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Abstract
Background:
The 3q29 microdeletion syndrome is a genomic disorder characterized by mental retardation, developmental delay, microcephaly, and slight facial dysmorphism. In most cases, the microdeletion spans a 1.6-Mb region between low-copy repeats (LCRs). We identified a novel 4.0-Mb deletion using oligonucleotide array comparative genomic hybridization (array CGH) in monozygotic twin sisters.
Methods:
G-banded chromosome analysis was performed in the twins and their parents. High-resolution oligonucleotide array CGH was performed using the human whole genome 244K CGH microarray (Agilent Technologies, USA) followed by validation using FISH, and the obtained results were analyzed using the genome database resources.
Results:
G-banding revealed that the twins had de novo 46,XX,del(3)(q29) karyotype. Array CGH showed a 4.0-Mb interstitial deletion on 3q29, which contained 39 genes and no breakpoints flanked by LCRs. In addition to the typical characteristics of the 3q29 microdeletion syndrome, the twins had attention deficit-hyperactivity disorder, strabismus, congenital heart defect, and gray hair. Besides the p21-activated protein kinase (PAK2) and discs large homolog 1 (DLG1) genes, which are known to play a critical role in mental retardation, the hairy and enhancer of split 1 (HES1) and antigen p97 (melanoma associated; MFI2) genes might be possible candidate genes associated with strabismus, congenital heart defect, and gray hair.
Conclusions:
The novel 4.0-Mb 3q29 microdeletion found in the twins suggested the occurrence of genomic rearrangement mediated by mechanisms other than nonallelic homologous recombination. Molecular genetic and functional studies are required to elucidate the contribution of each gene to a specific phenotype.
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Fig. 1.
Karyotype of one of the monozygotic twin sisters. The deletion in the long arm of chromosome 3 was apparently a terminal deletion, as shown by the arrow. The karyotype was initially designated 46,XX,del(3)(q29).
Fig. 2.
Array CGH profile of chromosome 3 in one of the monozygotic twin sisters. X-axis represents the probe index on chromosome 3, and Y-axis represents the signal log2 ratio of the probe. (A) The whole chromosome 3 view showed copy number loss in the 3q29 region. The green dots with log2 value of −1 represent a 1:2 copy number ratio of the test to reference genomic DNA, indicating a heterozygous deletion. (B) The expansion view of the 3q29 region distinctly revealed a 4.0-Mb heterozygous interstitial deletion in the Chr3:195,007,970-199,085,431.
Fig. 3.
Metaphase fluorescence in situ hybridization (FISH) analysis of one of the monozygotic twin sisters using TelVysion 3q SpectrumOrange probe and TelVysion 3p SpectrumGreen probe (Abbott Molecular Inc., USA). (A) TelVysion 3q deletion was detected (arrow), but 2 TelVysion 3p signals were intact. (B) TelVysion 3q deletion was also identified in the same metaphase with G-banding obtained using 4,6-diamidino-2-phenylindole (DAPI) staining (arrow).
Fig. 4.
Visualization of the novel deletion region on 3q29 using the University of California Santa Cruz (UCSC) Genome Browser. The UCSC browser shows a 4.0-Mb region (within positions Chr3:195,007,970-199,085,431), encompassing the reference genes, copy number variation regions, and segmental duplications.
Table 1.
Clinical features of the monozygotic twins with the 3q29 deletion and patients from previous studies
| Twin 1 | Twin 2 | Previous reports∗ | |
|---|---|---|---|
| Birth weight | 2.1 kg | 2.0 kg | 2.3-3.1 kg |
| Gestational age | 40 weeks | 40 weeks | 38-41 weeks |
| Developmental delay | Mild | Mild | Mild-moderate |
| Age at walking | 12 months | 12 months | 16-36 months |
| Age at toilet training | 5 yr | 5 yr | ND |
| Age at first words | 12 months | 12 months | 19-28 months |
| Speech delay | Normal | Normal | + (53%) |
| Mental retardation | Mild | Mild | Mild-moderate |
| IQ | 61 | 56 | |
| SQ | 69 | 66 | |
| Learning disabilities | + | + | + |
| Microcephaly (percentile) | <3rd | <3rd | 3rd-50th |
| Height (percentile) | 17th | 17th | 3rd-40th |
| Weight (percentile) | 10th | 6th | 3rd-25th |
| Facial dysmorphism | Subtle | Subtle | Variable (20-60%) |
| Behavior | ADHD | ADHD | Autistic features (27%) |
| Ataxic gait | - | - | + (33%) |
| Additional feature | |||
| Congenital heart defect | - | VSD | - |
| Strabismus | + | + | - |
| Gray hair | + | + | - |
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