De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions

Abstract

Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are associated with developmental delay, intellectual disability, and defects involving the brain, eye, ear, heart, and kidney. Arginine-glutamic acid dipeptide repeats (RERE) is located in the proximal 1p36 critical region. RERE is a widely-expressed nuclear receptor coregulator that positively regulates retinoic acid signaling. Animal models suggest that RERE deficiency might contribute to many of the structural and developmental birth defects and medical problems seen in individuals with 1p36 deletion syndrome, although human evidence supporting this role has been lacking. In this report, we describe ten individuals with intellectual disability, developmental delay, and/or autism spectrum disorder who carry rare and putatively damaging changes in RERE. In all cases in which both parental DNA samples were available, these changes were found to be de novo. Associated features that were recurrently seen in these individuals included hypotonia, seizures, behavioral problems, structural CNS anomalies, ophthalmologic anomalies, congenital heart defects, and genitourinary abnormalities. The spectrum of defects documented in these individuals is similar to that of a cohort of 31 individuals with isolated 1p36 deletions that include RERE and are recapitulated in RERE-deficient zebrafish and mice. Taken together, our findings suggest that mutations in RERE cause a genetic syndrome and that haploinsufficiency of RERE might be sufficient to cause many of the phenotypes associated with proximal 1p36 deletions.

Figure 1

Molecular Changes and Selected Clinical Findings for Individuals with Putatively Deleterious Changes in RERE (A) The predicted locations of domains within RERE are presented along with the locations of the RERE changes seen in subjects 1–10. (B) Craniofacial changes noted in subjects. Subject 1, at 3 years of age, presents with bilateral optic colobomas, unilateral micropthalmia, low-set ears, and micrognathia. Subject 2, at 11 months of age, presents with a unilateral iris coloboma and simple ears. Subject 4, at 9 years of age, presents with deep-set eyes, epicanthal folds, and abnormal ears. (C) Sagital (Sag) and axial brain MRI scans of subjects 1, 2, and 4 demonstrating characteristic findings. Subject 1, at 7 months of age, had a thin corpus callosum (red arrow), a small anterior vermis, a small pons with a ventral cleft at the ponto-medullary junction, delayed myelination, and severely decreased white matter volume. Subject 2, at 4 months of age, had a thin corpus callosum, ventriculomegaly (green arrow), incompletely folded hippocampi, and severely diminished white matter volume. Subject 4, at 1 year and 2 months of age, had a thin corpus callosum, a diminished cerebellar vermis with a deep fissures (blue arrow), and significantly diminished white matter volume. For comparison, we have shown a mid-sagittal T1-weighted image showing a normal sized corpus callosum and intact cerebellar vermis and an axial T2-weighted image showing normal sized ventricles without increased extra-axial space.

Figure 2

RERE-Deficient Rere^om/eyes3 Mice and Embryos Have Ventriculomegaly, Microphthalmia, and Coloboma (A and B) Representative cresyl-violet-stained sagittal brain sections from a wild-type mouse (A) and its Rere^om/eyes3 littermate (B) show enlargement of the lateral ventricles (black arrows). Ventriculomegaly was seen in 3/3 Rere^om/eyes3 adult mice harvested between 5 and 10 months of age. Scale bar represents 200 μm. (C–F) Representative eyes from wild-type embryos harvested at E13.5 (C) and E17.5 (E) and their Rere^om/eyes3 littermates (D and F) demonstrate microphthalmia and incomplete closure of the optic fissure (white arrows in D and F). Failure of closure was seen in 8/10 (80%) of Rere^om/eyes3 eyes examined at E13.5 and in 6/6 (100%) of Rere^om/eyes3 eyes examined at E17.5. Scale bar represents 0.5 mm (C and D) or 1 mm (E and F).