Whole exome sequencing reveals concomitant mutations of multiple FA genes in individual Fanconi anemia patients

BMC Medical Genomics

Xiaofan Zhu³  Tao Cheng³  Yungui Yang¹  Fengchun Yang²  Mingjiang Xu²  Xiaomin Wang³  Miaomiao Li¹  Jianfeng Zhou³  Wei Wei³  Quanquan Zhou³  Huimin Zeng³  Weiping Yuan³  Lixian Chang³ 

[1] Beijing Institute of Genomics, CAS, Beijing, China;Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA;Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, China

关键词: Concomitant mutation;    DNA repair;    Exome sequencing;    Fanconi anemia;   

Others  :  797040
DOI  :  10.1186/1755-8794-7-24

 received in 2014-01-05, accepted in 2014-04-29,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Chang et al.; licensee BioMed Central Ltd.

【 图 表 】

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