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Case Reports
. 2018 May;39(5):666-675.
doi: 10.1002/humu.23400. Epub 2018 Jan 25.

Genotype-phenotype correlations in individuals with pathogenic RERE variants

Valerie K Jordan  1 , Brieana Fregeau  2 , Xiaoyan Ge  3   4 , Jessica Giordano  5 , Ronald J Wapner  5 , Tugce B Balci  6 , Melissa T Carter  6 , John A Bernat  7 , Amanda N Moccia  8 , Anshika Srivastava  8 , Donna M Martin  8   9 , Stephanie L Bielas  8 , John Pappas  10 , Melissa D Svoboda  11 , Marlène Rio  12   13 , Nathalie Boddaert  12   14 , Vincent Cantagrel  12   15 , Andrea M Lewis  3   16 , Fernando Scaglia  3   16 ; Undiagnosed Diseases Network; Jennefer N Kohler  17 , Jonathan A Bernstein  17 , Annika M Dries  17 , Jill A Rosenfeld  3 , Colette DeFilippo  18 , Willa Thorson  19 , Yaping Yang  3   4 , Elliott H Sherr  2 , Weimin Bi  3   4 , Daryl A Scott  1   3   16
Affiliations
Case Reports

Genotype-phenotype correlations in individuals with pathogenic RERE variants

Valerie K Jordan et al. Hum Mutat. 2018 May.

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.

Keywords: 1p36 deletion syndrome; CHARGE syndrome; CHD7; NEDBEH; RERE; genotype-phenotype correlations.

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Conflict of interest statement

DISCLOSURE STATEMENT

The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from clinical laboratory testing conducted at Baylor Genetics. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All other authors report no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
A–E: Photos of Subjects 3, 5, 6 (at 6 years of age), 7 (postmortem), and 8, respectively. As previously reported, a consistent pattern of dysmorphic features is not seen among individuals with NEDBEH (Fregeau et al., 2016). F: The locations of the RERE deletions and sequence variants reported in individuals with NEDBEH are shown in relation to the protein domains of RERE. Deletions and sequence variants found in Subjects 1–9 are shown in red if only a single variant was detected and in blue if two variants were detected. Previously published sequence variants are shown in black. A high percentage of RERE pathogenic variants affect a 21 amino acid (amino acids 1425–1445), histidine-rich region of the Atrophin-1 domain. Nucleotide (cDNA) numbering uses +1 as the A of the ATG translation initiation codon in the reference sequence, with the initiation codon as codon 1
See this image and copyright information in PMC

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