title: 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.
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Brieana
authors.initials: B
authors.lastname: Fregeau
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Bum Jun
authors.initials: BJ
authors.lastname: Kim
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Andrés
authors.initials: A
authors.lastname: Hernández-García
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Valerie K
authors.initials: VK
authors.lastname: Jordan
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Cho
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Rhonda E
authors.initials: RE
authors.lastname: Schnur
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Monaghan
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Juusola
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bhoj
authors.affiliation: Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Elaine H
authors.initials: EH
authors.lastname: Zackai
authors.affiliation: Division of Medical Genetics, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Sacharow
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Barañano
authors.affiliation: 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.
authors.forename: Daniëlle G M
authors.initials: DGM
authors.lastname: Bosch
authors.affiliation: 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.
authors.forename: Bert B A
authors.initials: BBA
authors.lastname: de Vries
authors.affiliation: Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85006, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Lindstrom
authors.affiliation: Division of Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Schroeder
authors.affiliation: Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85006, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: James
authors.affiliation: Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85006, USA.
authors.forename: Peggy
authors.initials: P
authors.lastname: Kulch
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Seema R
authors.initials: SR
authors.lastname: Lalani
authors.affiliation: Department of Genetics, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands.
authors.forename: Mieke M
authors.initials: MM
authors.lastname: van Haelst
authors.affiliation: Department of Genetics, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands.
authors.forename: Koen L I
authors.initials: KLI
authors.lastname: van Gassen
authors.affiliation: Department of Genetics, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: van Binsbergen
authors.affiliation: Department of Radiology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: A James
authors.initials: AJ
authors.lastname: Barkovich
authors.affiliation: 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.
authors.forename: Daryl A
authors.initials: DA
authors.lastname: Scott
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: elliott.sherr@ucsf.edu.
authors.forename: Elliott H
authors.initials: EH
authors.lastname: Sherr
mesh_terms: D000015:Abnormalities, Multiple / Q000209:etiology*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000209:etiology*; D002878:Chromosomes, Human, Pair 1; D002658:Developmental Disabilities / Q000209:etiology*; D005260:Female; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011379:Prognosis
chemical_list: D002352:Carrier Proteins; C412477:RERE protein, human