Identification of a Gene for Renal-Hepatic-Pancreatic Dysplasia by Microarray-Based Homozygosity Mapping Torunn Fiskerstrand, Gunnar Houge, Staale Sund,

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Identification of a Gene for Renal-Hepatic-Pancreatic Dysplasia by Microarray-Based Homozygosity Mapping Torunn Fiskerstrand, Gunnar Houge, Staale Sund, David Scheie, Sabine Leh, Helge Boman, Per M. Knappskog The Journal of Molecular Diagnostics Volume 12, Issue 1, Pages 125-131 (January 2010) DOI: 10.2353/jmoldx.2010.090033 Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 1 Pedigree and haplotypes in the candidate region on chromosome 3q. Selected single nucleotide polymorphisms and their distance in megabases from the end of the short arm of chromosome 3 are shown in the left columns in consecutive order. Parental haplotypes have been given different colors, with the shared (ancestral) haplotype in red. The boundaries of the candidate region are indicated by dashed lines. The NPHP3 gene is located 133.88 to 133.92 Mb and the IQCB1 gene 122.97 to 123.03 Mb from the start of chromosome 3 (3pter). The Journal of Molecular Diagnostics 2010 12, 125-131DOI: (10.2353/jmoldx.2010.090033) Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 2 Case 1. Kidneys with cystic dysplasia (A and B). Primitive tubules surrounded by mesenchymal tissue with foci of cartilage and a malformed glomerulus (B). Liver with portal fibrosis and paucity of bile ducts; this portal area contains vessels, but no ducts (C). The pancreatic tissue shows marked fibrosis and dysplastic ducts. Two islets of Langerhans are also seen (D). A and B: H&E; C and D: trichrome. Scale bars: 5 mm (A) and 200 μm (B–D). The Journal of Molecular Diagnostics 2010 12, 125-131DOI: (10.2353/jmoldx.2010.090033) Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 3 Case 2. Situs inversus with dextroposition of the heart (A, asterisk) and sinistroposed liver with gall bladder (B, white arrow). Flexion contractures of the elbows and wrists (A). Curvatura major of the stomach to the right (B, arrowhead) and ileocoecal segment with appendix on the left side of the abdomen (B, red arrow). Hepatic dysplasia with abnormally branching medium-sized bile ducts (Masson trichrome) (C). Brain: The cingulate gyri demonstrated polymicrogyria (arrow) (H&E) (D). Scale bars: 100 μm (C) and 2000 μm (D). The Journal of Molecular Diagnostics 2010 12, 125-131DOI: (10.2353/jmoldx.2010.090033) Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 4 The mutation c.2694-2_2694-1delAG. The normal sequence is shown on top (wild type (WT)), with the fetal sequence below. The fetus was homozygous for the mutation. The Journal of Molecular Diagnostics 2010 12, 125-131DOI: (10.2353/jmoldx.2010.090033) Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 5 Effect of the c.2694-3_2694-1delAG mutation on the NPHP3 mRNA. The mutation leads to activation of a novel cryptic splice site (A), resulting in insertion of 19 bases of intronic sequence in the NPHP3 transcript expressed in the lymphocytes (B). The Journal of Molecular Diagnostics 2010 12, 125-131DOI: (10.2353/jmoldx.2010.090033) Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 6 Immunohistochemical investigation of nephrocystin-3 in case 1. Some tubules are marked by asterisks. The dysplastic kidney tubules are negative (A), whereas the age-matched control kidney shows distinct cytoplasmic positivity in some tubular segments (B). Scale bars, 50 μm. The Journal of Molecular Diagnostics 2010 12, 125-131DOI: (10.2353/jmoldx.2010.090033) Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions