Loss-of-Function FANCL Mutations Associate with Severe Fanconi Anemia Overlapping the VACTERL Association

Human Mutation
Annalisa VetroOrsetta Zuffardi

Abstract

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.

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Citations

Nov 23, 2015·American Journal of Medical Genetics. Part a·Sharon A SavageUNKNOWN NCI DCEG Cancer Sequencing Working Group
Mar 31, 2016·American Journal of Medical Genetics. Part a·Blanche P Alter, Neelam Giri
Dec 18, 2016·Indian Journal of Pediatrics·Rosalba Sevilla-MontoyaPatricia Grether
Feb 16, 2017·European Journal of Human Genetics : EJHG·Annalisa VetroOrsetta Zuffardi
Aug 13, 2017·Pediatric Blood & Cancer·Neelam GiriBlanche P Alter
Aug 17, 2019·Journal of Developmental Biology·Philippa Harding, Mariya Moosajee
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Dec 5, 2020·Human Molecular Genetics·Ella M M A MartinGavin Chapman
Mar 18, 2021·European Journal of Human Genetics : EJHG·Beatrice SpedicatiGiorgia Girotto

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