A novel heterozygous germline deletion in MSH2 gene in a five generation Chinese family with Lynch syndrome

// Bin Wu 1, * , Wuyang Ji 1, * , Shengran Liang 2 , Chao Ling 3 , Yan You 4 , Lai Xu 1 , Min-Er Zhong 1 , Yi Xiao 1 , Hui-Zhong Qiu 1 , Jun-Yang Lu 1 and Santasree Banerjee 5 1 Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China 2 School of Life Science and Biopharmaceutical, Guangdong Pharmaceutical University, Guangzhou 510006, China 3 Laboratory of Clinical Genetic, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China 4 Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China 5 Department of Cell Biology and Medical Genetics, School of Medicine, Zhejiang University, Hangzhou 310000, China * These authors contributed equally to this work Correspondence to: Santasree Banerjee, email: santasree.banerjee@yahoo.com Jun-Yang Lu, email: lujunyang@pumch.cn Keywords: Lynch syndrome, MSH2 gene, targeted next generation sequencing, novel mutation, DNA mismatch repair gene Received: September 22, 2016      Accepted: June 27, 2017      Published: July 14, 2017 ABSTRACT Lynch syndrome (LS) is one of the most common familial forms of colorectal cancer predisposing syndrome with an autosomal dominant mode of inheritance. LS is caused by the germline mutations in DNA mismatch repair (MMR) genes including MSH2, MLH1, MSH6 and PMS2 . Clinically, LS is characterized by high incidence of early-onset colorectal cancer as well as endometrial, small intestinal and urinary tract cancers, usually occur in the third to fourth decade of the life. Here we describe a five generation Chinese family with LS clinically diagnosed according to the Amsterdam II criteria. Immuno-histochemical staining of MSH2 and MSH6 shows only foci nuclear positive on the surface of the tumor with strong expression of MLH1 and PMS2 with diffuse immunoreactivity. In order to dig into the molecular basis of this LS pedigree, we collected the proband’s blood sample, extracted the genomic DNA and applied the genetic screening. As a result, we identified a novel heterozygous deletion in MSH2 gene by targeted next generation sequencing, which is also proved to be co-segregated among other affected family members by following validation. To our knowledge, this novel heterozygous deletion (c.1676_1679 delTAAA) in MSH2 gene causes frameshift mutation (p.Asn560Lysfs*29) and leads to the formation of a truncated MSH2 protein which is confirmed to be a deleterious mutation according to the variant interpretation guidelines of American College of Medical Genetics and Genomics (ACMG). Identification of novel DNA mismatch repair (MMR) gene mutations can definitely benefit to the clinical diagnosis and management.