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...

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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
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Summary:	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.
Bibliography:	ArticleID:HUMU22784 Telethon Foundation - No. GGP10121C Italian Ministry of University and Scientific research FIRB - No. RBPR05ZK2Z istex:D3531742AB1EDFAEACEEF8BD395304A0BB536615 Cariplo Foundation - No. 2009-2609 F.B.; PRIN - No. 2008XA48SC ark:/67375/WNG-4MHW9J3L-T Contract grant sponsor(s): Almamater Foundation (Pavia) grant to O.Z. in the frame of the project "Nanomedicine in aging‐associated prototypic diseases: activation of a scientific and technological platform challenging seminal aspects of pathogenesis, diagnosis and therapy"; Cariplo Foundation grant 2009‐2609; Telethon Foundation (project GGP10121C) to O.Z.; the Italian Ministry of University and Scientific research FIRB grant RBPR05ZK2Z to F.B.; PRIN grant 2008XA48SC to A.F.; KWF (Dutch Cancer Society) for N.A. and J.C.D. Deceased. Communicated by Stylianos E. Antonarakis ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	1059-7794 1098-1004
DOI:	10.1002/humu.22784