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. 2019 Apr 24:10:358.
doi: 10.3389/fgene.2019.00358. eCollection 2019.

Intra-Familial Phenotypic Heterogeneity and Telomere Abnormality in von Hippel- Lindau Disease: Implications for Personalized Surveillance Plan and Pathogenesis of VHL-Associated Tumors

Jiangyi Wang  1   2   3   4   5 , Xiang Peng  1   2   3   6 , Cen Chen  7 , Xianghui Ning  1   2   3   8 , Shuanghe Peng  1   2   3   9 , Teng Li  1   2   3   10 , Shengjie Liu  1   2   3   11 , Baoan Hong  1   2   3 , Jingcheng Zhou  1   2   3 , Kaifang Ma  1   2   3 , Lin Cai  1   2   3 , Kan Gong  1   2   3
Affiliations

Intra-Familial Phenotypic Heterogeneity and Telomere Abnormality in von Hippel- Lindau Disease: Implications for Personalized Surveillance Plan and Pathogenesis of VHL-Associated Tumors

Jiangyi Wang et al. Front Genet. .

Abstract

von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome with poor survival. The current recommendations have proposed uniform surveillance strategies for all patients, neglecting the obvious phenotypic varieties. In this study, we aim to confirm the phenotypic heterogeneity in VHL disease and the underlying mechanism. A total of 151 parent-child pairs were enrolled for genetic anticipation analysis, and 77 sibling pairs for birth order effect analysis. Four statistical methods were used to compare the onset age of patients among different generations and different birth orders. The results showed that the average onset age was 18.9 years earlier in children than in their parents, which was statistically significant in all of the four statistical methods. Furthermore, the first-born siblings were affected 8.3 years later than the other ones among the maternal patients. Telomere shortening was confirmed to be associated with genetic anticipation in VHL families, while it failed to explain the birth order effect. Moreover, no significant difference was observed for overall survival between parents and children (p = 0.834) and between first-born patients and the other siblings (p = 0.390). This study provides definitive evidence and possible mechanisms of intra-familial phenotypic heterogeneity in VHL families, which is helpful to the update of surveillance guidelines.

Keywords: birth order effect; genetic anticipation; phenotypic heterogeneity; telomere length; von Hippel-Lindau disease.

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Figures

FIGURE 1
FIGURE 1
Genetic anticipation between parents and children in different generations. Children showed higher age-related risk than their parents for overall tumors (A) and CHB (B), RCC (C), PCT (D), RA (E), PHEO (F), respectively. Age-related penetrance was also assessed in 16 families with three generations and showed the same tendency (G).
FIGURE 2
FIGURE 2
The effect of mutation origin and mutation type on genetic anticipation. Children had higher age-related penetrance than their parents among paternal (A) and maternal (B) patients. The mutation type had no effect on the genetic anticipation (C,D).
FIGURE 3
FIGURE 3
Birth order effect between the first-born siblings and the others in the same generation. The first-born siblings displayed lower age-related penetrance than the others for overall tumors (A). Among siblings with an identical affected mother, the birth order effect became more evident (B). The birth order effect disappeared among paternal patients (C). When the mutated VHL allele was from fathers or the origin was not clear, the effect disappeared (D).
FIGURE 4
FIGURE 4
Age-adjusted relative telomere length in parents and children and in patients with different birth order. (A) Children showed a significant shorter telomere length than their parents. (B) No significant difference of telomere length was observed between the first-born sibling and the others.
FIGURE 5
FIGURE 5
The relationship between genetic anticipation and telomere shortening in 16 VHL families with three generations.
FIGURE 6
FIGURE 6
Overall survivals of patients in different generations and in different birth order. No significant difference was observed between parents and children (A) and between the first-born sibling and the others (B).
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References

    1. Aronoff L., Malkin D., Van Engelen K., Gallinger B., Wasserman J., Kim R. H., et al. (2018). Evidence for genetic anticipation in von Hippel-Lindau syndrome. J. Med. Genet. 55 395–402. 10.1136/jmedgenet-2017-104882 - DOI - PubMed
    1. Binderup M. L., Bisgaard M. L., Harbud V., Moller H. U., Gimsing S., Friis-Hansen L., et al. (2013). Von Hippel-Lindau disease (vHL). National clinical guideline for diagnosis and surveillance in Denmark. 3rd edition. Dan. Med. J. 60:B4763. - PubMed
    1. Boonstra P. S., Gruber S. B., Raymond V. M., Huang S. C., Timshel S., Nilbert M., et al. (2010). A review of statistical methods for testing genetic anticipation: looking for an answer in Lynch syndrome. Genet. Epidemiol. 34 756–768. 10.1002/gepi.20534 - DOI - PMC - PubMed
    1. Butman J. A., Linehan W. M., Lonser R. R. (2008). Neurologic manifestations of von Hippel-Lindau disease. JAMA 300 1334–1342. 10.1001/jama.300.11.1334 - DOI - PMC - PubMed
    1. Cawthon R. M. (2002). Telomere measurement by quantitative PCR. Nucleic Acids Res. 30:e47 10.1093/nar/30.10.e47 - DOI - PMC - PubMed

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