Identification of a New Gene Locus for Adolescent Nephronophthisis, on Chromosome 3q22 in a Large Venezuelan Pedigree Heymut Omran, Carmen Fernandez,

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Copyright © 2000 American Medical Association. All rights reserved.

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Identification of a New Gene Locus for Adolescent Nephronophthisis, on Chromosome 3q22 in a Large Venezuelan Pedigree Heymut Omran, Carmen Fernandez, Martin Jung, Karsten Häffner, Bernardo Fargier, Aminta Villaquiran, Rüdiger Waldherr, Norbert Gretz, Matthias Brandis, Franz Rüschendorf, André Reis, Friedhelm Hildebrandt The American Journal of Human Genetics Volume 66, Issue 1, Pages 118-127 (January 2000) DOI: 10.1086/302705 Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 1 Haplotypes and recombination in the Venezuelan kindred with adolescent nephronophthisis. Genotypes are shown in centromere-to-telomere order (top to bottom) for microsatellite markers D3S1292, D3S1587, D3S1273, D3S1290, D3S3713, D3S3657, D3S1238, and D3S3684 on chromosome 3q22. Inferred alleles are shown in parentheses. For genotypes represented by a question mark (?), no data were available. Haplotypes were assembled by minimization of recombinants, and the chromosomal region cosegregating with the disease locus is represented by a blackened bar. No attempt has been made to show crossovers on the nondisease chromosome, depicted by an unblackened bar. Vertical positioning of pedigree members does not represent generational order, because of extended consanguinity within the pedigree. Consanguineous relationships are depicted by a double line. Individuals whose numerical designations are below their symbols were available for genotyping. In the index case (left, above arrow) a nephrectomy specimen, and in seven individuals a renal biopsy (left arrow), were available. For LOD-score analysis, the pedigree was fragmented into four subsets (A–D). Characters below symbols identify the individuals who were used for linkage calculation in each subset. Circles denote females, squares males, blackened symbols affected individuals, unblackened symbols unaffected individuals, and symbols with a slash deceased family members. Note that D3S1587, D3S1273, D3S1290, D3S3713, and D3S3657 are cosegregating markers, which are compatible with linkage in five affected individuals, as well as in all facultative and obligate carriers. The American Journal of Human Genetics 2000 66, 118-127DOI: (10.1086/302705) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 2 Cumulative probability of terminal renal failure. The cumulative probability of terminal renal failure was determined for 24 patients from the large kindred with adolescent nephronophthisis (solid lines) and was compared with that in a historical sample of genetically proved NPH1 (dashed lines [Hildebrandt et al. 1997b]), by use of the life-table method of Kaplan and Meier (1958). The data were compared by use of the Wilcoxon test. In the group with adolescent nephronophthisis, one patient, and, in the group with NPH1, four patients, were censored (vertical strokes), because terminal renal failure did not occur during the observation period. The American Journal of Human Genetics 2000 66, 118-127DOI: (10.1086/302705) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 3 Macroscopic and microscopic pathology in adolescent nephronophthisis. A, Shrunken kidney with cyst formation predominantly at the corticomedullary junction in a nephrectomy specimen from the index case. The cortex is thin and fibrotic. B, PAS-stained renal biopsy specimen from the same individual, with irregularity in thickness of tubular basement membranes, with tubular atrophy and ectasia. In addition, there are mononuclear interstitial infiltrates and marked interstitial fibrosis. Original magnification ×100. The American Journal of Human Genetics 2000 66, 118-127DOI: (10.1086/302705) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 4 Genetic map of markers of the critical region for adolescent nephronophthisis. The haplotype, depicted as a blackened bar, cosegregates with the disease. The disease interval is flanked by markers D3S1292 and D3S1238 and contains a 2.4-cM interval because of recombination events that occurred in individual D1 and individual C76, an obligate heterozygote. The American Journal of Human Genetics 2000 66, 118-127DOI: (10.1086/302705) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 5 Autoradiograph of PCR products of marker D3S1238, for a subset of individuals of the presented pedigree. Affected individuals (A137, D1, and A134) are homozygous for the disease-associated allele, which they inherited through homozygosity by descent. One parent (A130) and unaffected siblings are heterozygous for this allele. The American Journal of Human Genetics 2000 66, 118-127DOI: (10.1086/302705) Copyright © 2000 The American Society of Human Genetics Terms and Conditions