Clinical aspects of Fanconi anemia individuals with the same mutation of FANCF identified by next generation sequencing.

BACKGROUND Fanconi anemia (FA) is a rare genetic disease characterized by congenital malformations, aplastic anemia and increased risk of developing malignancies. FA is genetically heterogeneous as it is caused by at least 17 different genes. Among these, FANCA, FANCC, and FANCG account for approximately 85% of the patients whereas the remaining genes are mutated in only a small percentage of cases. For this reason, the molecular diagnostic process is complex and not always extended to all the FA genes, preventing the characterization of individuals belonging to rare groups. METHODS The FA genes were analyzed using a next generation sequencing approach in two unrelated families. RESULTS The analysis identified the same, c.484_485del, homozygous mutation of FANCF in both families. A careful examination of three electively aborted fetuses in one family and one affected girl in the other indicated an association of the FANCF loss-of-function mutation with a severe phenotype characterized by multiple malformations. CONCLUSION The systematic use of next generation sequencing will allow the recognition of individuals from rare complementation groups, a better definition of their clinical phenotypes, and consequently, an appropriate genetic counseling.

[1]  Martin Kircher,et al.  Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype. , 2015, Cancer discovery.

[2]  S. Perrotta,et al.  Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology , 2014, Haematologica.

[3]  E. Ostrander,et al.  Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi anemia. , 2013, Blood.

[4]  Chantal Stoepker,et al.  Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. , 2013, American journal of human genetics.

[5]  Molly C. Kottemann,et al.  Fanconi anaemia and the repair of Watson and Crick DNA crosslinks , 2013, Nature.

[6]  B. Alter,et al.  VACTERL-H Association and Fanconi Anemia , 2012, Molecular Syndromology.

[7]  D. Tibboel,et al.  Clinical geneticists' views of VACTERL/VATER association , 2012, American journal of medical genetics. Part A.

[8]  A. D’Andrea,et al.  Molecular pathogenesis and clinical management of Fanconi anemia. , 2012, The Journal of clinical investigation.

[9]  N. Ameziane,et al.  Diagnosis of Fanconi Anemia: Mutation Analysis by Multiplex Ligation-Dependent Probe Amplification and PCR-Based Sanger Sequencing , 2012, Anemia.

[10]  B. Ylstra,et al.  Diagnosis of Fanconi Anemia: Mutation Analysis by Next-Generation Sequencing , 2012, Anemia.

[11]  S. Holden,et al.  X‐linked VACTERL with hydrocephalus syndrome: Further delineation of the phenotype caused by FANCB mutations , 2011, American journal of medical genetics. Part A.

[12]  B. Solomon.  VACTERL/VATER Association , 2011, Orphanet journal of rare diseases.

[13]  A. Figuera,et al.  Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations. , 2011, Blood.

[14]  David A. Williams,et al.  A rapid method for retrovirus-mediated identification of complementation groups in Fanconi anemia patients. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[15]  C. Mathew,et al.  Should chromosome breakage studies be performed in patients with VACTERL association? , 2005, American journal of medical genetics. Part A.

[16]  A. Carnevale,et al.  DEB test for Fanconi anemia detection in patients with atypical phenotypes , 2004, American journal of medical genetics. Part A.

[17]  A. Savoia,et al.  Spectrum of FANCA mutations in Italian Fanconi anemia patients: Identification of six novel alleles and phenotypic characterization of the S858R variant , 2003, Human mutation.

[18]  S. Bonin,et al.  PCR analysis in archival postmortem tissues , 2003, Molecular pathology : MP.

[19]  David A. Williams,et al.  Phenotypic correction of primary Fanconi anemia T cells with retroviral vectors as a diagnostic tool. , 2002, Experimental hematology.

[20]  C. Lewis,et al.  Association of complementation group and mutation type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group. , 2000, Blood.

[21]  Hans Joenje,et al.  The Fanconi anaemia gene FANCF encodes a novel protein with homology to ROM , 2000, Nature Genetics.

[22]  C. Mathew,et al.  High frequency of large intragenic deletions in the Fanconi anemia group A gene. , 1999, American journal of human genetics.

[23]  A. Auerbach.  Fanconi anemia diagnosis and the diepoxybutane (DEB) test. , 1993, Experimental hematology.