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Marjolijn C. J. Jongmans, Eugene T. P

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1 Revertant Somatic Mosaicism by Mitotic Recombination in Dyskeratosis Congenita 
Marjolijn C.J. Jongmans, Eugene T.P. Verwiel, Yvonne Heijdra, Tom Vulliamy, Eveline J. Kamping, Jayne Y. Hehir-Kwa, Ernie M.H.F. Bongers, Rolph Pfundt, Liesbeth van Emst, Frank N. van Leeuwen, Koen L.I. van Gassen, Ad Geurts van Kessel, Inderjeet Dokal, Nicoline Hoogerbrugge, Marjolijn J.L. Ligtenberg, Roland P. Kuiper  The American Journal of Human Genetics  Volume 90, Issue 3, Pages (March 2012) DOI: /j.ajhg Copyright © 2012 The American Society of Human Genetics Terms and Conditions

2 Figure 1 Pedigree of the Dutch Family Affected by DC
The proband (III:12) is marked by an arrow. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

3 Figure 2 Sequence Analysis of TERC
Sequence analysis of TERC revealed a heterozygous 4 bp deletion, n.54_57del (RefSeq accession number NR_ ), in the proband (III:12). The wild-type allele was observed more than the mutated allele in DNA isolated from peripheral blood cells from the father (II:7) and an uncle (II:1) of the proband. Analysis of DNA from the father's lung tissue and from the uncle's cultured fibroblasts revealed that the mutation was heterozygous. These data are in concordance with somatic events in the hematopoietic compartments of II:7 and II:1; these events resulted in loss of the germline mutation in a considerable fraction of the peripheral blood cells. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

4 Figure 3 Mitotic Recombination on Chromosome 3q Results in Isodisomy of TERC B-allele frequencies (y axis) of chromosome 3 of proband III:12 (his DNA was derived from the liver), his father, II:7, and his uncle, II:1 (their DNA was derived from peripheral blood). This analysis revealed UPD of the long arm of chromosome 3 in subject II:7. This is likely the result of a mitotic recombination event in the centromeric region (indicated by the triangle) of chromosome 3q. In subject II:1, mosaic UPD was observed, and two adjacent regions of chromosome 3q had different degrees of mosaicism. This suggests the presence of two subpopulations of cells (marked as 1 and 2) resulting from independent mitotic-recombination events with different breakpoints. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

5 Figure 4 Additional DC-Affected Individuals Show Revertant Somatic Mosaicism SNP-array analysis revealed stretches of UPD on chromosome 3q in peripheral blood DNA of subjects 7 and 15, as observed in the B-allele-frequency plot. The starting points of these homologous stretches are indicated by a triangle. No indication of UPD was observed in the SNP-array data of chromosome 3q in subjects 4 and 14. However, quantitative analysis of the SNP data revealed an allelic imbalance in these samples (Table S2), indicating the presence of a significant population of cells homozygous for a region on 3qter. The sequence data were scored for an imbalance in peak heights between the wild-type and mutant peaks, as summarized in Table 2. All four samples showed an overrepresentation of higher wild-type peaks. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

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