A novel method for detecting uniparental disomy from trio genotypes identifies a significant excess in children with developmental disorders

Abstract

Exome sequencing of parent-offspring trios is a popular strategy for identifying 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 have 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. This tool is the first to read VCF-formatted genotypes, to perform integrated copy number filtering, and to use a statistical test inherently robust for use in platforms of varying genotyping density and noise characteristics. Simulations demonstrated superior accuracy compared with previously developed approaches. We implemented the method on 1057 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.

Incidental finding of paternal UPD15 in a child with a deletion of 11q21–q22.3, presenting with developmental delay, coloboma and characteristic dysmorphic features

“…In addition, the higher cost of SNP array technology, as compared with array CGH, may limit the use of the SNP array in some centers as a first-line genetic test in children with developmental delay. Although UPD seems to be quite rare in the general population and is estimated at one in 3500 live births, a recent study showed a significant 25 × enrichment of UPD in children with developmental disorders (Robinson, 2000;King et al, 2014). The possibility of UPD may therefore be an argument for including SNP arrays in the genetic workup of children with developmental delay, especially those with complex phenotypes.…”

Systematic reanalysis of genomic data improves quality of variant interpretation

“…UPD was called using UPDio 14 . CNV calls (Supplemental Materials and Methods), were masked and not considered by UPDio.…”

Absence of Heterozygosity Due to Template Switching during Replicative Rearrangements

“…18 Array comparative genomic hybridization was performed with a custom, exome-focused, two million probe Agilent aCGH array; CNVs were called via CNsolidate, a Sanger Centre in-house algorithm that integrates 12 change-point detection algorithms (T. Fitzpatrick, P. Vijayarangakannan, N. Carter, M.E.H., data not shown); uniparental disomy was detected with UPDio. 19 To confirm triplication and AOH independently, samples were run on two different array platforms. For instance, BAB4539 plus parental samples were run on an Affymetrix CytoScan SNP array and samples BAB3922, BAB3923, and BAB3924 plus parental samples were analyzed with A B C Figure 1.…”