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How many cases of disease in a pedigree imply familial disease?

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posted on 2017-12-19, 11:48 authored by Frank Dudbridge, Suzanne J. Brown, Lynley Ward, Scott G. Wilson, John P. Walsh
The ability to perform whole-exome and, increasingly, whole-genome sequencing on large numbers of individuals has led to increased efforts to identify rare genetic variants that affect the risk of both common and rare diseases. In such applications, it is important to identify families that are segregating the rare variants of interest. For rare diseases or rare familial forms of common diseases, pedigrees with multiple affected members are clearly harbouring risk variants. For more common diseases, however, it may be unclear whether a family with a few affected members is segregating a familial disease, is the result of multiple sporadic cases, or is a mixture of familial cases and phenocopies. We provide calculations for the probability that a family is harbouring familial disease, presented in general terms that admit working guidelines for selecting families for current sequencing studies. Using examples motivated by our own studies of thyroid cancer and published studies of colorectal cancer, we show that for common diseases, families with exactly two affected first-degree relatives have only a moderate probability of segregating familial disease, but this probability is higher for families with three or more affected relatives, and those families should therefore be prioritised in sequencing studies.

Funding

This work was supported by the Medical Research Council (MR/K006215/1), Australian National Health and Medical Research Council (PG 1087407) and the Sir Charles Gairdner Hospital Research Advisory Committee (PG 2016–17/038).

History

Citation

Annals of Human Genetics, 2018, 82 (2), PP. 109-113

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Health Sciences

Version

  • VoR (Version of Record)

Published in

Annals of Human Genetics

Publisher

Wiley for University College London

issn

0003-4800

eissn

1469-1809

Acceptance date

2017-09-05

Copyright date

2017

Available date

2017-12-19

Publisher version

http://onlinelibrary.wiley.com/doi/10.1111/ahg.12222/abstract

Notes

Additional Supporting Information may be found online in the supporting information tab for this article.

Language

en

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