title: Whole exome sequencing reveals concomitant mutations of multiple FA genes in individual Fanconi anemia patients.
abstract: BACKGROUND
  Fanconi anemia (FA) is a rare inherited genetic syndrome with highly variable clinical manifestations. Fifteen genetic subtypes of FA have been identified. Traditional complementation tests for grouping studies have been used generally in FA patients and in stepwise methods to identify the FA type, which can result in incomplete genetic information from FA patients.
  
  
  METHODS
  We diagnosed five pediatric patients with FA based on clinical manifestations, and we performed exome sequencing of peripheral blood specimens from these patients and their family members. The related sequencing data were then analyzed by bioinformatics, and the FANC gene mutations identified by exome sequencing were confirmed by PCR re-sequencing.
  
  
  RESULTS
  Homozygous and compound heterozygous mutations of FANC genes were identified in all of the patients. The FA subtypes of the patients included FANCA, FANCM and FANCD2. Interestingly, four FA patients harbored multiple mutations in at least two FA genes, and some of these mutations have not been previously reported. These patients' clinical manifestations were vastly different from each other, as were their treatment responses to androstanazol and prednisone. This finding suggests that heterozygous mutation(s) in FA genes could also have diverse biological and/or pathophysiological effects on FA patients or FA gene carriers. Interestingly, we were not able to identify de novo mutations in the genes implicated in DNA repair pathways when the sequencing data of patients were compared with those of their parents.
  
  
  CONCLUSIONS
  Our results indicate that Chinese FA patients and carriers might have higher and more complex mutation rates in FANC genes than have been conventionally recognized. Testing of the fifteen FANC genes in FA patients and their family members should be a regular clinical practice to determine the optimal care for the individual patient, to counsel the family and to obtain a better understanding of FA pathophysiology.
authors.forename: Lixian
authors.initials: L
authors.lastname: Chang
authors.forename: Weiping
authors.initials: W
authors.lastname: Yuan
authors.forename: Huimin
authors.initials: H
authors.lastname: Zeng
authors.forename: Quanquan
authors.initials: Q
authors.lastname: Zhou
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Li
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Xu
authors.forename: Fengchun
authors.initials: F
authors.lastname: Yang
authors.forename: Yungui
authors.initials: Y
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China. chengt@pumc.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Zhu
mesh_terms: D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002873:Chromosome Fragility / Q000187:drug effects / Q000235:genetics; D020552:Comet Assay; D004252:DNA Mutational Analysis / Q000379:methods*; D059472:Exome / Q000235:genetics*; D005199:Fanconi Anemia / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006801:Humans; D007621:Karyotyping; D008297:Male; D016685:Mitomycin / Q000494:pharmacology; D009154:Mutation / Q000235:genetics*; D015203:Reproducibility of Results; D012984:Software; D013223:Statistics as Topic
chemical_list: D016685:Mitomycin