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Case Reports
. 2009 May;17(5):573-81.
doi: 10.1038/ejhg.2008.220. Epub 2008 Nov 26.

Interstitial deletion of 6q25.2-q25.3: a novel microdeletion syndrome associated with microcephaly, developmental delay, dysmorphic features and hearing loss

Sandesh Chakravarthy Sreenath Nagamani  1 , Ayelet Erez, Christine Eng, Zhishuo Ou, Craig Chinault, Laura Workman, James Coldwell, Pawel Stankiewicz, Ankita Patel, James R Lupski, Sau Wai Cheung
Affiliations
Case Reports

Interstitial deletion of 6q25.2-q25.3: a novel microdeletion syndrome associated with microcephaly, developmental delay, dysmorphic features and hearing loss

Sandesh Chakravarthy Sreenath Nagamani et al. Eur J Hum Genet. 2009 May.

Abstract

Interstitial deletions of 6q are rare. We report a detailed clinical and molecular characterization of four patients with interstitial deletion involving 6q25. All of our patients presented with microcephaly, developmental delay, dysmorphic features and hearing loss, whereas two of them had agenesis of the corpus callosum. We determined the size, extent and genomic content of the deletions using high-density array-comparative genomic hybridization (a-CGH), and found that a common segment spanning 3.52 Mb within the 6q25.2-q25.3 region was deleted in all four cases. We hypothesize that a subset of genes in the commonly deleted region are dosage sensitive and that haploinsufficieny of these genes impairs normal development of the brain and hearing.

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Figures

Figure 1
Figure 1
Photographs of patients 1 (a), 2 (b) and 4 (c) showing facial characteristics. Note that hypertelorism, posteriorly rotated auricles, broad nasal root and midface hypoplasia are common to all. In addition, patient 1 has epicanthic folds, down-slanting palpebral fissures and retrognathia; patient 2 has a bulbous nose and thin upper lip, whereas patient 4 has malformed, low-set auricles and a thin upper lip.
Figure 2
Figure 2
Imaging showing normal two and a half turns of the cochlea in patients 2 (a), 3 (b, c) and 4 (d). The normal cochlear anatomy implies that the hearing loss could be secondary to abnormal sensory epithelium or its connecting pathways.
Figure 3
Figure 3
(a) MRI showing the absence of corpus callosum in patient 4. CT scan showing parallel orientation of lateral ventricles (b) and colpocephaly (c) suggestive of agenesis of corpus callosum in patient 3.
Figure 4
Figure 4
Mapping of breakpoints and common deleted region (blue; a, b, c and d). Each point represents an oligonucleotide probe. The normalized data for each probe is represented along a vertical line that indicates its relative position on 6q. Loss of copy number is indicated by deviation to the left of the center (depicted in green), whereas gain of copy number is indicated by deviation to the right of the center (depicted in red). The deletions of four patients span 3.77, 6.7, 10.3 and 13.81 Mb. The commonly deleted region (shaded) spans 3.52 Mb from 155349955 to 158870729 bp. The spike in the 6q25.3 region represents the copy number variation (CNV) of the only one oligonucleotide (60 mer, positioned at 157888702–157888761 bp) in the flanking 420-Kb genomic region. The oligonucleotide is located in a known CNV region and is most likely indicative of polymorphism. Note that there is grouping of proximal breakpoints in patients 1, 2 and 4. A full-colour version of this figure is available at the EJHG journal online.
Figure 5
Figure 5
Protein-coding genes in the smallest region of overlap (SRO). All the genes except NOX3 are expressed in the brain.
Figure 6
Figure 6
The distal deletions of 6q associated with agenesis of the corpus callosum (ACC) share a common minimal region (gray) that is within the smallest region of overlap (SRO) seen in our cases (red bars). This indicates that a gene important for normal corpus callosal development lies in the 6q25.2–q25.3 region. A full-colour version of this figure is available at the EJHG journal online.
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