title: Novel pathogenic ACAN variants in non-syndromic short stature patients.
abstract: BACKGROUND
  Pathogenic variants of ACAN have been reported to cause spondyloepiphyseal dysplasia Kimberley type, spondyloepimetaphyseal dysplasia, familial osteochondritis dissecans and idiopathic short stature with normal to advanced bone age. A recent international cohort study significantly expanded the ACAN mutation spectrum, further delineated the heterogeneous clinical characteristics of ACAN mutation patients. The prevalence of ACAN mutation in short stature patients is yet unknown.
  
  
  METHODS
  Here we set to assess the frequency of ACAN variants among a cohort of 218 Chinese children with non-syndromic short stature.
  
  
  RESULTS
  We identified three novel truncating variants at the 5' end of ACAN gene. All these pathogenic variants co-segregate with severe short stature phenotype in families. In addition, none of the probands showed significant advanced bone age. All affected individuals showed no signs of significant dysmorphic features or skeletal abnormities. The prevalence of ACAN defect in this cohort is estimated to be 1.4% (3/218). It is higher among families with parents also affected with severe short stature, up to 7.0% (3/43) if parental height is <2.5 SD or 16.7% (3/18) if parental height is <3.0 SD.
  
  
  CONCLUSIONS
  Our data suggest that ACAN mutation is a relative common cause of familial severe short stature.
authors.affiliation: Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, Guangxi, PR China.
authors.forename: Xuyun
authors.initials: X
authors.lastname: Hu
authors.affiliation: Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, Guangxi, PR China.
authors.forename: Baoheng
authors.initials: B
authors.lastname: Gui
authors.affiliation: Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, Guangxi, PR China.
authors.forename: Jiasun
authors.initials: J
authors.lastname: Su
authors.affiliation: Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, Guangxi, PR China.
authors.forename: Hongdou
authors.initials: H
authors.lastname: Li
authors.affiliation: Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Niu
authors.initials: N
authors.lastname: Li
authors.affiliation: Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Yu
authors.affiliation: Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, Guangxi, PR China.
authors.forename: Qinle
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Li
authors.affiliation: Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Yanrong
authors.initials: Y
authors.lastname: Qing
authors.affiliation: Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, Guangxi, PR China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Li
authors.affiliation: Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, Guangxi, PR China.
authors.forename: Jingsi
authors.initials: J
authors.lastname: Luo
authors.affiliation: Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, Guangxi, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Fan
authors.affiliation: Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Xiumin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, Guangxi, PR China.
authors.forename: Shaoke
authors.initials: S
authors.lastname: Chen
authors.affiliation: Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning, Guangxi, PR China; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, United States; Department of Neurology, Harvard Medical School, Boston, MA, United States. Electronic address: yiping.shen@childrens.harvard.edu.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Shen
mesh_terms: D000328:Adult; D053674:Aggrecans / Q000235:genetics*; D002648:Child; D004392:Dwarfism / Q000000981:diagnostic imaging / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D014057:Tomography, X-Ray Computed
chemical_list: C508319:ACAN protein, human; D053674:Aggrecans
keywords: ACAN mutation; Bone age; Pathogenic variants; Prevalence; Short stature