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Genotype-phenotype correlations
Short report
Hypermobile Ehlers-Danlos syndrome (hEDS) phenotype in fragile X premutation carriers: case series
  1. Nattaporn Tassanakijpanich1,2,
  2. Forrest J McKenzie2,3,
  3. Yingratana A McLennan2,4,
  4. Elisabeth Makhoul2,5,
  5. Flora Tassone2,5,
  6. Mittal J Jasoliya5,
  7. Christopher Romney2,
  8. Ignacio Cortina Petrasic2,3,
  9. Kaye Napalinga2,6,
  10. Caroline B Buchanan7,
  11. Paul Hagerman2,5,
  12. Randi Hagerman2,4,
  13. Emily L Casanova8
  1. 1 Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
  2. 2 UC Davis MIND Institute, UC Davis Health, Sacramento, California, USA
  3. 3 University of California, Davis, School of Medicine, Sacramento, California, USA
  4. 4 Department of Pediatrics, University of California, Davis, School of Medicine, Sacramento, California, USA
  5. 5 Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Sacramento, California, USA
  6. 6 MedMom Institute for Human Development, Pasig City, Philippines
  7. 7 Greenwood Genetic Center, Greenville, South Carolina, USA
  8. 8 Department of Biomedical Sciences, University of South Carolina School of Medicine Greenville, Greenville, South Carolina, USA
  1. Correspondence to Dr Randi Hagerman, UC Davis MIND Institute, UC Davis Health, Sacramento, California 95817, USA; rjhagerman{at}ucdavis.edu

Abstract

Background While an association between full mutation CGG-repeat expansions of the Fragile X Mental Retardation 1 (FMR1) gene and connective tissue problems are clearly described, problems in fragile X premutation carriers (fXPCs) CGG-repeat range (55–200 repeats) of the FMR1 gene may be overlooked.

Objective To report five FMR1 fXPCs cases with the hypermobile Ehlers-Danlos syndrome (hEDS) phenotype.

Methods We collected medical histories and FMR1 molecular measures from five cases who presented with joint hypermobility and loose connective tissue and met inclusion criteria for hEDS.

Results Five cases were female and ranged between 16 and 49 years. The range of CGG-repeat allele sizes ranged from 66 to 150 repeats. All had symptoms of hEDS since early childhood. Commonalities in molecular pathogenesis and coexisting conditions between the fXPCs and hEDS are also presented. The premutation can lead to a reduction of fragile X mental retardation protein, which is crucial in maintaining functions of the extracellular matrix-related proteins, particularly matrix metallopeptidase 9 and elastin. Moreover, elevated FMR1 messenger RNA causes sequestration of proteins, which results in RNA toxicity.

Conclusion Both hEDS phenotype and premutation involvement may co-occur because of related commonalities in pathogenesis.

  • genetic predisposition to disease
  • genetics
  • medical
  • human genetics
  • gene expression

https://doi.org/10.1136/jmedgenet-2020-107609

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    Footnotes

    • Correction notice This article has been corrected since it was published online first. The name of author FJMcK has been amended.

    • Contributors RH, ELC and NT made substantial contributions to the conception of the work. RH, ELC, NT, EM, KN and ICP drafted the manuscript. RH, ELC, CBB and CR wrote case histories. FJMcK, FT and PH wrote the Methods section. FT, MJJ and PH did the molecular analysis and provided the results. NT and ELC wrote the Discussion. FJMcK, YAMcL, EM, FT, RH and ELC made critical revisions. RH, ELC and CBB made substantial contributions to funding, patient recruitment and ascertainment, and data collection. All authors approved the submitted version of the manuscript.

    • Funding This study was funded by NICHD HD036071, the Tides Foundation, the MIND Institute IDDRC (grant U54 HD079125), and the National Centre for Advancing Translational Sciences and National Institutes of Health (grant UL1 TR001860).

    • Competing interests FT has received from Azrieli Foundation, from Zynerba and from Asuragen, Inc. for studies in fragile X syndrome.

    • Provenance and peer review Not commissioned; externally peer reviewed.