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Reticular dysgenesis caused by an intronic pathogenic variant in AK2.

Shoji Ichikawa1, Susan Prockop2,3, Charlotte Cunningham-Rundles4

  • 1Department of Clinical Diagnostics, Ambry Genetics, Aliso Viejo, California 92656, USA.

Cold Spring Harbor Molecular Case Studies
|June 14, 2020
PubMed
Summary

Reticular dysgenesis, a severe combined immunodeficiency (SCID), was diagnosed in a boy with a novel AK2 variant. RNA sequencing confirmed the variant causes exon skipping, reclassifying it as pathogenic.

Keywords:
severe combined immunodeficiency

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Area of Science:

  • Genetics
  • Immunology
  • Molecular Biology

Background:

  • Severe combined immunodeficiency (SCID) is a group of rare genetic disorders characterized by profound defects in the cellular and humoral immune systems.
  • Reticular dysgenesis (RD) is a specific form of SCID caused by biallelic pathogenic variants in the AK2 gene, affecting both T-cell and B-cell immunity.
  • Newborn screening (NBS) plays a crucial role in the early detection of SCID, enabling timely intervention.

Observation:

  • A boy diagnosed with SCID via NBS presented with a homozygous variant in the AK2 gene (c.330 + 5G > A).
  • In silico analysis suggested the variant might affect RNA splicing, but it was initially classified as a variant of uncertain significance (VUS).
  • RNA sequencing of the patient and parents was performed to investigate the splicing impact of the identified AK2 variant.

Findings:

  • Massively parallel RNA sequencing demonstrated that the AK2 c.330 + 5G > A variant leads to exon 3 skipping.
  • Exon 3 encodes a critical region of the AK2 protein, and its skipping results in a non-functional protein.
  • The variant was reclassified from VUS to pathogenic based on the observed functional consequence on mRNA splicing.

Implications:

  • This case highlights the challenge of interpreting variants of uncertain significance (VUS) at noncanonical splice sites.
  • RNA sequencing is a powerful tool for assessing the functional impact of intronic variants on mRNA splicing, aiding in variant reclassification.
  • RNA-based analyses are particularly valuable for interpreting genetic variants in disorders of hematopoiesis and immunity due to high RNA expression in blood samples.