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01-04-2018 | Original Article

Utility of DNA, RNA, Protein, and Functional Approaches to Solve Cryptic Immunodeficiencies

Authors: Margot A. Cousin, Matthew J. Smith, Ashley N. Sigafoos, Jay J. Jin, Marine I. Murphree, Nicole J. Boczek, Patrick R. Blackburn, Gavin R. Oliver, Ross A. Aleff, Karl J. Clark, Eric D. Wieben, Avni Y. Joshi, Pavel N. Pichurin, Roshini S. Abraham, Eric W. Klee

Published in: Journal of Clinical Immunology | Issue 3/2018

Abstract

Purpose

We report a female infant identified by newborn screening for severe combined immunodeficiencies (NBS SCID) with T cell lymphopenia (TCL). The patient had persistently elevated alpha-fetoprotein (AFP) with IgA deficiency, and elevated IgM. Gene sequencing for a SCID panel was uninformative. We sought to determine the cause of the immunodeficiency in this infant.

Methods

We performed whole-exome sequencing (WES) on the patient and parents to identify a genetic diagnosis. Based on the WES result, we developed a novel flow cytometric panel for rapid assessment of DNA repair defects using blood samples. We also performed whole transcriptome sequencing (WTS) on fibroblast RNA from the patient and father for abnormal transcript analysis.

Results

WES revealed a pathogenic paternally inherited indel in ATM. We used the flow panel to assess several proteins in the DNA repair pathway in lymphocyte subsets. The patient had absent phosphorylation of ATM, resulting in absent or aberrant phosphorylation of downstream proteins, including γH2AX. However, ataxia-telangiectasia (AT) is an autosomal recessive condition, and the abnormal functional data did not correspond with a single ATM variant. WTS revealed in-frame reciprocal fusion transcripts involving ATM and SLC35F2 indicating a chromosome 11 inversion within 11q22.3, of maternal origin. Inversion breakpoints were identified within ATM intron 16 and SLC35F2 intron 7.

Conclusions

We identified a novel ATM-breaking chromosome 11 inversion in trans with a pathogenic indel (compound heterozygote) resulting in non-functional ATM protein, consistent with a diagnosis of AT. Utilization of several molecular and functional assays allowed successful resolution of this case.

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Title: Utility of DNA, RNA, Protein, and Functional Approaches to Solve Cryptic Immunodeficiencies
Authors: Margot A. Cousin
Matthew J. Smith
Ashley N. Sigafoos
Jay J. Jin
Marine I. Murphree
Nicole J. Boczek
Patrick R. Blackburn
Gavin R. Oliver
Ross A. Aleff
Karl J. Clark
Eric D. Wieben
Avni Y. Joshi
Pavel N. Pichurin
Roshini S. Abraham
Eric W. Klee
Publication date: 01-04-2018
Publisher: Springer US
Published in: Journal of Clinical Immunology / Issue 3/2018
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-018-0499-6

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