Bilineal Disease and Trans-Heterozygotes in Autosomal Dominant Polycystic Kidney Disease York Pei, Andrew D. Paterson, Kai Rong Wang, Ning He, Donna.

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Bilineal Disease and Trans-Heterozygotes in Autosomal Dominant Polycystic Kidney Disease York Pei, Andrew D. Paterson, Kai Rong Wang, Ning He, Donna Hefferton, Terry Watnick, Greg G. Germino, Patrick Parfrey, Stefan Somlo, Peter St. George-Hyslop The American Journal of Human Genetics Volume 68, Issue 2, Pages 355-363 (February 2001) DOI: 10.1086/318188 Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 1 Simplified pedigree structure of NFL10, and haplotype analysis at the PKD1 and PKD2 loci. In the present study, we have identified three previously unknown consanguineous relationships (between individuals OP9 and OP10, between OP11 and OP12, and between OP125 and OP140; denoted by double lines between the individuals) and two additional branches of the family (represented by individuals numbered “OP100”–”OP111” and “OP120”–”OP131”). The combination of the PKD1 haplotype 3-4-1-7-8-5 (blue bar) and the PKD2 haplotype 2-4-6-6-9 (red bar) accounted for the disease in all affected individuals except OP14; OP14, who had two renal cysts at age 22 years, was considered to be affected with ADPKD. These findings suggest the possibility of bilineal disease from independently segregating PKD1 and PKD2 mutations. Individuals with indeterminate disease status are denoted by the half-blackened symbols. The age at the last ultrasound test is shown in parentheses. All individuals with the slanted-T symbols have been genotyped. The American Journal of Human Genetics 2001 68, 355-363DOI: (10.1086/318188) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 2 PKD2 mutation analysis in NFL10. a, Sequence tracings of exon 11 PCR products from a control subject (top panel) and individual OP120 (bottom panel). A heterozygous PKD2 frameshift mutation (i.e., 2152delA) is detected in OP120. This mutation is expected to truncate the mutant protein product at codon 736 (i.e., L736X). b, Representative data from ASO hybridization analysis. Cosegregation of the mutation depicted in panel a occurs only with the affected individuals with the PKD2 haplotype 2-4-6-6-9 and not with the unaffected individuals. The American Journal of Human Genetics 2001 68, 355-363DOI: (10.1086/318188) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 3 Genotype-phenotype correlation in NFL10. Age-adjusted creatinine clearances are plotted against individuals with a mutation in either PKD1 (blue symbol), PKD2 (red symbol), or both mutations (green symbol). The renal-disease severity is similar in individuals with either the PKD1 or PKD2 mutation but is more severe in the two individuals (i.e., OP8 and OP13) with the compound heterozygous mutations. The normal reference range is 95–130 ml/min/1.73 m2. The American Journal of Human Genetics 2001 68, 355-363DOI: (10.1086/318188) Copyright © 2001 The American Society of Human Genetics Terms and Conditions