Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities

Nicola Brunetti-Pierri, Jonathan S. Berg, Fernando Scaglia, John Belmont, Carlos A. Bacino, Trilochan Sahoo, Seema R. Lalani, Brett Graham, Brendan Lee, Marwan Shinawi, Joseph Shen, Sung Hae L. Kang, Amber Pursley, Timothy Lotze, Gail Kennedy, Susan Lansky-Shafer, Christine Weaver, Elizabeth R. Roeder, Theresa A. Grebe, Georgianne L. ArnoldTerry Hutchison, Tyler Reimschisel, Stephen Amato, Michael T. Geragthy, Jeffrey W. Innis, Ewa Obersztyn, Beata Nowakowska, Sally S. Rosengren, Patricia I. Bader, Dorothy K. Grange, Sayed Naqvi, Adolfo D. Garnica, Saunder M. Bernes, Chin To Fong, Anne Summers, W. David Walters, James R. Lupski, Pawel Stankiewicz, Sau Wai Cheung, Ankita Patel

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470 Scopus citations


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 defects, developmental delay, schizophrenia and related psychoses. 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 hydrocephalus was inserted into the 1q21.1 region during the evolution of Homo sapiens; 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.

Original languageEnglish
Pages (from-to)1466-1471
Number of pages6
JournalNature Genetics
Issue number12
StatePublished - Dec 2008


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