title: Maternal germline mosaicism of kinesin family member 21A (KIF21A) mutation causes complex phenotypes in a Chinese family with congenital fibrosis of the extraocular muscles.
abstract: OBJECTIVE
  To identify the causative mutation with its possible origin in a Chinese family with congenital fibrosis of extraocular muscles type 1 (CFEOM1) and to characterize the ocular phenotypes and lesions in the corresponding intracranial nerves.
  
  
  METHODS
  Three affected siblings and their asymptomatic parents underwent comprehensive ophthalmic examinations and neuropathologic analysis involving magnetic resonance imaging (MRI). KIF21A, PHOX2A, and TUBB3 genes were sequenced on the leukocyte-derived DNA to detect variants. The disease-linked haplotype was analyzed using four microsatellite markers across the KIF21A locus.
  
  
  RESULTS
  All three affected individuals displayed typical CFEOM1. MRI revealed complicated but consistent neuromuscular abnormalities in the two patients examined, including hypoplastic oculomotor nerves, complete absence of bilateral superior rectus muscles, and unilateral absence of the abducens nerve with marked atrophy of the corresponding lateral rectus muscle. A heterozygous hotspot mutation KIF21A c.2860C>T was identified in all patients, but it was absent in both parents. Haplotype analysis of the disease locus showed the likely maternal inheritance of the disease-associated haplotype to all three affected offspring, strongly suggesting maternal germline mosaicism of the mutation.
  
  
  CONCLUSIONS
  Germline mosaicism of KIF21A c.2860C>T is likely to cause the high occurrence of this mutation in the population. This information may be useful for genetic counseling. KIF21A mutations can affect the abducens nerve and cause complete absence of the bilateral superior rectus muscles. MRI characterization of new CFEOM1 phenotypes would assist clinical management.
authors.affiliation: Department of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital University of Medical Sciences, Beijing, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China ; Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Xue
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology, Children's Hospital of Zhengzhou, Zhengzhou, China.
authors.forename: Xiantao
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Genetics, Tianjin Eye Hospital, Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Medical University, Tianjin, China.
authors.forename: Kanxing
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Department of Radiology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital University of Medical Sciences, Beijing, China.
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Chang
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
authors.forename: Songtao
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
authors.forename: Qinghuai
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
mesh_terms: D044466:Asian People / Q000235:genetics*; D002681:China; D019295:Computational Biology; D015785:Eye Diseases, Hereditary / Q000150:complications / Q000235:genetics* / Q000473:pathology; D005260:Female; D005355:Fibrosis / Q000150:complications / Q000235:genetics* / Q000473:pathology; D005854:Germ Cells / Q000378:metabolism*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D008297:Male; D009030:Mosaicism; D009154:Mutation / Q000235:genetics*; D015835:Ocular Motility Disorders / Q000150:complications / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D013285:Strabismus / Q000150:complications / Q000235:genetics / Q000473:pathology
chemical_list: C119023:KIF21A protein, human; D016547:Kinesins