title: X-linked congenital hypertrichosis syndrome is associated with interchromosomal insertions mediated by a human-specific palindrome near SOX3.
abstract: X-linked congenital generalized hypertrichosis (CGH), an extremely rare condition characterized by universal overgrowth of terminal hair, was first mapped to chromosome Xq24-q27.1 in a Mexican family. However, the underlying genetic defect remains unknown. We ascertained a large Chinese family with an X-linked congenital hypertrichosis syndrome combining CGH, scoliosis, and spina bifida and mapped the disease locus to a 5.6 Mb critical region within the interval defined by the previously reported Mexican family. Through the combination of a high-resolution copy-number variation (CNV) scan and targeted genomic sequencing, we identified an interchromosomal insertion at Xq27.1 of a 125,577 bp intragenic fragment of COL23A1 on 5q35.3, with one X breakpoint within and the other very close to a human-specific short palindromic sequence located 82 kb downstream of SOX3. In the Mexican family, we found an interchromosomal insertion at the same Xq27.1 site of a 300,036 bp genomic fragment on 4q31.2, encompassing PRMT10 and TMEM184C and involving parts of ARHGAP10 and EDNRA. Notably, both of the two X breakpoints were within the short palindrome. The two palindrome-mediated insertions fully segregate with the CGH phenotype in each of the families, and the CNV gains of the respective autosomal genomic segments are not present in the public database and were not found in 1274 control individuals. Analysis of control individuals revealed deletions ranging from 173 bp to 9104 bp at the site of the insertions with no phenotypic consequence. Taken together, our results strongly support the pathogenicity of the identified insertions and establish X-linked congenital hypertrichosis syndrome as a genomic disorder.
authors.affiliation: McKusick-Zhang Center for Genetic Medicine and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China; Center for Genetic Medicine, Lanzhou University School of Basic Medical Sciences, Lanzhou 730000, China.
authors.forename: Hongwen
authors.initials: H
authors.lastname: Zhu
authors.affiliation: McKusick-Zhang Center for Genetic Medicine and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Shang
authors.affiliation: McKusick-Zhang Center for Genetic Medicine and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Sun
authors.affiliation: Institute for Genetic Medicine and Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Sunju
authors.initials: S
authors.lastname: Choi
authors.affiliation: McKusick-Zhang Center for Genetic Medicine and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Jiajie
authors.initials: J
authors.lastname: Hao
authors.affiliation: División de Genética, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Jalisco, Mexico.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Figuera
authors.affiliation: MOE Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Kwong Wai
authors.initials: KW
authors.lastname: Choy
authors.affiliation: McKusick-Zhang Center for Genetic Medicine and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ao
authors.affiliation: The Research Center for Medical Genomics, China Medical University, Shenyang 110001, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: McKusick-Zhang Center for Genetic Medicine and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Zhang
authors.affiliation: Center for Genetic Medicine, Lanzhou University School of Basic Medical Sciences, Lanzhou 730000, China.
authors.forename: Fengzhen
authors.initials: F
authors.lastname: Yue
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Wang
authors.affiliation: MOE Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.affiliation: Institute for Genetic Medicine and Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Pragna I
authors.initials: PI
authors.lastname: Patel
authors.affiliation: Center for Genetic Medicine, Lanzhou University School of Basic Medical Sciences, Lanzhou 730000, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jing
authors.affiliation: McKusick-Zhang Center for Genetic Medicine and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China; The Research Center for Medical Genomics, China Medical University, Shenyang 110001, China. Electronic address: xuezhang@pumc.edu.cn.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
mesh_terms: D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D041321:Chromosomes, Human, X / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000473:pathology; D006801:Humans; D006983:Hypertrichosis / Q000151:congenital / Q000235:genetics / Q000473:pathology; D055029:Inverted Repeat Sequences; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D010375:Pedigree; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D020742:rhoA GTP-Binding Protein
chemical_list: C486050:ARHGAP10 protein, human; D020690:GTPase-Activating Proteins; C527785:SOX3 protein, human; D055748:SOXB1 Transcription Factors; D020742:rhoA GTP-Binding Protein