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Genotype–phenotype correlations in individuals with pathogenic RERE variants
Author(s) -
Jordan Valerie K.,
Fregeau Brieana,
Ge Xiaoyan,
Giordano Jessica,
Wapner Ronald J.,
Balci Tugce B.,
Carter Melissa T.,
Bernat John A.,
Moccia Amanda N.,
Srivastava Anshika,
Martin Donna M.,
Bielas Stephanie L.,
Pappas John,
Svoboda Melissa D.,
Rio Marlène,
Boddaert Nathalie,
Cantagrel Vincent,
Lewis Andrea M.,
Scaglia Fernando,
Kohler Jennefer N.,
Bernstein Jonathan A.,
Dries Annika M.,
Rosenfeld Jill A.,
DeFilippo Colette,
Thorson Willa,
Yang Yaping,
Sherr Elliott H.,
Bi Weimin,
Scott Daryl A.
Publication year - 2018
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23400
Subject(s) - biology , haploinsufficiency , phenotype , genetics , genotype , genotype phenotype distinction , gene
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 .