze, Alexandre; Boisson, Bertrand; Itan, Yuval; Belkadi, Aziz; Pedergnana, Vincent; Moens, Leen; Pïcard, Capucine; Cobat, Aurélie; Bossuyt, Xavier; Abel, Laurent; Casanova, Jean‐Laurent

doi:10.1016/j.jaci.2016.08.003

Cited by 167 publications

(156 citation statements)

References 89 publications

Supporting

Mentioning

148

Contrasting

Unclassified

Order By: Relevance

“…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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Diagnosismentioning

confidence: 99%

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

Moens

Hershfield

Arts

et al. 2018

Immunological Reviews

Self Cite

View full text Add to dashboard Cite

show abstract

“…These disease manifestations cause increased morbidity and mortality in patients, and treatment choices are often complex. With the increased accessibility of next‐generation sequencing (NGS), the rate of discovery of genetic causes for PID has increased exponentially in recent years, with now over 300 monogenic causes for PID described …”

Section: Introductionmentioning

confidence: 99%

Clinical efficacy of a next‐generation sequencing gene panel for primary immunodeficiency diagnostics

et al. 2018

View full text Add to dashboard Cite

Primary immunodeficiencies (PIDs) are rare monogenic inborn errors of immunity that result in impairment of functions of the human immune system. PIDs have a broad phenotype with increased morbidity and mortality, and treatment choices are often complex. With increased accessibility of next-generation sequencing (NGS), the rate of discovery of genetic causes for PID has increased exponentially. Identification of an underlying monogenic diagnosis provides important clinical benefits for patients with the potential to alter treatments, facilitate genetic counselling, and pre-implantation diagnostics. We investigated a NGS PID panel of 242 genes within clinical care across a range of PID phenotypes. We also evaluated Phenomizer to predict causal genes from human phenotype ontology (HPO) terms. Twenty-seven participants were recruited, and a total of 15 reportable variants were identified in 48% (13/27) of the participants. The panel results had implications for treatment in 37% (10/27) of participants. Phenomizer identified the genes harbouring variants from HPO terms in 33% (9/27) of participants. This study shows the clinical efficacy that genetic testing has in the care of PID. However, it also highlights some of the disadvantages of gene panels in the rapidly moving field of PID genomics and current challenges in HPO term assignment for PID.

show abstract

“…Increasingly, mutations and new genes are being identified that render the host susceptible to a specific pathogen [23]. Several genetic defects in the defence against TB have been identified [24].…”

Section: Discussionmentioning

confidence: 99%

Cystic fibrosis carriership and tuberculosis: hints toward an evolutionary selective advantage based on data from the Brazilian territory

Bosch

Boeck

et al. 2017

BMC Infect Dis

Self Cite

View full text Add to dashboard Cite

BackgroundThe reason why Cystic Fibrosis (CF) is the most common fatal genetic disease among Caucasians has been incompletely studied. We aimed at deepening the hypothesis that CF carriers have a relative protection against Mycobacterium tuberculosis (Mtb) infection.MethodsApplying spatial epidemiology, we studied the link between CF carriership rate and tuberculosis (TB) incidence in Brazil. We corrected for 5 potential environmental and 2 immunological confounders in this relation: monthly income, sanitary provisions, literacy rates, racial composition and population density along with AIDS incidence rates and diabetes mellitus type 2. Smoking data were incomplete and not available for analysis.ResultsA significant, negative correlation between CF carriership rate and TB incidence, independent of any of the seven confounders was found.ConclusionWe provide exploratory support for the hypothesis that carrying a single CFTR mutation arms against Mtb infections.

show abstract

Exome and genome sequencing for inborn errors of immunity

Cited by 167 publications

References 89 publications

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

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

Clinical efficacy of a next‐generation sequencing gene panel for primary immunodeficiency diagnostics

Cystic fibrosis carriership and tuberculosis: hints toward an evolutionary selective advantage based on data from the Brazilian territory

Contact Info

Product

Resources

About