Mapping of Deletion and Translocation Breakpoints in 1q44 Implicates the Serine/Threonine Kinase AKT3 in Postnatal Microcephaly and Agenesis of the Corpus.

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Mapping of Deletion and Translocation Breakpoints in 1q44 Implicates the Serine/Threonine Kinase AKT3 in Postnatal Microcephaly and Agenesis of the Corpus Callosum Elena Boland, Jill Clayton-Smith, Victoria G. Woo, Shane McKee, Forbes D.C. Manson, Livija Medne, Elaine Zackai, Eric A. Swanson, David Fitzpatrick, Kathleen J. Millen, Elliott H. Sherr, William B. Dobyns, Graeme C.M. Black The American Journal of Human Genetics Volume 81, Issue 2, Pages 292-303 (August 2007) DOI: 10.1086/519999 Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 1 Brain-imaging abnormalities in patients with deletion 1q4, shown with T1-weighted midline sagittal (left column), T2-weighted low axial (middle column), and T2-weighted higher axial (right column) sequences in an unaffected 3-year-old child (LR06-130) (A–C) and in patients LR05-202 (D–F), LR06-076 (G–I), LR02-409 (J–L), and LR05-101 (M–O). In the normal scans, the corpus callosum is marked by an asterisk (*) (A and C), and the inferior margin of the vermis is marked by a solid white horizontal line at the level of the obex (A). In the images of the four patients, the corpus callosum is either absent (white arrows in panels D and M and two black arrows in panels F and O) or small with a narrow body and absent splenium (white arrow in panels G and J and single black arrow indicating absent posterior callosum in panels I and L). The cerebellar vermis is small in three patients who have the 1q4 deletion, with the inferior margin (dashed white lines in panels D, G, and J) located well above the level of the obex (solid white lines in panels D, G, and J). The vermis appears mildly small in the boy with the 1q;13q translocation, with a mildly reduced anterior-posterior diameter of the vermis resulting in an enlarged cisterna magna extending behind the cerebellum (M), even though the inferior vermis is located near the level of the obex (dashed and solid lines in panel M). The cerebellar hemispheres are normal (E, H, K, and N), and the fourth ventricle is normal (E, H, and N) or mildly enlarged (“4V” in panel K). Lower-resolution images of our other two patients (LP94-079 and LR04-249) are shown in figure 2. The American Journal of Human Genetics 2007 81, 292-303DOI: (10.1086/519999) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 2 Brain-imaging abnormalities in patients with deletion 1q4, shown with head CT scan (A–C) or with T1-weighted midline sagittal (D) and T2-weighted axial (E and F) MRI sequences in patients LP94-079 (A–C) and LR04-249 (D–F). In patient LP94-079, the cortex appears thickened in the posterior frontal and perisylvian regions (white arrow[s] in panels A–C), suggesting PMG, although the resolution is low. The lateral ventricles are located in the normal position close to the midline (A and B), suggesting that the corpus callosum is normal. The cerebellar vermis is small, since it is not seen at the level of the low midbrain (white arrowhead in panel A), and a small skull defect is seen beneath an occipital cephalocele (white arrowhead in panel C). In LR04-249, gyral pattern is poorly developed, even for 35 wk gestation, and the corpus callosum is absent (white arrow in panel D and two black arrows in panel E). The cerebellar vermis is small, with the inferior margin (dashed line in panel D) well above the level of the obex (solid line in panel D). The American Journal of Human Genetics 2007 81, 292-303DOI: (10.1086/519999) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 3 Precise delineation of chromosome rearrangements in distal 1q42-q44 in study patients. Deletion mapping of patients LR02-409 and LR05-202 defines a minimal deleted region of 1.25 Mb between BACs RP11-657L23 and RP1-241M7. This region is deleted in four patients, all of whom had ACC and MIC. Patient LP94-079 has a subtelomeric deletion that is distal to RP1-241M7 and had neither ACC or MIC. In patient LR05-101, the breakpoint of the t(1;13) balanced de novo translocation lies within this region and is situated with BAC clone RP11-351N5 and fosmid clone G248P89661B9. This is upstream of the first exon of AKT3. The American Journal of Human Genetics 2007 81, 292-303DOI: (10.1086/519999) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 4 aCGH demonstrating deletions (arrows) in patients with the 1q4 deletion. Data are represented as the corrected log2 ratios between control and patient DNA. A, LR05-202. B, LR06-076. C, LR02-409. The distal region that is not deleted in LR06-076 is marked with an arrowhead. The American Journal of Human Genetics 2007 81, 292-303DOI: (10.1086/519999) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 5 FISH mapping of patients LR05-101 (A) and LR02-409 (B–D). Analysis of LR05-101, who has a de novo 46,XY,t(1;13) translocation, shows signals for fosmid G248P89661B9 (red) located on the normal and derived chromosomes 1, as well as on the derived chromosome 13. This confirms that it spans the breakpoint on chromosome 1q44. Analysis of LR02-409 with probes RP11-90B9 (green) and RP11-399B15 (red [B]) shows the distal inversion, since the position of the two probes is reversed on the two chromosome 1 homologs. The associated deletion inside the distal inversion is demonstrated by loss of RP11-553N16 (red [C]) and by loss of RP11-411G13 (green [D]) compared with RP11-438H8 (red [D]). The American Journal of Human Genetics 2007 81, 292-303DOI: (10.1086/519999) Copyright © 2007 The American Society of Human Genetics Terms and Conditions