REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis

  • Am J Hum Genet. 2017 Jul 6;101(1):149-156. doi: 10.1016/j.ajhg.2017.06.006.
Yavuz Bayram  1 ,  Janson J White  1 ,  Nursel Elcioglu  2 ,  Megan T Cho  3 ,  Neda Zadeh  4 ,  Asuman Gedikbasi  5 ,  Sukru Palanduz  5 ,  Sukru Ozturk  5 ,  Kivanc Cefle  5 ,  Ozgur Kasapcopur  6 ,  Zeynep Coban Akdemir  1 ,  Davut Pehlivan  7 ,  Amber Begtrup  3 ,  Claudia M B Carvalho  1 ,  Ingrid Sophie Paine  1 ,  Ali Mentes  8 ,  Kivanc Bektas-Kayhan  9 ,  Ender Karaca  1 ,  Shalini N Jhangiani  10 ,  Donna M Muzny  10 ,  Baylor-Hopkins Center for Mendelian Genomics ,  Richard A Gibbs  11 ,  James R Lupski  12
Affiliations
  • 1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 2. Department of Pediatric Genetics, Marmara University School of Medicine, Istanbul 34899, Turkey; Eastern Mediterranean University School of Medicine, Cyprus, Mersin 10 99628, Turkey.
  • 3. GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
  • 4. Genetics Center, Orange, CA 92868, USA; Division of Medical Genetics, Children's Hospital of Orange County, Orange, CA 92868, USA.
  • 5. Department of Internal Medicine, Division of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul 34093, Turkey.
  • 6. Department of Child Rheumatology, Cerrahpasa Medical School, Istanbul University, Istanbul 34093, Turkey.
  • 7. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
  • 8. Department of Pediatric Dentistry, Faculty of Dentistry, Marmara University, Istanbul 34854, Turkey.
  • 9. Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Istanbul University, Istanbul 34899, Turkey.
  • 10. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 11. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 12. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].
PMID: 28686854 DOI: 10.1016/j.ajhg.2017.06.006
Abstract

Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis that develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. HGF is a genetically heterogeneous disorder and can be transmitted either as an autosomal-dominant or autosomal-recessive trait or appear sporadically. To date, four loci (2p22.1, 2p23.3-p22.3, 5q13-q22, and 11p15) have been mapped to autosomes and one gene (SOS1) has been associated with the HGF trait observed to segregate in a dominant inheritance pattern. Here we report 11 individuals with HGF from three unrelated families. Whole-exome Sequencing (WES) revealed three different truncating mutations including two frameshifts and one nonsense variant in RE1-silencing transcription factor (REST) in the probands from all families and further genetic and genomic analyses confirmed the WES-identified findings. REST is a transcriptional repressor that is expressed throughout the body; it has different roles in different cellular contexts, such as oncogenic and tumor-suppressor functions and hematopoietic and cardiac differentiation. Here we show the consequences of germline final-exon-truncating mutations in REST for organismal development and the association with the HGF phenotype.

Keywords
RE1-silencing transcription factor; REST; gingival fibromatosis; mosaic mutation; nonsense-mediated decay; whole-exome sequencing.