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, 40 (12), 1466-71

Recurrent Reciprocal 1q21.1 Deletions and Duplications Associated With Microcephaly or Macrocephaly and Developmental and Behavioral Abnormalities

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Recurrent Reciprocal 1q21.1 Deletions and Duplications Associated With Microcephaly or Macrocephaly and Developmental and Behavioral Abnormalities

Nicola Brunetti-Pierri et al. Nat Genet.

Abstract

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.

Figures

Figure 1
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. (a) An enlargement of the region between 144 and 146 Mb. Known genes are indicated by black bars. (b) The region from 142 to 148 Mb. The minimal regions for the TAR syndrome deletion and the distal 1q21.1 deletion/duplication are shown with blue boxes. Array-CGH clones are shown in dark violet, and additional FISH clones used during the course of the study are shown in magenta. Gaps in the reference sequence are indicated by gray breaks in the chromosome bar. The putative location of the HYDIN paralog is indicated by a gray triangle bounded by dashed lines. Regions of segmental duplication are depicted by colored boxes. A pair of large, directly oriented intrachromosomal repeats flanks the distal 1q21.1 region (blue blocks labeled A and A′). In addition, there is another pair of directly oriented repeats flanking the first ∼4 Mb of the sub-band and encompassing both the TAR region and the distal 1q21.1 region (red blocks labeled B and B′). Finally, there is a pair of blocks flanking a large portion of the sub-band 1q21.1 (yellow blocks labeled C and C′), in opposite orientation. Several other blocks are present, but gaps in the reference sequence preclude further detailed characterization at this time. (c) Overview of the deletions and duplications in affected individuals described in this report. Thick red horizontal lines indicate minimally deleted regions, whereas thick green horizontal lines indicate minimally duplicated regions. The complex deletion/duplication rearrangement in individual 36 is depicted with red and green bars, and the single case with atypical TAR region deletion is indicated with a solid red and dashed red line (see text for details).
Figure 2
Figure 2
Facial appearance of individuals with the 1q21.1 microdeletion. (a) Subject 1. (b) Subject 2. (c) Subject 2FATHER. (d) Subject 3. (e) Subject 5. (f) Subjects 8 and 8FATHER. (g) Subject 9. (h) Subject 11. (i) Subject 12. (j) Subject 12FATHER. (k) Subject 14. (l) Subject 14SIBLING. (m) Subject 15. (n) Subject 18. (o) Subject 19. (p) Subject 7. Frontal bossing, deep-set eyes and bulbous nose were frequently present.
Figure 3
Figure 3
Facial appearance of individuals with the 1q21.1 microduplication. (a) Subject 36MOTHER. (b) Subject 36SIBLING 1. (c) Subject 36SIBLING 2. (d) Subject 36. (e) Subject 22. (f) Subject 27. (g) Subject 35. (h) Subject 32. (i) Subject 33. (j) Subject 33SIBLING. (k) Subject 33MOTHER. Hypertelorism and frontal bossing seem to be common in individuals with the microduplication.
Figure 4
Figure 4
Microdeletions and microduplications of 1q21.1 are associated with head size abnormalities and include the 1q21.1 HYDIN paralog. (a) Head circumference measurements in individuals with microdeletion (triangles), controls (circles) and individuals with microduplication (squares) are plotted as age- and sex-matched Z scores. Parents carrying the CNVs are represented by filled symbols. Bars indicate mean and 95% confidence intervals. The vertical dashed lines mark the −2 and +2 Z scores. (b–d) FISH for HYDIN using BAC clone RP11-424M24 (red signals) and centromere probe for chromosome 1 (green signal). In the control sample (b), red signals are seen on both 16q22 and 1q21.1, confirming the previously reported intrachromosomal HYDIN duplication. In samples from affected individuals, the 1q21.1 HYDIN paralog is deleted in individuals with 1q21.1 microdeletion (c) and duplicated in individuals with 1q21.1 microduplication (d).

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