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J Med Genet 51:159-164 doi:10.1136/jmedgenet-2013-101978
  • Genotype-phenotype correlations
  • Short report

Correlation between FMR1 expression and clinical phenotype in discordant dichorionic–diamniotic monozygotic twin sisters with the fragile x mutation

  1. Ranhui Duan1
  1. 1State Key Laboratory of Medical Genetics, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
  2. 2Psychiatry Department, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
  1. Correspondence to Professor Ranhui Duan, and Professor Lingqian Wu, State Key Laboratory of Medical Genetics, Central South University, 110, Xiangya Road, Changsha, Hunan 410078, China. duanranhui{at}sklmg.edu.cn or wulingqian{at}sklmg.edu.cn.
  • Received 2 August 2013
  • Revised 25 September 2013
  • Accepted 14 October 2013
  • Published Online First 27 November 2013

Abstract

Background The clinical phenotypes of females with fragile X full mutations vary drastically. Comparisons of discordant monozygotic twins provide opportunities to ascertain crucial factors that influence disease phenotype penetrance.

Objective To identify crucial factors influencing the phenotypic expression of fragile X syndrome (FXS).

Methods and results We describe a pair of discordant monozygotic female twins (dichorionic–diamniotic, Di–Di) with full mutation. The degrees of their phenotypic discordance regarding physical, psychiatric and behavioural features were quantified in a series of neuropsychological tests that varied significantly. Their FMR1 expression levels and whole genome DNA methylation profiling in blood were similar. Their similar life experiences also suggested that environmental factors had limited influence. However, the skewed inactivation of the normal X chromosome in the hair roots of twin A, resulting in large reduction in FMR1 expression compared to that of twin B, could adequately explain their widely variable phenotypes.

Conclusions The sixfold variation in hair root FMR1 expression, which reflected FMRP (fragile X mental retardation protein) expression in the brain, accounted for the disparate phenotypes in IQ, cognition, and social capability between the twins. Additionally, considering the Di–Di type twinning and different CGG repeat sizes, CGG expansion should occur before splitting at day 3 of gestation.

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