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Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing.

Anne Rensing-Ehl1, Myriam Ricarda Lorenz2, Marita Führer3

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Summary

Complex genetic alterations in the FAS gene and FAS pathway genes explain autoimmune lymphoproliferative syndrome (ALPS) cases missed by standard sequencing. Biomarkers and double-negative T-cell (DNT) phenotyping accurately identify these ALPS patients.

Keywords:
ALPSALPS-UDNTFADDFASdouble-negative T cellsgenetic defect accumulationloss of heterozygositypromotersomatic mutations

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Area of Science:

  • Immunology
  • Genetics
  • Molecular Biology

Background:

  • Autoimmune lymphoproliferative syndrome (ALPS) is often identified by elevated double-negative T-cells (DNT) and serum biomarkers.
  • Standard exome sequencing fails to detect FAS mutations in some ALPS patients, termed ALPS-undetermined (ALPS-U).

Purpose of the Study:

  • Investigate complex genetic alterations in the FAS gene and related FAS pathway genes in ALPS-U patients.
  • Determine if these alterations explain ALPS cases not identified by standard sequencing.

Main Methods:

  • Whole FAS gene sequencing, copy number variation analysis, and FAS cDNA sequencing.
  • Sequencing of other FAS pathway-related genes.
  • FAS expression analysis on CD57+ DNT to predict somatic loss of heterozygosity (sLOH).

Main Results:

  • Nine of 16 ALPS-U patients showed reduced FAS expression on DNT, indicating heterozygous FAS mutations with acquired somatic second hits.
  • Seven patients had deep intronic mutations or large deletions in FAS, one had a FAS exon duplication.
  • Three patients had FAS promoter mutations; three had FADD mutations with sLOH.

Conclusions:

  • Complex genetic alterations in FAS and FADD, including deep intronic mutations and promoter variants, contribute to ALPS-U.
  • Combining serum biomarkers and DNT phenotyping is crucial for diagnosing ALPS patients missed by routine exome sequencing.