title: Loss-of-Function FANCL Mutations Associate with Severe Fanconi Anemia Overlapping the VACTERL Association.
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.
authors.affiliation: Biotechnology Research Laboratories, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Vetro
authors.forename: Maria
authors.initials: M
authors.lastname: Iascone
authors.forename: Ivan
authors.initials: I
authors.lastname: Limongelli
authors.forename: Najim
authors.initials: N
authors.lastname: Ameziane
authors.forename: Simone
authors.initials: S
authors.lastname: Gana
authors.forename: Erika
authors.initials: E
authors.lastname: Della Mina
authors.forename: Ursula
authors.initials: U
authors.lastname: Giussani
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccone
authors.forename: Antonella
authors.initials: A
authors.lastname: Forlino
authors.forename: Laura
authors.initials: L
authors.lastname: Pezzoli
authors.forename: Martin A
authors.initials: MA
authors.lastname: Rooimans
authors.forename: Antoni J
authors.initials: AJ
authors.lastname: van Essen
authors.forename: Jole
authors.initials: J
authors.lastname: Messa
authors.forename: Tommaso
authors.initials: T
authors.lastname: Rizzuti
authors.forename: Paolo
authors.initials: P
authors.lastname: Bianchi
authors.forename: Josephine
authors.initials: J
authors.lastname: Dorsman
authors.forename: Johan P
authors.initials: JP
authors.lastname: de Winter
authors.forename: Faustina
authors.initials: F
authors.lastname: Lalatta
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
mesh_terms: D000028:Abortion, Induced; D001003:Anal Canal / Q000002:abnormalities*; D019457:Chromosome Breakage; D003937:Diagnosis, Differential; D004947:Esophagus / Q000002:abnormalities*; D059472:Exome; D005199:Fanconi Anemia / Q000175:diagnosis* / Q000235:genetics*; D052240:Fanconi Anemia Complementation Group L Protein / Q000235:genetics*; D005260:Female; D006330:Heart Defects, Congenital / Q000175:diagnosis* / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007231:Infant, Newborn; D007668:Kidney / Q000002:abnormalities*; D017880:Limb Deformities, Congenital / Q000175:diagnosis* / Q000235:genetics*; D050498:Live Birth; D008297:Male; D009154:Mutation; D010641:Phenotype; D011247:Pregnancy; D011296:Prenatal Diagnosis; D012720:Severity of Illness Index; D013131:Spine / Q000002:abnormalities*; D014132:Trachea / Q000002:abnormalities*
chemical_list: D052240:Fanconi Anemia Complementation Group L Protein
keywords: FANCL; Fanconi anemia; VACTERL; exome sequencing; prenatal diagnosis