Deficiency of Adenosine Deaminase 2 (DADA2): Hidden Variants, Reduced Penetrance, and Unusual Inheritance
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ORIGINAL ARTICLE
Deficiency of Adenosine Deaminase 2 (DADA2): Hidden Variants, Reduced Penetrance, and Unusual Inheritance Oskar Schnappauf 1 & Qing Zhou 1 & Natalia Sampaio Moura 1 & Amanda K. Ombrello 1 & Drew G. Michael 2 & Natalie Deuitch 1 & Karyl Barron 3 & Deborah L. Stone 1 & Patrycja Hoffmann 1 & Michael Hershfield 4 & Carolyn Applegate 5 & Hans T. Bjornsson 5,6,7 & David B. Beck 1 & P. Dane Witmer 5 & Nara Sobreira 5 & Elizabeth Wohler 5 & John A. Chiorini 8 & The American Genome Center 9 & Clifton L. Dalgard 10 & NIH Intramural Sequencing Center 1 & Daniel L. Kastner 1 & Ivona Aksentijevich 1 Received: 2 March 2020 / Accepted: 29 June 2020 # This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2020
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 14year-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.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10875-020-00817-3) contains supplementary material, which is available to authorized users. * Oskar Schnappauf [email protected] 1
Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch, National Human Genome Research Institute (NHGRI), Bethesda, MD, USA
2
Department of Laboratory Medi
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