Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities
Open accessAbstract
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.
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For some well-characterized genomic disorders, a relationship between CNV genotype and clinical phenotype is beginning to emerge.
“For some of the more well-characterized genomic disorders, a relationship between CNV genotype and clinical phenotype is beginning to emerge (Brunetti-Pierri et al., 2008; McCarthy et al., 2009).”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Brunetti-Pierri et al., 2008
Clinical phenotypes associated with rearrangements at 1q21.1 and 16p11.2 are diverse and include pediatric neurodevelopmental disorders and adult psychiatric conditions.
“The clinical phenotypes associated with a single allele are diverse and include pediatric neurodevelopmental disorders and adult psychiatric conditions.”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Brunetti-Pierri et al., 2008
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- Authors
- Brunetti-Pierri, N., Berg, J. S., Scaglia, F., Belmont, J., Bacino, C. A., Sahoo, T., Lalani, S. R., Graham, B., Lee, B., Shinawi, M., Shen, J., Kang, S.-H. L., Pursley, A., Lotze, T., Kennedy, G., Lansky-Shafer, S., Weaver, C., Roeder, E. R., Grebe, T. A., Arnold, G. L., Hutchison, T., Reimschisel, T., Amato, S., Geragthy, M. T., Innis, J. W., Obersztyn, E., Nowakowska, B., Rosengren, S. S., Bader, P. I., Grange, D. K., Naqvi, S., Garnica, A. D., Bernes, S. M., Fong, C.-T., Summers, A., Walters, W. D., Lupski, J. R., Stankiewicz, P., Cheung, S. W., & Patel, A.
- Affiliations
- Baylor College of Medicine (US)
- Howard Hughes Medical Institute (US)
- Texas Children's Hospital (US)
- Carle Foundation Hospital (US)
- The University of Texas at San Antonio Health Science Center (US)
- St. Joseph's Hospital and Medical Center (US)
- University of Rochester Medicine (US)
- University of California, San Francisco (US)
- Washington University in St. Louis (US)
- Eastern Maine Medical Center (US)
- Children's Hospital of Eastern Ontario (CA)
- University of Michigan (US)
- Instytut Matki i Dziecka (PL)
- University of Connecticut (US)
- Parkview Health (US)
- Miami Children's Hospital (US)
- Oklahoma State University (US)
- Phoenix Children's Hospital (US)
- North York General Hospital (CA)
- Arkansas Children's Hospital (US)
- Corresponding author
- Patel, Ankita
- ORCID
- Berg, Jonathan S
- Scaglia, Fernando
- Belmont, John
- Bacino, Carlos A
- Sahoo, Trilochan
- Lalani, Seema R
- Graham, Brett
- Lee, Brendan
- Shinawi, Marwan
- Shen, Joseph
- Lotze, Timothy
- Roeder, Elizabeth R
- Arnold, Georgianne L
- Innis, Jeffrey W
- Obersztyn, Ewa
- Nowakowska, Beata
- Grange, Dorothy K
- Summers, Anne
- Lupski, James R
- Cheung, Sau Wai
- Patel, Ankita
- Venue
- Nature Genetics
- Published
- 2008-11-23
- Volume
- 40
- Issue
- 12
- Pages
- 1466-1471
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2680128
- OpenAlex
- W2077016335
- Cited by
- 625
- References
- 25
- Citations by year
- 2026: 15 · 2025: 20 · 2024: 13 · 2023: 20 · 2022: 19 · 2021: 27 · 2020: 27 · 2019: 33 · 2018: 39 · 2017: 33 · 2016: 23 · 2015: 40 · 2014: 27 · 2013: 48 · 2012: 67
- FWCI
- 32.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01hl091771-04)
- National Heart, Lung, and Blood Institute (R01-HL091771)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- copy number variation, microcephaly, macrocephaly, developmental delay, neuropsychiatric abnormalities, dysmorphic features, congenital malformations, segmental duplication, genomic disorders, incomplete penetrance, variable expressivity
- MeSH terms
- Adolescent, Adult, Mental Disorders, Child, Child, Preschool, Chromosomes, Human, Pair 1, Female, Humans, Male, Microcephaly, Schizophrenia, Gene Deletion, Craniofacial Abnormalities, Gene Duplication, Young Adult
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