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: jlupski@bcm.edu.

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.

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