Ataxia Telangiectasia Diagnosed on Newborn Screening–Case Cohort of 5 Years' Experience

Abstract

Ataxia telangiectasia (AT) is a genetic condition caused by mutations involving ATM (Ataxia Telangiectasia Mutated). This gene is responsible for the expression of a DNA double stranded break repair kinase, the ATM protein kinase. The syndrome encompasses combined immunodeficiency and various degrees of neurological abnormalities and increased risk of malignancy. Typically, patients present early in life with delay in neurological milestones, but very infrequently, with life threatening infections typical of a profound T cell deficiency. It would therefore be unexpected to identify this condition immediately after birth using T cell receptor excision circle (TREC)-based newborn screening (NBS) for SCID. We sought to evaluate the frequency of AT detected by NBS, and to assess immunity as well as the genetic aberrations associated with this early presentation. Here, we describe the clinical, laboratory, and genetic features of patients diagnosed with AT through the Ontario NBS program for SCID, and followed in our center since its inception in 2013. Four patients were diagnosed with AT as a result of low TRECs on NBS. In each case, whole exome sequencing was diagnostic. All of our patients had compound heterozygous mutations involving the FRAP-ATM-TRRAP (FAT) domain of the ATM gene, which appears critical for kinase activity and is highly sensitive to mutagenesis. Our patients presented with profound lymphopenia involving both B and T cells. The ratio of naïve/memory CD45+RA/RO T cells population was variable. T cell repertoire showed decreased T cell diversity. Two out of four patients had decreased specific antibody response to vaccination and hypogammaglobulinemia requiring IVIG replacement. In two patients, profound decreased responses to phytohemagglutinin stimulation was observed. In the other two patients, the initial robust response declined with time. In summary, the rate of detection of AT through NBS had been surprisingly high at our center. One case was identified per year, while the total rate for SCID has been five new cases per year. This early detection may allow for better prospective evaluation of AT shortly after birth, and may assist in formulating early and more effective interventions both for the neurological as well as the immune abnormalities in this syndrome.

Second-Tier Next Generation Sequencing Integrated in Nationwide Newborn Screening Provides Rapid Molecular Diagnostics of Severe Combined Immunodeficiency

“…With this approach we are also able to identify Ataxia Telangiectasia (AT), which was previously reported by Mallot et al (57) and others (58). We have not identified any AT patient in the pilot, or so far in the nationwide NBS.…”

An appraisal of the Wilson & Jungner criteria in the context of genomic-based newborn screening for inborn errors of immunity

“…75 From the clinical perspective, AT identified in screened newborns enabled earlier identification and treatment for immunologic abnormalities, and also has the potential to facilitate earlier, coordinated approaches to multidisciplinary management. 76 In addition to IEI, there are several lethal conditions that may be detected on newborn screening tests for which no treatment is available, and the benefits of very early identification of these infants in the presymptomatic phase also needs to be considered in the context of ethical and social factors. Ongoing discussion regarding these ethical and social issues is recommended and requires engagement of a range of representatives from different disciplines: medicine, law, philosophy, government, and importantly, families with affected children and the general community.…”

Newborn Screening for SCID and Other Severe Primary Immunodeficiency in the Polish-German Transborder Area: Experience From the First 14 Months of Collaboration

“…Primary immunodeficiency diseases (PID) are a heterogenous group of inborn errors of immunity affecting ∼1 in 10,000 to 1 in 50,000 births (10). Currently, over 400 different genetic mutations and diseases are recognized, yet the collective prevalence is likely to be higher (11)(12)(13). Patients with PID are classified into one out of 10 groups, such as predominant antibody deficiency, cellular deficiency, combined immunodeficiency, and others (13).…”