title: Rapid gene identification in a Chinese osteopetrosis family by whole exome sequencing.
abstract: Osteopetrosis is a rare genetically heterogeneous disorder of bone metabolism characterized by increased skeleton density. In the past, standard methods for genetic diagnosis of osteopetrosis have primarily been performed by candidate gene screening and positional cloning. However, these methods are time and labor consumptive; and the genetic basis of approximately 30% of the cases is yet to be elucidated. Here, we employed whole exome sequencing of two affected individuals from an osteopetrosis family to identify a candidate mutation in CLCN7 (Y99C). It was identified from a total of 1757 and 1728 genetic variations found in either patient, which were then distilled using filtering strategies and confirmed using Sanger sequencing. We identified this mutation in six family members, while not in population matched controls. This mutation was previously found in osteopetrosis patients by other researchers. Our evolutionary analysis also indicated that it is under extremely high selective pressure, and is likely to be critical for the correct function of ClC-7, and thus is likely to be the responsible cause of disease. Collectively, our data further indicated that mutation (Y99C) may be a cause of osteopetrosis, and highlights the use of whole exome sequencing as a valuable approach to identifying disease mutations in a cost and time efficient manner.
authors.affiliation: Guangxi Key laboratory of Metabolic Diseases Research, Central Laboratory of Guilin 181st Hospital, Guilin, 541002, China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Sui
authors.forename: Minglin
authors.initials: M
authors.lastname: Ou
authors.forename: Jinlong
authors.initials: J
authors.lastname: Liang
authors.forename: Min
authors.initials: M
authors.lastname: Ding
authors.forename: Jiejing
authors.initials: J
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Ruo
authors.initials: R
authors.lastname: Xiao
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Meng
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wang
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Pan
authors.forename: Peng
authors.initials: P
authors.lastname: Zhu
authors.forename: Wen
authors.initials: W
authors.lastname: Xue
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Lin
authors.forename: Fengyan
authors.initials: F
authors.lastname: Li
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics*; D002675:Child, Preschool; D059472:Exome / Q000235:genetics; D005190:Family; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010022:Osteopetrosis / Q000208:ethnology / Q000235:genetics*; D010375:Pedigree; D013997:Time Factors; D055815:Young Adult