A novel method for detecting Uniparental Disomy from trio genotypes identifies a significant excess in children with developmental disorders
- Daniel A King1,
- Tomas W Fitzgerald1,
- Ray Miller1,
- Natalie Canham2,
- Jill Clayton-Smith3,
- Diana Johnson4,
- Sahar Mansour5,
- Fiona Steward6,
- Pradeep Vasudevan7 and
- Matthew E. Hurles1,8
- 1 Wellcome Trust Sanger Institute;
- 2 North West London Hospitals NHS Trust;
- 3 University of Manchester;
- 4 Sheffield Children's NHS Foundation Trust;
- 5 St George's Healthcare NHS Trust;
- 6 Belfast City Hospital;
- 7 University Hospitals of Leicester
- ↵* Corresponding author; email: meh{at}sanger.ac.uk
Abstract
Exome sequencing of parent-offspring trios is a popular strategy to identify causative genetic variants in children with rare diseases. This method owes its strength to the leveraging of inheritance information, which facilitates de novo variant calling, inference of compound heterozygosity, and the identification of inheritance anomalies. Uniparental disomy describes the inheritance of a homologous chromosome pair from only one parent. This aberration is important to detect in genetic disease studies because it can result in imprinting disorders, and recessive diseases. We developed a software tool to detect uniparental disomy from child-mother-father genotype data that uses a binomial test to identify chromosomes with a significant burden of uniparentally-inherited genotypes. The tool is the first to read VCF-formatted genotypes, to perform integrated copy number filtering, and to use a statistical test inherently robust to platforms of varying genotyping density and noise characteristics. Simulations demonstrated superior accuracy compared with previously developed approaches. We implemented the method on 1,057 trios from the Deciphering Developmental Disorders project, a trio-based rare disease study, and detected six validated events, a significant enrichment compared with the population prevalence of UPD (1 in 3500), suggesting that most of these events are pathogenic. One of these events represents a known imprinting disorder, and exome analyses have identified rare homozygous candidate variants, mainly in the isodisomic regions of UPD chromosomes, which, among other variants, provide targets for further genetic and functional evaluation.
- Received May 14, 2013.
- Accepted December 13, 2013.
- Published by Cold Spring Harbor Laboratory Press
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.
