Genotype–phenotype correlations in individuals with pathogenic RERE variants

Authors

Valerie K. Jordan, Baylor College of Medicine
Brieana Fregeau, University of California, San Francisco
Xiaoyan Ge, Baylor College of Medicine
Jessica Giordano, Columbia University Irving Medical Center
Ronald J. Wapner, Columbia University Irving Medical Center
Tugce B. Balci, Children's Hospital of Eastern Ontario, OttawaFollow
Melissa T. Carter, Children's Hospital of Eastern Ontario, Ottawa
John A. Bernat, University of Iowa
Amanda N. Moccia, University of Michigan Medical School
Anshika Srivastava, University of Michigan Medical School
Donna M. Martin, University of Michigan Medical School
Stephanie L. Bielas, University of Michigan Medical School
John Pappas, NYU Grossman School of Medicine
Melissa D. Svoboda, Baylor College of Medicine
Marlène Rio, Inserm
Nathalie Boddaert, Inserm
Vincent Cantagrel, Inserm
Andrea M. Lewis, Baylor College of Medicine
Fernando Scaglia, Baylor College of Medicine
Jennefer N. Kohler, Stanford University School of Medicine
Jonathan A. Bernstein, Stanford University School of Medicine
Annika M. Dries, Stanford University School of Medicine
Jill A. Rosenfeld, Baylor College of Medicine
Colette DeFilippo, Lucille Packard Children's Hospital
Willa Thorson, University of Miami Leonard M. Miller School of Medicine
Yaping Yang, Baylor College of Medicine
Elliott H. Sherr, University of California, San Francisco
Weimin Bi, Baylor College of Medicine
Daryl A. Scott, Baylor College of Medicine

Document Type

Article

Publication Date

5-1-2018

Journal

Human Mutation

Volume

39

Issue

5

First Page

666

Last Page

675

URL with Digital Object Identifier

10.1002/humu.23400

Abstract

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype–phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7.