Loss-of-function FANCL mutations associate with severe fanconi anemia overlapping the VACTERL association

Annalisa Vetro, Maria Iascone, Ivan Limongelli, Najim Ameziane, Simone Gana, Erika Della Mina, Ursula Giussani, Roberto Ciccone, Antonella Forlino, Laura Pezzoli, Martin A. Rooimans, Antoni J. van Essen, Jole Messa, Tommaso Rizzuti, Paolo Bianchi, Josephine Dorsman, Johan P. de Winter, Faustina Lalatta, Orsetta Zuffardi

Research output: Contribution to journalArticlepeer-review


The diagnosis of VACTERL syndrome can be elusive, especially in the prenatal life, due to the presence of malformations that overlap those present in other genetic conditions, including the Fanconi anemia (FA). We report on three VACTERL cases within two families, where the two who arrived to be born died shortly after birth due to severe organs' malformations. The suspicion of VACTERL association was based on prenatal ultrasound assessment and postnatal features. Subsequent chromosome breakage analysis suggested the diagnosis of FA. Finally, by next-generation sequencing based on the analysis of the exome in one family and of a panel of Fanconi genes in the second one, we identified novel FANCL truncating mutations in both families. We used ectopic expression of wild-type FANCL to functionally correct the cellular FA phenotype for both mutations. Our study emphasizes that the diagnosis of FA should be considered when VACTERL association is suspected. Furthermore, we show that loss-of-function mutations in FANCL result in a severe clinical phenotype characterized by early postnatal death.

Original languageEnglish
Pages (from-to)562-568
Number of pages7
JournalHuman Mutation
Issue number5
Publication statusPublished - May 1 2015


  • Exome sequencing
  • Fanconi anemia
  • Prenatal diagnosis

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Medicine(all)


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