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


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.

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Figure 1: Schematic representation of chromosome 1q21.1 based on the March 2006 freeze of the reference human genome sequence (NCBI build 36.1) and summary of molecular findings.
Figure 2: Facial appearance of individuals with the 1q21.1 microdeletion.
Figure 3: Facial appearance of individuals with the 1q21.1 microduplication.
Figure 4: Microdeletions and microduplications of 1q21.1 are associated with head size abnormalities and include the 1q21.1 HYDIN paralog.


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N.B.-P. coordinated clinical data collection. Clinical information was provided by N.B.-P., J.S.B., F.S., J.B., C.A.B., B.G., B.L., M.S., J.S., A.P., T.L., G.K., S.L.-S., C.W., E.R.R., T.A.G., G.L.A., T.H., T.R., S.A., M.T.G., J.W.I., E.O., B.N., S.S.R., P.I.B., D.K.G., S.N., A.D.G., S.M.B., C.-T.F., A.S. and W.D.W. Array-CGH and FISH analysis were carried out by A.P., C.A.B., T.S., S.R.L., S.-H.L.K., P.S. and S.-W.C. Data interpretation, critical revisions and writing of the manuscript were carried out by N.B.-P., J.S.B. and A.P. J.R.L., P.S. and S.W.C. contributed to the writing of the manuscript. A.P. provided supervision and oversaw manuscript preparation and revision.

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Correspondence to Ankita Patel.

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Competing interests

Some authors are based in the Department of Molecular and Human Genetics at Baylor College of Medicine (BCM), which offers extensive genetic laboratory testing, including use of arrays for genomic copy number analysis, and derives revenue from this activity.

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Brunetti-Pierri, N., Berg, J., Scaglia, F. et al. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet 40, 1466–1471 (2008).

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