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

Genotype-phenotype correlations in individuals with pathogenic RERE variants.

Jordan VK¹, Fregeau B², Ge X^3,⁴, Giordano J⁵, Wapner RJ⁵, Balci TB⁶, Carter MT⁶, Bernat JA⁷, Moccia AN⁸, Srivastava A⁸, Martin DM^8,⁹, Bielas SL⁸, Pappas J¹⁰, Svoboda MD¹¹, Rio M^12,¹³, Boddaert N^12,¹⁴, Cantagrel V^12,¹⁵, Lewis AM^3,¹⁶, Scaglia F^3,¹⁶; Undiagnosed Diseases Network, Kohler JN¹⁷, Bernstein JA¹⁷, Dries AM¹⁷, Rosenfeld JA³, DeFilippo C¹⁸, Thorson W¹⁹, Yang Y^3,⁴, Sherr EH², Bi W^3,⁴, Scott DA^1,^3,¹⁶.

Author information

1: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas.
2: Department of Neurology, University of California, San Francisco, San Francisco, California.
3: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
4: Baylor Genetics, Houston, Texas.
5: Institute of Genomic Medicine and Department of OB/GYN, Columbia University Medical Center, New York, New York.
6: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
7: Stead Family Department of Pediatrics, The University of Iowa, Iowa City, Iowa.
8: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan.
9: Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan.
10: New York University School of Medicine, New York, New York.
11: Department of Pediatrics, Children's Hospital of San Antonio/Baylor College of Medicine, San Antonio, Texas.
12: Laboratory of Developmental Brain Disorders, INSERM UMR 1163, Paris, France.
13: Service de Génétique, Necker Enfants Malades University Hospital, APHP, Paris, France.
14: Pediatric Radiology, Necker Enfants Malades University Hospital, APHP, Paris, France.
15: Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
16: Texas Children's Hospital, Houston, Texas.
17: Stanford University School of Medicine, Stanford, California.
18: Stanford Children's Health/Lucile Packard Children's Hospital Stanford, Palo Alto, California.
19: University of Miami, Miller School of Medicine, Miami, Florida.

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.