Germline BHD-Mutation Spectrum and Phenotype Analysis of a Large Cohort of Families with Birt-Hogg-Dubé Syndrome Laura S. Schmidt, Michael L. Nickerson,

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Germline BHD-Mutation Spectrum and Phenotype Analysis of a Large Cohort of Families with Birt-Hogg-Dubé Syndrome Laura S. Schmidt, Michael L. Nickerson, Michelle B. Warren, Gladys M. Glenn, Jorge R. Toro, Maria J. Merino, Maria L. Turner, Peter L. Choyke, Nirmala Sharma, James Peterson, Patrick Morrison, Eamonn R. Maher, McClellan M. Walther, Berton Zbar, W. Marston Linehan The American Journal of Human Genetics Volume 76, Issue 6, Pages 1023-1033 (June 2005) DOI: 10.1086/430842 Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 1 BHD mutations in affected families. Sequencing chromatograms of genomic DNA of patients with BHD are shown on the left (the arrow indicates position of nucleotide variation), and family pedigrees are shown on the right. Quadrants within pedigree symbols indicate presence of FFs (blue), lung cysts/pneumothorax (yellow), and/or renal tumor (red) in each family member. WT=wild-type BHD sequence; ND=not determined; diagonal line=deceased. A, Mutation in a splice-donor site in intron 9 (IVS9+2T→G) is predicted to cause exon skipping. B and C, Mutations at c.2034C→T and c.1844C→G encode premature termination codons predicted to truncate the BHD protein. D, A 2-bp deletion, c.1126delCA, will cause a shift in the reading frame and lead to a premature stop codon downstream, truncating the BHD protein. The American Journal of Human Genetics 2005 76, 1023-1033DOI: (10.1086/430842) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 2 BHD exon-intron structure showing the location of germline mutations identified in 51 families with BHD. Frameshift (red) and nonsense (blue) mutations, predicted to prematurely truncate the BHD protein, were identified along the entire length of the coding region (exons 4–14). Splice-site (yellow) mutations predicted to cause exon skipping were identified in introns 4 and 9. The insertion or deletion of a cytosine in a C8 tract in exon 11 was identified in 27 of 51 families with BHD mutations. The American Journal of Human Genetics 2005 76, 1023-1033DOI: (10.1086/430842) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 3 Frequency of BHD phenotypic manifestations in patients with the C-insertion mutation versus the C-deletion mutation in the C8 tract of exon 11. Patients with the c.1733delC mutation developed renal tumors at a significantly lower frequency than did patients with the c.1733insC mutation (P=.03). Hatched bar indicates c.1733insC mutation carriers (n=64); blackened bar indicates c.1733delC mutation carriers (n=27); unblackened bar indicates all BHD-mutation/haplotype carriers (n=219), included for comparison. Renal tumors were identified from medical histories, surgical reports, and abdominal CT scans. Spontaneous pneumothorax episodes were determined by patient history and thoracic CT scans. Lung cysts were identified by thoracic CT scans. Skin biopsies were evaluated by a dermatologist for FF-positive histology. The American Journal of Human Genetics 2005 76, 1023-1033DOI: (10.1086/430842) Copyright © 2005 The American Society of Human Genetics Terms and Conditions