<i>ADA2</i> deficiency due to a novel structural variation in 22q11.1

Grossi, Alice; Cusano, Roberto; Rusmini, Marta; Penco, Federica; Schena, Francesca; Podda, Rosa Anna; Caorsi, Roberta; Gattorno, Marco; Uva, Paolo; Ceccherini, Isabella

doi:10.1111/cge.13518

Cited by 12 publications

(16 citation statements)

References 5 publications

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“…Among the unsolved patients, namely, those left with no genetic diagnosis, we cannot exclude the possibility of novel genetic/clinical entities, especially in the light of the many atypical cases included in our cohort. Indeed, novel genetic causes of IEI are likely to be enriched in negative cases that can also include (1) defects in genes not included in our panel because they are not yet described in the literature, even in the case of the use of the CES [ 23 ], (2) defects located in regulatory regions not sequenced by targeted panels, and (3) missed detection of copy number variants (CNVs) and regions of homozygosity [ 56 , 57 ]. This limitation of our study might indeed account for a proportion of those cases that are heterozygotes for variants of genes responsible for recessive conditions, with undetected large indels affecting the second apparently normal allele.…”

Section: Discussionmentioning

confidence: 99%

Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

Grossi

Miano

Lanciotti

et al. 2021

Genes

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Inborn errors of immunity (IEI) include a large group of inherited diseases sharing either poor, dysregulated, or absent and/or acquired function in one or more components of the immune system. Next-generation sequencing (NGS) has driven a rapid increase in the recognition of such defects, though the wide heterogeneity of genetically diverse but phenotypically overlapping diseases has often prevented the molecular characterization of the most complex patients. Two hundred and seventy-two patients were submitted to three successive NGS-based gene panels composed of 58, 146, and 312 genes. Along with pathogenic and likely pathogenic causative gene variants, accounting for the corresponding disorders (37/272 patients, 13.6%), a number of either rare (probably) damaging variants in genes unrelated to patients’ phenotype, variants of unknown significance (VUS) in genes consistent with their clinics, or apparently inconsistent benign, likely benign, or VUS variants were also detected. Finally, a remarkable amount of yet unreported variants of unknown significance were also found, often recurring in our dataset. The NGS approach demonstrated an expected IEI diagnostic rate. However, defining the appropriate list of genes for these panels may not be straightforward, and the application of unbiased approaches should be taken into consideration, especially when patients show atypical clinical pictures.

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Section: Discussionmentioning

confidence: 99%

Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

Grossi

Miano

Lanciotti

et al. 2021

Genes

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“…In this line, it is important to note that the genetic analysis of ADA2 gene could be rather laborious. ADA2 is, in fact, located in the chromosome 22q11, an unstable region subjected to copy number variations and other structural genomic alterations [ 12 ]. Therefore, the availability of a fast and reliable functional assay is particularly important in order to alert the clinicians before the results of the genetic analysis in order to start the appropriate treatment as soon as possible.…”

Section: Discussionmentioning

confidence: 99%

A Novel LC–MS/MS-Based Method for the Diagnosis of ADA2 Deficiency from Dried Plasma Spot

et al. 2021

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Adenosine Deaminase 2 Deficiency (DADA2) (OMIM: 607575) is a monogenic, autoinflammatory disease caused by the loss of functional homozygous or heterozygous mutations in the ADA 2 gene (previously CECR1, Cat Eye Syndrome Chromosome Region 1). A timely diagnosis is crucial to start Anti-TNF therapies that are efficacious in controlling the disease. The confirmation of DADA2 is based on DNA sequencing and enzymatic assay. It is, thus, very important to have robust and reliable assays that can be rapidly utilized in specialized laboratories that can centralize samples from other centers. In this paper, we show a novel enzymatic assay based on liquid chromatography-tandem mass spectrometry that allows the accurate determination of the ADA2 enzyme activity starting from very small amounts of plasma spotted on filter paper (dried plasma spot). The method allows significantly distinguishing healthy controls from affected patients and carriers and could be of help in implementing the diagnostic workflow of DADA2.

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“…Direct cardiopulmonary involvement is less common. Cardiac involvement specifically has included pericarditis, myocarditis, cardiomyopathy, long QT syndrome, and aortic root enlargement [ 17 •, 40 •, 47 , 48 ]. Cavitary lung lesions, ARDS, and pleuritis have been described, in addition to recurrent pneumonias in the setting of immunodeficiency and cytopenias [ 20 •, 32 •, 37 •, 49 ].…”

Section: Clinical Manifestations Of Dada2mentioning

confidence: 99%

The Many Faces of a Monogenic Autoinflammatory Disease: Adenosine Deaminase 2 Deficiency

Kendall

Springer

2020

Curr Rheumatol Rep

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Purpose of Review We aim to describe the pathophysiology, clinical findings, diagnosis, and treatment of deficiency of adenosine deaminase 2 (DADA2). Recent Findings DADA2 is a multi-organ disease of children and less often adults, which can present with wide-ranging manifestations including strokes, medium vessel vasculitis, hematologic disease, and immunodeficiency. Diagnosis is through detection of reduced activity level of the adenosine deaminase 2 (ADA2) enzyme and/or identification of bi-allelic mutations in the ADA2 gene. Outside of high-dose glucocorticoids, conventional immunosuppression has been largely ineffective in treating this relapsing and remitting disease. Vasculitic-predominant manifestations respond extremely well to tumor necrosis factor-α inhibition. Hematopoietic stem cell transplantation can lead to normalization of enzyme activity, as well as resolution of vasculitic, hematologic, and immunologic manifestations, although treatment-related adverse effects are not uncommon. Summary Early detection of this disease across multiple disciplines could prevent devastating clinical outcomes, especially in genetically pre-disposed populations.

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ADA2 deficiency due to a novel structural variation in 22q11.1

Cited by 12 publications

References 5 publications

Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

A Novel LC–MS/MS-Based Method for the Diagnosis of ADA2 Deficiency from Dried Plasma Spot

The Many Faces of a Monogenic Autoinflammatory Disease: Adenosine Deaminase 2 Deficiency

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