Novel Compound Heterozygous Mutations in CRTAP Cause Rare Autosomal Recessive Osteogenesis Imperfecta

Frontiers in Genetics

卷:11

Chiao-May Chang¹  I-Wen Lee⁵  Wen-Hui Tsai⁶  Yen-An Tang⁷  H. Sunny Sun⁷  Lin-Yen Wang⁸ 

[1] Center for Genomic Medicine, Research and Service Headquarter, National Cheng Kung University, Tainan, Taiwan;

[2] Department of Childhood Education and Nursery, Chia Nan University of Pharmacy and Science, Tainan, Taiwan;

[3] Division of Genetics and Metabolism, Department of Pediatrics, Chi Mei Medical Center, Tainan, Taiwan;

[4] Division of Hematology Oncology, Department of Pediatrics, Chi Mei Medical Center, Tainan, Taiwan;

[5] FMC Fetal Medicine Center, Tainan, Taiwan;

[6] Graduate Institute of Medical Sciences, College of Health Sciences, Chang Jung Christian University, Tainan, Taiwan;

[7] Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan;

[8] School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;

关键词: whole-exome sequencing;    CRTAP;    skeletal dysplasia;    osteogenesis imperfecta;    splicing-altering variant;   

DOI  :  10.3389/fgene.2020.00897

来源: DOAJ

【 摘 要 】

Whole-exome sequencing (WES) has advantages over the traditional molecular test by screening 20,000 genes simultaneously and has become an invaluable tool for genetic diagnosis in clinical practice. Here, we reported a family with a child and a fetus presenting undiagnosed skeletal dysplasia phenotypes, while the parents were asymptomatic. WES was applied to the parents and affected fetus to identify the genetic cause of the phenotypes. We identified novel compound heterozygous mutations consisting of a single-nucleotide variant (SNV) and a large deletion in the CRTAP gene (NM_006371.4:c.1153-3C > G/hg19 chr3:g.32398837_34210906del). Genetic alterations of CRTAP are known to cause osteogenesis imperfecta (OI) in an autosomal recessive manner. Further examination of the proband’s elder sibling who was diagnosed as OI after birth found that she shares the inherited compound heterozygous mutations of CRTAP; thus, the findings support the disease-causing role of CRTAP mutations. Through the in vitro molecular test and in silico analysis, the deleterious effects of the splicing-altering SNV in CRTAP (c.1153-3C > G) on gene product were confirmed. Collectively, our WES-based pathogenic variant discovery pipeline identifies the SNVs and copy number variation to delineate the genetic cause on the proband affected with OI. The data not only extend the knowledge of mutation spectrum in patients with skeletal dysplasia but also demonstrate that WES holds great promise for genetic screening of rare diseases in clinical settings.

【 授权许可】

Unknown