Dan Doherty, Albert E. Chudley, Gail Coghlan, Gisele E. Ishak, A

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GPSM2 Mutations Cause the Brain Malformations and Hearing Loss in Chudley- McCullough Syndrome Dan Doherty, Albert E. Chudley, Gail Coghlan, Gisele E. Ishak, A. Micheil Innes, Edmond G. Lemire, R. Curtis Rogers, Aizeddin A. Mhanni, Ian G. Phelps, Steven J.M. Jones, Shing H. Zhan, Anthony P. Fejes, Hashem Shahin, Moien Kanaan, Hatice Akay, Mustafa Tekin, Barbara Triggs-Raine, Teresa Zelinski The American Journal of Human Genetics Volume 90, Issue 6, Pages 1088-1093 (June 2012) DOI: 10.1016/j.ajhg.2012.04.008 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Characteristic Neuroimaging Features of GPSM2-related Chudley-McCullough Syndrome (A) illustrates posterior agenesis of the corpus callosum (bracket indicates remaining corpus callosum) and a quadrigeminal plate cistern cyst (white plus sign) causing mass effect on the cerebellum and tectum in individual 8A at 3 years of age. (B) illustrates severe ventriculomegaly (black asterisks) and frontal polymicrogyria (white arrows) in individual 8B at 6 months of age. (C) illustrates large frontal gray matter heterotopia (white arrowheads) located superior and medial to the enlarged lateral ventricles (black asterisks) in individual 8A at 3 years of age. (D) illustrates inferior cerebellar hemisphere dysplasia in individual 8B at 6 months of age. (E) and (F) illustrate a short corpus callosum (bracket indicates remaining corpus callosum) and a quadrigeminal plate cistern cyst (black plus sign) causing mass effect on the cerebellum and tectum as well as cerebellar hemisphere dysplasia in individual 9A (CG6 from Walsh et al.9) at 26 years of age. (G) and (H) illustrate similar findings in individual 10B (IV-2 from Yariz et al.10) at 12 years of age, although the corpus callosum is thinned posteriorly and dysplastic anteriorly, rather than short. (A) and (G) are sagittal T1-weighted images; (B)–(D), (F), and (H) are axial T2-weighted images, and (E) is a sagittal T2-weighted image. The American Journal of Human Genetics 2012 90, 1088-1093DOI: (10.1016/j.ajhg.2012.04.008) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 GPSM2 Sequence Analysis and GPSM2 Schematic With the use of the primers specified in Table S2, genomic DNA from each subject was PCR-amplified, and the products were isolated and purified, as described in Supplemental Data. Sanger sequencing was conducted on both the forward and reverse strand; only the forward strand is shown here. The reference (ref.) sequence (NM_013296.4) is depicted directly below the variant sequence in each panel. (A) depicts the c.1471delG mutation identified in five subjects. (B) depicts the c.741delC homozygous mutation identified in three subjects. Two other study subjects were heterozygous for this mutation (sequence not shown). (C) depicts the c.1661C>A heterozygous mutation from one of the two subjects who was also heterozygous for c.741delC. (D) depicts the homozygous splice-site mutation identified in siblings 8A and 8B. (E) depicts the effect of the splice-site mutation on the splicing of exon 9. Primers in exons 8 and 9 generated a ∼200 base-pair (bp) product in the unaffected control, but no product in subjects 8A and 8B. Primers in exons 8 and 10 generated a ∼300 bp fragment in the control and a ∼200 bp product in subjects 8A and 8B, consistent with the loss of exon 9. Sequencing of this product revealed that exon 8 is spliced to exon 10 in the affected siblings (data not shown). The horizontal arrows indicate the primer positions; the vertical red arrow indicates the location of the splice-site mutation. “lad” indicates the ladder lane and “C” indicates the control lanes. The expected exon composition and size of the various products are indicated to the right of the gel. (F) depicts the positions of amino-acid variants that account for NSHL and CMS, and includes the mouse-engineered variant ΔC. Three of the variants occur within the seven tetratricopeptide repeat domains of GPSM2, and three within the four GoLoco motifs. The American Journal of Human Genetics 2012 90, 1088-1093DOI: (10.1016/j.ajhg.2012.04.008) Copyright © 2012 The American Society of Human Genetics Terms and Conditions