title: Targeted exome sequencing identifies novel compound heterozygous mutations in P3H1 in a fetus with osteogenesis imperfecta type VIII.
abstract: Osteogenesis imperfecta (OI) is a highly clinically and genetically heterogeneous group of disorders. It is difficult to identify severe OI in the perinatal period. Here, a Chinese woman with a suspected history of fetal OI was referred to our institution at 19weeks of gestation, due to ultrasound inspection during antenatal screening, which revealed bulbous metaphyses, short humeri, and short thick bent femora in the fetus. Using targeted exome sequencing of 248 genes known to be involved in skeletal system diseases, we identified novel compound heterozygous mutation in the P3H1 gene in the fetus with OI type VIII: c.105_120del (p.D36Rfs*16) and c.2164C>T (p.Q722*). These two mutations were inherited from the father and mother, respectively. The mRNA level of P3H1 wasn't changed suggested that mRNA with this mutation escaped from nonsense-mediated RNA decay. Besides, the level of P3H1 was absence while the CRTAP was mildly decreased. In conclusion, our findings imply this novel compound heterozygous mutation as the molecular pathogenetic in a Chinese fetus with OI type VIII, and demonstrate that targeted next-generation sequencing (NGS) is an accurate, rapid, and cost-effective method in the genetic diagnosis of fetal skeletal dysplasia with genetic and clinical heterogeneity, especially for autosomal recessive skeletal disorders.
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, PR China.
authors.forename: Yanru
authors.initials: Y
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, PR China.
authors.forename: Libin
authors.initials: L
authors.lastname: Mei
authors.affiliation: Hunan Jiahui Genetics Hospital, 110 Xiangya Road, Changsha, Hunan 410078, PR China.
authors.forename: Weigang
authors.initials: W
authors.lastname: Lv
authors.affiliation: Hunan Jiahui Genetics Hospital, 110 Xiangya Road, Changsha, Hunan 410078, PR China.
authors.forename: Haoxian
authors.initials: H
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, PR China; Hunan Jiahui Genetics Hospital, 110 Xiangya Road, Changsha, Hunan 410078, PR China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, PR China.
authors.forename: Hu
authors.initials: H
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, PR China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, PR China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, PR China; Hunan Jiahui Genetics Hospital, 110 Xiangya Road, Changsha, Hunan 410078, PR China. Electronic address: liangdesheng@sklmg.edu.cn.
authors.forename: Desheng
authors.initials: D
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, PR China; Hunan Jiahui Genetics Hospital, 110 Xiangya Road, Changsha, Hunan 410078, PR China. Electronic address: wulingqian@sklmg.edu.cn.
authors.forename: Lingqian
authors.initials: L
authors.lastname: Wu
mesh_terms: D000328:Adult; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D005260:Female; D005333:Fetus; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D011247:Pregnancy; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics*
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D011393:Procollagen-Proline Dioxygenase; C030606:proline, 2-oxoglutarate 3-dioxygenase
keywords: Compound heterozygous mutations; Osteogenesis imperfecta type VIII; P3H1; Targeted exome sequencing