TY - JOUR
T1 - De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions
AU - Fregeau, Brieana
AU - Kim, Bum Jun
AU - Hernández-García, Andrés
AU - Jordan, Valerie K.
AU - Cho, Megan T.
AU - Schnur, Rhonda E.
AU - Monaghan, Kristin G.
AU - Juusola, Jane
AU - Rosenfeld, Jill A.
AU - Bhoj, Elizabeth
AU - Zackai, Elaine H.
AU - Sacharow, Stephanie
AU - Barañano, Kristin
AU - Bosch, Daniëlle G.M.
AU - De Vries, Bert B.A.
AU - Lindstrom, Kristin
AU - Schroeder, Audrey
AU - James, Philip
AU - Kulch, Peggy
AU - Lalani, Seema R.
AU - Van Haelst, Mieke M.
AU - Van Gassen, Koen L.I.
AU - Van Binsbergen, Ellen
AU - Barkovich, A. James
AU - Scott, Daryl A.
AU - Sherr, Elliott H.
N1 - Funding Information:
The authors thank the family members for participating in this research. This work was supported by the National Institute of Neurological Disorders and Stroke (grant R01 NS058721 to E.H.S.), the Netherlands Organization for Health Research and Development (grant 912-12-109 to B.B.A.d.V), and ODAS Stichting (to D.G.M.B. and B.B.A.d.V). E.H.S is a member of the clinical advisory board of InVitae and consults for Personalis. M.T.C, R.S., K.G.M, and J.J. are all employees of GeneDx, which provides exome sequencing on a clinical basis. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from clinical laboratory testing conducted at Baylor Miraca Genetics Laboratories, which provides exome sequencing on a clinical basis.
Publisher Copyright:
© 2016 The American Society of Human Genetics All rights reserved.
PY - 2016/5/5
Y1 - 2016/5/5
N2 - 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.
AB - 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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U2 - 10.1016/j.ajhg.2016.03.002
DO - 10.1016/j.ajhg.2016.03.002
M3 - Article
C2 - 27087320
AN - SCOPUS:84963604366
SN - 0002-9297
VL - 98
SP - 963
EP - 970
JO - American journal of human genetics
JF - American journal of human genetics
IS - 5
ER -