Deficiency of Adenosine Deaminase 2 (DADA2): Hidden Variants, Reduced Penetrance, and Unusual Inheritance

Oskar Schnappauf, Qing Zhou, Natalia Sampaio Moura, Amanda K. Ombrello, Drew G. Michael, Natalie Deuitch, Karyl Barron, Deborah L. Stone, Patrycja Hoffmann, Michael Hershfield, Carolyn Applegate, Hans T. Bjornsson, David B. Beck, P. Dane Witmer, Nara Sobreira, Elizabeth Wohler, John A. Chiorini, The American Genome Center, Clifton L. Dalgard, Nih Intramural Sequencing CenterDaniel L. Kastner, Ivona Aksentijevich

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disorder that manifests with fever, early-onset vasculitis, strokes, and hematologic dysfunction. This study aimed to identify disease-causing variants by conventional Sanger and whole exome sequencing in two families suspected to have DADA2 and non-confirmatory genotypes. ADA2 enzymatic assay confirmed the clinical diagnosis of DADA2. Molecular diagnosis was important to accurately identify other family members at risk. Methods: We used a variety of sequencing technologies, ADA2 enzymatic testing, and molecular methods including qRT-PCR and MLPA. Results: Exome sequencing identified heterozygosity for the known pathogenic variant ADA2: c.1358A>G, p.Tyr453Cys in a 14-year-old female with a history of ischemic strokes, livedo, and vasculitis. No second pathogenic variant could be identified. ADA2 enzymatic testing in combination with quantitative RT-PCR suggested a loss-of-function allele. Subsequent genome sequencing identified a canonical splice site variant, c.-47+2T>C, within the 5′UTR of ADA2. Two of her unaffected siblings were found to carry the same two pathogenic variants. A homozygous 800-bp duplication comprising exon 7 of ADA2 was identified in a 5-year-old female with features consistent with Diamond-Blackfan anemia (DBA). The duplication was missed by Sanger sequencing of ADA2, chromosomal microarray, and exome sequencing but was detected by MLPA in combination with long-read PCR sequencing. The exon 7 duplication was also identified in her non-symptomatic father and younger sister. Conclusions: ADA2 pathogenic variants may not be detected by conventional sequencing and genetic testing and may require the incorporation of additional diagnostic methods. A definitive molecular diagnosis is crucial for all family members to make informed treatment decisions.

Original languageEnglish (US)
Pages (from-to)917-926
Number of pages10
JournalJournal of Clinical Immunology
Volume40
Issue number6
DOIs
StatePublished - Aug 1 2020

Keywords

  • deficiency of adenosine deaminase 2
  • Exome sequencing
  • genome sequencing
  • loss-of-function variants

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Deficiency of Adenosine Deaminase 2 (DADA2): Hidden Variants, Reduced Penetrance, and Unusual Inheritance'. Together they form a unique fingerprint.

Cite this