Original Investigation

Human Genetics

, Volume 128, Issue 1, pp 51-60

First online:

Use of genome-wide SNP homozygosity mapping in small pedigrees to identify new mutations in VSX2 causing recessive microphthalmia and a semidominant inner retinal dystrophy

  • Sibel Ugur IseriAffiliated withDepartment of Physiology, Anatomy, and Genetics, University of Oxford
  • , Alexander W. WyattAffiliated withDepartment of Physiology, Anatomy, and Genetics, University of Oxford
  • , Gudrun NürnbergAffiliated withCologne Center for Genomics, University of CologneCenter for Molecular Medicine Cologne, University of CologneCologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne
  • , Christian KluckAffiliated withCologne Center for Genomics, University of Cologne
  • , Peter NürnbergAffiliated withCologne Center for Genomics, University of CologneCenter for Molecular Medicine Cologne, University of CologneCologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne
  • , Graham E. HolderAffiliated withDepartment of Electrophysiology, Moorfields Eye Hospital
  • , Ed BlairAffiliated withDepartment of Clinical Genetics, Oxford Radcliffe Hospitals
  • , Alison SaltAffiliated withDepartment of Paediatrics, Moorfields Eye HospitalWolfson Neurodisability Service, Great Ormond St Hospital
  • , Nicola K. RaggeAffiliated withDepartment of Physiology, Anatomy, and Genetics, University of OxfordDepartment of Adnexal Surgery, Moorfields Eye HospitalDepartment of Ophthalmology, Birmingham Children’s Hospital Email author 

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Abstract

Mutations in the visual system homeobox 2 gene (VSX2, also known as CHX10), which encodes a retinal transcription factor from the paired homeobox family, have been implicated in recessive isolated microphthalmia. In this study, we use genome-wide single nucleotide polymorphism homozygosity mapping in unrelated small consanguineous pedigrees and a candidate gene approach to identify three further causative VSX2 mutations (two novel and one previously reported). All affected individuals with homozygous mutations had bilateral anophthalmia or severe microphthalmia with absent vision. In addition, we identified a novel inner retinal dystrophy in two carrier parents suggesting a semidominant effect for this particular VSX2 mutation. A further study of individuals with retinal degenerative conditions may reveal a causative role for heterozygous mutations in VSX2.