Association of clinical severity with FANCB variant type in Fanconi anemia

Moonjung Jung, Ramanagouda Ramanagoudr-Bhojappa, Sylvie van Twest, Rasim Ozgur Rosti, Vincent Murphy, Winnie Tan, Frank X Donovan, Francis P Lach, Danielle C Kimble, Caroline S Jiang, Roger Vaughan, Parinda A Mehta, Filomena Pierri, Carlo Dufour, Arleen D Auerbach, Andrew J Deans, Agata Smogorzewska, Settara C Chandrasekharappa

Research output: Contribution to journalArticlepeer-review


Fanconi anemia (FA) is the most common genetic cause of bone marrow failure and is caused by inherited pathogenic variants in any of 22 genes. Of these, only FANCB is X-linked. We describe a cohort of 19 children with FANCB variants, from 16 families of the International Fanconi Anemia Registry. Those with FANCB deletion or truncation demonstrate earlier-than-average onset of bone marrow failure and more severe congenital abnormalities compared with a large series of FA individuals in published reports. This reflects the indispensable role of FANCB protein in the enzymatic activation of FANCD2 monoubiquitination, an essential step in the repair of DNA interstrand crosslinks. For FANCB missense variants, more variable severity is associated with the extent of residual FANCD2 monoubiquitination activity. We used transcript analysis, genetic complementation, and biochemical reconstitution of FANCD2 monoubiquitination to determine the pathogenicity of each variant. Aberrant splicing and transcript destabilization were associated with 2 missense variants. Individuals carrying missense variants with drastically reduced FANCD2 monoubiquitination in biochemical and/or cell-based assays tended to show earlier onset of hematologic disease and shorter survival. Conversely, variants with near-normal FANCD2 monoubiquitination were associated with more favorable outcome. Our study reveals a genotype-phenotype correlation within the FA-B complementation group of FA, where severity is associated with level of residual FANCD2 monoubiquitination.

Original languageEnglish
Pages (from-to)1588-1602
Number of pages15
Issue number18
Publication statusPublished - Apr 30 2020


  • Alleles
  • Alternative Splicing
  • Cell Line, Tumor
  • Fanconi Anemia/diagnosis
  • Fanconi Anemia Complementation Group Proteins/genetics
  • Fibroblasts/metabolism
  • Genetic Association Studies
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Humans
  • Models, Biological
  • Mutation
  • Phenotype
  • RNA Stability
  • Severity of Illness Index
  • Ubiquitination


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