GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome

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GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome Nisha Patel, Hanan E. Shamseldin, Nadia Sakati, Arif O. Khan, Ameen Softa, Fatima M. Al-Fadhli, Mais Hashem, Firdous M. Abdulwahab, Tarfa Alshidi, Rana Alomar, Eman Alobeid, Salma M. Wakil, Dilek Colak, Fowzan S. Alkuraya The American Journal of Human Genetics Volume 100, Issue 5, Pages 831-836 (May 2017) DOI: 10.1016/j.ajhg.2017.04.008 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Clinical Images of Two Families with the Autosomal-Recessive Larsen Phenotype (A) Pedigree of family 1. (B) Facial photograph of the family 1 index individual, who has prominent eyes and severe myopia. (C–F) Radiographic images of the family 1 index individual show severe scoliosis (C), severe kyphosis (D), right talipes (E), and bilateral hip dislocation (F). (G) Facial photograph of the family 1 index individual’s brother, who has prominent eyes. (H and I) Radiographic images of the family 1 index individual’s brother show scoliosis and hip dysplasia (H) and talipes (I). (J) Pedigree of family 2. (K) Photograph of the entire family 2 sibship, which is arranged from left to right in birth order. Note the short stature of the three affected children and their bulging eyes. (L and M) Facial photographs of the family 2 index individual’s brothers (V:3 in L and V:4 in M), who have prominent eyes (note the cloudy cornea due to congenital glaucoma, M). (N) Radiographic images of the family 2 index individual show mild scoliosis. (O) Hyperlaxity of the elbow in the family 2 index individual. The American Journal of Human Genetics 2017 100, 831-836DOI: (10.1016/j.ajhg.2017.04.008) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 GZF1 Is Mutated in Two Families with the Larsen Phenotype (A) An EasyLinkage output image shows a statistically significant linkage peak (pLOD = 3.97) spanning GZF1. (B) Genomic DNA sequence chromatogram of GZF1 shows the two truncating variants. (C) A schematic of GZF1 (top) and its encoded protein (bottom) shows the location of the two variants. The American Journal of Human Genetics 2017 100, 831-836DOI: (10.1016/j.ajhg.2017.04.008) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 3 GZF1 Is Localized in Tissues Relevant to the Phenotype Observed in Affected Individuals (A–C) Immunofluorescence staining of GZF1 in the lens (A) and optic nerve (B) of embryonic day 12.5 mice and in the limb mesenchyme of embryonic day 14.5 mice (C). Note the strong localization of GZF1 in the lens, retina, and optic nerve of the eye and in the mesenchymal cells of the limbs. (D–F) Negative controls for (A), (B), and (C), respectively, were run according to the same protocol except for the primary antibody. Scale bars represent 50 μm (A, B, D, and E) and 100 μm (C and F). The American Journal of Human Genetics 2017 100, 831-836DOI: (10.1016/j.ajhg.2017.04.008) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 4 Genome-wide Expression Changes Associated with GZF1 Mutations (A) Unsupervised PCA clearly distinguished control from affected individuals (the latter also subclustered according to the severity of the disease as mild and severe groups, circled in orange and purple, respectively). The blue spheres refer to normal control individuals, and red spheres refer to affected individuals. (B) Heatmap of genes that were significantly dysregulated in affected individuals in comparison with normal control individuals. The unsupervised hierarchical clustering revealed two main clusters, one comprising affected individuals (also subclustered as severe and mild groups) and another comprising normal control individuals. Red and green in the heatmap denote highly and weakly expressed genes, respectively. (C) Gene-network analysis of differentially expressed genes (DEGs). Nodes represent genes, their shape represents the functional class of the gene product, and the edges indicate the biological relationship between the nodes (see legend). Green and red indicate down- and upregulation, respectively, in affected individuals in comparison with control individuals. The color intensity is correlated with fold change. The American Journal of Human Genetics 2017 100, 831-836DOI: (10.1016/j.ajhg.2017.04.008) Copyright © 2017 American Society of Human Genetics Terms and Conditions