TY - JOUR
T1 - Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder
AU - Mullegama, Sureni V.
AU - Rosenfeld, Jill A.
AU - Orellana, Carmen
AU - Van Bon, Bregje W.M.
AU - Halbach, Sara
AU - Repnikova, Elena A.
AU - Brick, Lauren
AU - Li, Chumei
AU - Dupuis, Lucie
AU - Rosello, Monica
AU - Aradhya, Swaroop
AU - Stavropoulos, D. James
AU - Manickam, Kandamurugu
AU - Mitchell, Elyse
AU - Hodge, Jennelle C.
AU - Talkowski, Michael E.
AU - Gusella, James F.
AU - Keller, Kory
AU - Zonana, Jonathan
AU - Schwartz, Stuart
AU - Pyatt, Robert E.
AU - Waggoner, Darrel J.
AU - Shaffer, Lisa G.
AU - Lin, Angela E.
AU - De Vries, Bert B.A.
AU - Mendoza-Londono, Roberto
AU - Elsea, Sarah H.
N1 - Funding Information:
We are thankful to all of the subjects and families involved in this study. We are grateful for the assistance of Dr Trang Le, Ms Zalak Shah, Mr Joshua Beach and Ms Jessica Webster in the collection of clinical data and in the preparation of this manuscript and to Dr Shelley Waite for neurologic evaluation of case MGH2. We thank the Fondation Jérôme Lejeune (SHE) for funding portions of this study. This work was supported in part by resources from Virginia Commonwealth University and the Ramón Areces Foundation.
PY - 2014/1
Y1 - 2014/1
N2 - Copy number variations associated with abnormal gene dosage have an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID) and autism. We hypothesize that the chromosome 2q23.1 region encompassing MBD5 is a dosage-dependent region, wherein deletion or duplication results in altered gene dosage. We previously established the 2q23.1 microdeletion syndrome and report herein 23 individuals with 2q23.1 duplications, thus establishing a complementary duplication syndrome. The observed phenotype includes ID, language impairments, infantile hypotonia and gross motor delay, behavioral problems, autistic features, dysmorphic facial features (pinnae anomalies, arched eyebrows, prominent nose, small chin, thin upper lip), and minor digital anomalies (fifth finger clinodactyly and large broad first toe). The microduplication size varies among all cases and ranges from 68 kb to 53.7 Mb, encompassing a region that includes MBD5, an important factor in methylation patterning and epigenetic regulation. We previously reported that haploinsufficiency of MBD5 is the primary causal factor in 2q23.1 microdeletion syndrome and that mutations in MBD5 are associated with autism. In this study, we demonstrate that MBD5 is the only gene in common among all duplication cases and that overexpression of MBD5 is likely responsible for the core clinical features present in 2q23.1 microduplication syndrome. Phenotypic analyses suggest that 2q23.1 duplication results in a slightly less severe phenotype than the reciprocal deletion. The features associated with a deletion, mutation or duplication of MBD5 and the gene expression changes observed support MBD5 as a dosage-sensitive gene critical for normal development.
AB - Copy number variations associated with abnormal gene dosage have an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID) and autism. We hypothesize that the chromosome 2q23.1 region encompassing MBD5 is a dosage-dependent region, wherein deletion or duplication results in altered gene dosage. We previously established the 2q23.1 microdeletion syndrome and report herein 23 individuals with 2q23.1 duplications, thus establishing a complementary duplication syndrome. The observed phenotype includes ID, language impairments, infantile hypotonia and gross motor delay, behavioral problems, autistic features, dysmorphic facial features (pinnae anomalies, arched eyebrows, prominent nose, small chin, thin upper lip), and minor digital anomalies (fifth finger clinodactyly and large broad first toe). The microduplication size varies among all cases and ranges from 68 kb to 53.7 Mb, encompassing a region that includes MBD5, an important factor in methylation patterning and epigenetic regulation. We previously reported that haploinsufficiency of MBD5 is the primary causal factor in 2q23.1 microdeletion syndrome and that mutations in MBD5 are associated with autism. In this study, we demonstrate that MBD5 is the only gene in common among all duplication cases and that overexpression of MBD5 is likely responsible for the core clinical features present in 2q23.1 microduplication syndrome. Phenotypic analyses suggest that 2q23.1 duplication results in a slightly less severe phenotype than the reciprocal deletion. The features associated with a deletion, mutation or duplication of MBD5 and the gene expression changes observed support MBD5 as a dosage-sensitive gene critical for normal development.
KW - 2q23.1
KW - MBD5
KW - autism spectrum disorder
KW - gene dosage
KW - microdeletion
KW - microduplication
UR - http://www.scopus.com/inward/record.url?scp=84890801954&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84890801954&partnerID=8YFLogxK
U2 - 10.1038/ejhg.2013.67
DO - 10.1038/ejhg.2013.67
M3 - Article
C2 - 23632792
AN - SCOPUS:84890801954
SN - 1018-4813
VL - 22
SP - 57
EP - 63
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 1
ER -