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

• Published in: Human mutation Vol. 36; no. 5; pp. 562 - 568
• Main Authors: Vetro, Annalisa, Iascone, Maria, Limongelli, Ivan, Ameziane, Najim, Gana, Simone, Mina, Erika Della, Giussani, Ursula, Ciccone, Roberto, Forlino, Antonella, Pezzoli, Laura, Rooimans, Martin A., van Essen, Antoni J., Messa, Jole, Rizzuti, Tommaso, Bianchi, Paolo, Dorsman, Josephine, de Winter, Johan P., Lalatta, Faustina, Zuffardi, Orsetta
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-05-2015; Hindawi Limited
• Subjects: Abortion, Induced; Anal Canal - abnormalities; Anemia; Chromosome Breakage; Congenital diseases; Diagnosis, Differential; Esophagus - abnormalities; Exome; exome sequencing; FANCL; Fanconi anemia; Fanconi Anemia - diagnosis; Fanconi Anemia - genetics; Fanconi Anemia Complementation Group L Protein - genetics; Female; Genotype & phenotype; Heart Defects, Congenital - diagnosis; Heart Defects, Congenital - genetics; High-Throughput Nucleotide Sequencing; Humans; Infant, Newborn; Kidney - abnormalities; Limb Deformities, Congenital - diagnosis; Limb Deformities, Congenital - genetics; Live Birth; Male; Mutation; Phenotype; Pregnancy; Prenatal Diagnosis; Severity of Illness Index; Spine - abnormalities; Trachea - abnormalities; VACTERL; VACTERL; exome sequencing; Fanconi anemia; prenatal diagnosis; FANCL
• DOI: 10.1002/humu.22784
• EISSN: 1098-1004
• ISSN: 1059-7794

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.
Loss‐of‐function variants in FANCL can be responsible for an early lethal Fanconi anemia (FA) phenotype, overlapping the VACTERL association in several features. Our findings suggest that FA should always be considered in cases of extremely severe VACTERL phenotypes, especially in the prenatal setting where the correct diagnosis is even more elusive. The picture shows the postmortem view of a fetus of 19 weeks of gestation showing several malformations and homozygous for FANCL mutation.