Identification of Novel FMR1 Variants by Massively Parallel Sequencing in Developmentally Delayed Males

• Type of Material: Article
• Authors: Stephen C. Collins, Emory University; Steven M. Bray, Emory University; Joshua A. Suhl, Emory University; David J Cutler, Emory University; Brad Coffee, Emory University; Michael Zwick, Emory University; Stephen Warren, Emory University
• Language: English
• Date: 2010-10
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010 Wiley-Liss, Inc.
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.33626/abstract
• Title of Journal or Parent Work: American Journal of Medical Genetics Part A
• ISSN: 1552-4825
• Volume: 152A
• Issue: 10
• Start Page: 2512
• End Page: 2520
• Grant/Funding Information: This research was supported by National Institutes of Health grants AG029749 (to S.C.C.) and HD020521 and HD024064 (to S.T.W.) and a FRAXA Foundation Fellowship (to J.A.S.).; We acknowledge the assistance of the Emory Genomics Center and its support through the Georgia Research Alliance and the Atlanta Clinical & Translational Science Institute (UL1 RR025008).
• Keywords: developmental delay; massively parallel sequencing; FMR1
• Research Categories: Biology, Genetics

Abstract

Fragile X syndrome (FXS), the most common inherited form of developmental delay, is typically caused by CGG-repeat expansion in FMR1. However, little attention has been paid to sequence variants in FMR1. Through the use of pooled-template massively parallel sequencing, we identified 130 novel FMR1 sequence variants in a population of 963 developmentally delayed males without CGG-repeat expansion mutations. Among these, we identified a novel missense change, p.R138Q, which alters a conserved residue in the nuclear localization signal of FMRP. We have also identified three promoter mutations in this population, all of which significantly reduce in vitro levels of FMR1 transcription. Additionally, we identified 10 noncoding variants of possible functional significance in the introns and 3’-untranslated region of FMR1, including two predicted splice site mutations. These findings greatly expand the catalogue of known FMR1 sequence variants and suggest that FMR1 sequence variants may represent an important cause of developmental delay.