title: Targeted sequencing identifies a novel SH2D1A pathogenic variant in a Chinese family: Carrier screening and prenatal genetic testing.
abstract: X-linked lymphoproliferative disease type 1 (XLP1) is a rare primary immunodeficiency characterized by a clinical triad consisting of severe EBV-induced hemophagocytic lymphohistiocytosis, B-cell lymphoma, and dysgammaglobulinemia. Mutations in SH2D1A gene have been revealed as the cause of XLP1. In this study, a pregnant woman with recurrence history of birthing immunodeficiency was screened for pathogenic variant because the proband sample was unavailable. We aimed to clarify the genetic diagnosis and provide prenatal testing for the family. Next-generation sequencing (NGS)-based multigene panel was used in carrier screening of the pregnant woman. Variants of immunodeficiency related genes were analyzed and prioritized. Candidate variant was verified by using Sanger sequencing. The possible influence of the identified variant was evaluated through RNA assay. Amniocentesis, karyotyping, and Sanger sequencing were performed for prenatal testing. We identified a novel de novo frameshift SH2D1A pathogenic variant (c.251_255delTTTCA) in the pregnant carrier. Peripheral blood RNA assay indicated that the mutant transcript could escape nonsense-mediated mRNA decay (NMD) and might encode a C-terminal truncated protein. Information of the variant led to success prenatal diagnosis of the fetus. In conclusion, our study clarified the genetic diagnosis and altered disease prevention for a pregnant carrier of XLP1.
authors.affiliation: The International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.|Institute of Embryo-Fetal Original Adult Disease Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.
authors.forename: Jun-Yu
authors.identifier: http://orcid.org/0000-0003-0239-6670
authors.initials: JY
authors.lastname: Zhang
authors.affiliation: The International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.|Institute of Embryo-Fetal Original Adult Disease Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.
authors.forename: Song-Chang
authors.initials: SC
authors.lastname: Chen
authors.affiliation: The International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.|Institute of Embryo-Fetal Original Adult Disease Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.
authors.forename: Yi-Yao
authors.initials: YY
authors.lastname: Chen
authors.affiliation: The International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.|Institute of Embryo-Fetal Original Adult Disease Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.
authors.forename: Shu-Yuan
authors.initials: SY
authors.lastname: Li
authors.affiliation: The International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.|Institute of Embryo-Fetal Original Adult Disease Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.
authors.forename: Lan-Lan
authors.initials: LL
authors.lastname: Zhang
authors.affiliation: The International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.|Institute of Embryo-Fetal Original Adult Disease Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Shen
authors.affiliation: The International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.|Institute of Embryo-Fetal Original Adult Disease Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.
authors.forename: Chun-Xin
authors.initials: CX
authors.lastname: Chang
authors.affiliation: The International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.|Institute of Embryo-Fetal Original Adult Disease Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.
authors.forename: Yu-Qian
authors.initials: YQ
authors.lastname: Xiang
authors.affiliation: The International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.|Institute of Embryo-Fetal Original Adult Disease Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.
authors.forename: He-Feng
authors.initials: HF
authors.lastname: Huang
authors.affiliation: The International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.|Institute of Embryo-Fetal Original Adult Disease Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.
authors.forename: Chen-Ming
authors.initials: CM
authors.lastname: Xu
mesh_terms: D000328:Adult; D005260:Female; D016368:Frameshift Mutation; D005820:Genetic Testing; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000235:genetics*; D008297:Male; D009154:Mutation; D059365:Nonsense Mediated mRNA Decay; D010375:Pedigree; D011247:Pregnancy; D011296:Prenatal Diagnosis; D012333:RNA, Messenger / Q000235:genetics; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein