2. Academic Validation
  3. De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions

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

  • Am J Hum Genet. 2016 May 5;98(5):963-970. doi: 10.1016/j.ajhg.2016.03.002.
Brieana Fregeau 1,  Bum Jun Kim 2,  Andrés Hernández-García 2,  Valerie K Jordan 3,  Megan T Cho 4,  Rhonda E Schnur 4,  Kristin G Monaghan 4,  Jane Juusola 4,  Jill A Rosenfeld 2,  Elizabeth Bhoj 5,  Elaine H Zackai 5,  Stephanie Sacharow 6,  Kristin Barañano 7,  Daniëlle G M Bosch 8,  Bert B A de Vries 9,  Kristin Lindstrom 10,  Audrey Schroeder 11,  Philip James 10,  Peggy Kulch 10,  Seema R Lalani 2,  Mieke M van Haelst 12,  Koen L I van Gassen 12,  Ellen van Binsbergen 12,  A James Barkovich 13,  Daryl A Scott 14,  Elliott H Sherr 15
Affiliations

Affiliations

  • 1 Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 3 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 4 GeneDx, Gaithersburg, MD 20877, USA.
  • 5 Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 6 Division of Medical Genetics, Boston Children's Hospital, Boston, MA 02115, USA.
  • 7 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 8 Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Bartiméus Institute for the Visually Impaired, 3702 AD Zeist, the Netherlands; Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
  • 9 Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
  • 10 Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85006, USA.
  • 11 Division of Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
  • 12 Department of Genetics, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands.
  • 13 Department of Radiology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 14 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: dscott@bcm.edu.
  • 15 Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: elliott.sherr@ucsf.edu.
PMID: 27087320 DOI: 10.1016/j.ajhg.2016.03.002
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.

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