Letter abstract
Nature Genetics 40, 1466 - 1471 (2008)
Published online: 23 November 2008 | doi:10.1038/ng.279
Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities
Nicola Brunetti-Pierri1,23, Jonathan S Berg1,23, Fernando Scaglia1,2, John Belmont1, Carlos A Bacino1,2, Trilochan Sahoo1, Seema R Lalani1, Brett Graham1, Brendan Lee1,3, Marwan Shinawi1, Joseph Shen1, Sung-Hae L Kang1, Amber Pursley1, Timothy Lotze4, Gail Kennedy5,6, Susan Lansky-Shafer5,6, Christine Weaver5,6, Elizabeth R Roeder7, Theresa A Grebe8, Georgianne L Arnold9, Terry Hutchison10, Tyler Reimschisel11, Stephen Amato12, Michael T Geragthy13, Jeffrey W Innis14, Ewa Obersztyn15, Beata Nowakowska15, Sally S Rosengren16, Patricia I Bader17, Dorothy K Grange11, Sayed Naqvi18, Adolfo D Garnica19, Saunder M Bernes20, Chin-To Fong9, Anne Summers21, W David Walters22, James R Lupski1,2, Pawel Stankiewicz1, Sau Wai Cheung1 & Ankita Patel1
Chromosome region 1q21.1 contains extensive and complex low-copy repeats, and copy number variants (CNVs) in this region have recently been reported in association with congenital heart defects1, developmental delay2, 3, schizophrenia and related psychoses4, 5. We describe 21 probands with the 1q21.1 microdeletion and 15 probands with the 1q21.1 microduplication. These CNVs were inherited in most of the cases in which parental studies were available. Consistent and statistically significant features of microcephaly and macrocephaly were found in individuals with microdeletion and microduplication, respectively. Notably, a paralog of the HYDIN gene located on 16q22.2 and implicated in autosomal recessive hydrocephalus6 was inserted into the 1q21.1 region during the evolution of Homo sapiens7; we found this locus to be deleted or duplicated in the individuals we studied, making it a probable candidate for the head size abnormalities observed. We propose that recurrent reciprocal microdeletions and microduplications within 1q21.1 represent previously unknown genomic disorders characterized by abnormal head size along with a spectrum of developmental delay, neuropsychiatric abnormalities, dysmorphic features and congenital anomalies. These phenotypes are subject to incomplete penetrance and variable expressivity.
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
- Texas Children's Hospital, Houston, Texas 77030, USA.
- Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
- Section of Neurology, Department of Pediatrics, Texas Children's Hospital, Houston, Texas 77030, USA.
- Carle Clinic, Urbana, Illinois 61821, USA.
- University of Illinois College of Medicine, Urbana-Champaign, Illinois 61801, USA.
- Department of Pediatrics, Division of Genetics and Metabolic Disorders, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78207, USA.
- St. Joseph's Hospital and Medical Center, CHC Phoenix Genetics Program, Phoenix, Arizona 85013, USA.
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
- Department of Neurology, University of California San Francisco, San Francisco, California 94143, USA.
- Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
- Department of Medical Genetics, Eastern Maine Medical Center, Bangor, Maine 04401, USA.
- Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada.
- Departments of Human Genetics and Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.
- Department of Medical Genetics, Institute of Mother and Child, 01-211, Warsaw, Poland.
- Division of Human Genetics, University of Connecticut School of Medicine, Farmington, Connecticut 06030, USA.
- Department of Cytogenetics, Parkview Hospital, Fort Wayne, Indiana 46805, USA.
- Department of Neurology, Miami Children's Hospital, Miami, Florida 33155, USA.
- Department of Pediatrics, Oklahoma State University, Tulsa, Oklahoma 74127, USA.
- Department of Neurology, Phoenix Children's Hospital, Phoenix, Arizona 85016, USA.
- Medical Genetics, North York General Hospital, Toronto, Ontario P1B 4E7, Canada.
- Department of Pediatrics, Arkansas Children's Hospital, Little Rock, Arkansas 72202, USA.
- These authors contributed equally to this work.
Correspondence to: Ankita Patel1 e-mail: ankitap@bcm.edu
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