Genotype-phenotype correlations in individuals with pathogenicREREvariants

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.

Molecular dissection of CHARGE syndrome highlights the vulnerability of neural crest cells to problems with alternative splicing and other transcription-related processes

“…Of note, the recent discovery of new CHARGE syndrome candidate genes [36,37] also strongly supports the idea that dysregulation of chromatin structure-dependent cotranscriptional alternative splicing plays a fundamental role in CHARGE syndrome pathogenesis. Indeed, direct and/or indirect evidence for a regulatory role in alternative splicing exists for all new five candidate genes (PUF60, EP300, RERE, KMT2D and KDM6A): PUF60 encodes a bona fide splicing factor [38,39]; EP300 codes for the p300 histone acetyltransferase, which has been shown to be directly involved in splicing regulation [40]; RERE codes for a transcriptional co-repressor that notably associates with HDAC1/2 [41][42][43], which are included in the Fam172a/spliceosome interactomes [22,35]; KMT2D encodes a H3K4methyltransferase that is included in the spliceosome interactome [35], and trimethylation of H3K4 is known to trigger the recruitment of splicing factors [33]; and finally, KDM6A codes for a demethylase of H3K27me3, a histone mark associated with AGO-mediated splicing regulation [28].…”

Type IV Laryngotracheoesophageal Cleft Associated with Type III Esophageal Atresia in 1p36 Deletions Containing the RERE Gene: Is There a Causal Role for the Genetic Alteration?

“…Subjects with terminal and interstitial deletions of chromosome 1p36 have a spectrum of defects that include eye anomalies, postnatal growth deficiency, structural brain anomalies, seizures, cognitive impairment, delayed motor development, behavior problems, hearing loss, cardiovascular malformations, cardiomyopathy, and renal anomalies [ 9 , 16 ]. The proximal 1p36 genes that contribute to these defects have not been clearly delineated.…”

“…RERE encodes a widely expressed nuclear receptor coregulator [ 11 , 12 ] that positively regulates retinoic acid signaling in multiple tissues during embryonic development [ 13 – 15 ]. Data from animal models suggest that haploinsufficiency of RERE might contribute to intellectual disability, developmental delay, structural brain anomalies, vision problems, hearing loss, congenital heart defects, cardiomyopathy, and renal anomalies seen in individuals with 1p36 deletions [ 16 ]. However, the exact role that RERE deficiency plays in 1p36 deletion syndrome, and more generally in human disease, remains unclear [ 9 ].…”

RERE deficiency leads to decreased expression of GATA4 and the development of ventricular septal defects

“…Recently, mutations affecting RERE have been shown to cause a new genetic syndrome, neurodevelopmental disorder with or without anomalies of the brain, eye or heart (NEDBEH) ( Fregeau et al, 2016 ; Jordan et al, 2018 ). The phenotypes seen in individuals with NEDBEH have a strong overlap with those associated with 1p36 deletion syndrome.…”