title: Whole exome sequencing confirms the clinical diagnosis of Marfan syndrome combined with X-linked hypophosphatemia.
abstract: BACKGROUND
  To determine the genetic lesions and to modify the clinical diagnosis for a Chinese family with significant intrafamilial phenotypic diversities and unusual presentations.
  
  
  METHODS
  Three affected patients and the asymptomatic father were included and received comprehensive systemic examinations. Whole exome sequencing (WES) was performed for mutation detection. Structural modeling test was applied to analyze the potential structural changes caused by the missense substitution.
  
  
  RESULTS
  The proband showed a wide spectrum of systemic anomalies, including bilateral ectopia lentis, atrial septal defect, ventricular septal defect, widening of tibial metaphysis with medial bowing, and dolichostenomelia in digits, while her mother and elder brother only demonstrated similar skeletal changes. A recurrent mutation, PHEX p.R291*, was found in all patients, while a de novo mutation, FBN1 p.C792F, was only detected in the proband. The FBN1 substitution was also predicted to cause significant conformational change in fibrillin-1 protein, thus changing its physical and biological properties.
  
  
  CONCLUSIONS
  Taken together, we finalized the diagnosis for this family as X-linked hypophosphatemia (XLH), and diagnosed this girl as Marfan syndrome combined with XLH, and congenital heart disease. Our study also emphasizes the importance of WES in assisting the clinical diagnosis for complicated cases when the original diagnoses are challenged.
authors.affiliation: Department of Ophthalmology, Ningxia Eye Hospital, Ningxia People's Hospital, Ningxia, China. shengxunlun@163.com.
authors.forename: Xunlun
authors.initials: X
authors.lastname: Sheng
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. drcx1990@163.com.
authors.forename: Xue
authors.initials: X
authors.lastname: Chen
authors.affiliation: Chongqing Key Laboratory of Ophthalmology, Department of Ophthalmology, Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. bolei99@163.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Lei
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. ruichen@bcm.edu.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. hw11@bcm.edu.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Ningxia Eye Hospital, Ningxia People's Hospital, Ningxia, China. fangxia_zhangnx@163.com.
authors.forename: Fangxia
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Ningxia Eye Hospital, Ningxia People's Hospital, Ningxia, China. rongweining426@126.com.
authors.forename: Weining
authors.initials: W
authors.lastname: Rong
authors.affiliation: Department of Radiology, Ningxia Eye Hospital, Ningxia People's Hospital, Ningxia, China. ruoshui_hanx@163.com.
authors.forename: Ruoshui
authors.initials: R
authors.lastname: Ha
authors.affiliation: Department of Ophthalmology, Ningxia Eye Hospital, Ningxia People's Hospital, Ningxia, China. yani.2007.happy@163.com.
authors.forename: Yani
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cardiology and Surgery, Tianjin Chest Hospital, Tianjin Medical University, Tianjin, China. fengzhaotj@126.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Chongqing Key Laboratory of Ophthalmology, Department of Ophthalmology, Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. peizengycmu@126.com.
authors.forename: Peizeng
authors.initials: P
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. dr_zhaochen@163.com.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D059472:Exome / Q000235:genetics*; D053098:Familial Hypophosphatemic Rickets / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D005190:Family; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000737:chemistry / Q000235:genetics; D010375:Pedigree; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA / Q000379:methods*; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C000605722:FBN1 protein, human; D054392:Adipokines; C506231:PHEX protein, human