Uniparental disomy in a population of 32,067 clinical exome trios

Julie Scuffins,Jennifer Keller-Ramey,Lindsay Dyer,Ganka Douglas,Rebecca Torene,Vladimir Gainullin,Jane Juusola,Jeanne Meck,Kyle Retterer

doi:10.1038/s41436-020-01092-8

Abstract

PurposeData on the clinical prevalence and spectrum of uniparental disomy (UPD) remain limited. Trio exome sequencing (ES) presents a comprehensive method for detection of UPD alongside sequence and copy-number variant analysis. MethodsWe analyzed 32,067 ES trios referred for diagnostic testing to create a profile of UPD events and their disease associations. ES single-nucleotide polymorphism (SNP) and copy-number data were used to identify both whole-chromosome and segmental UPD and to categorize whole-chromosome results as isodisomy, heterodisomy, or mixed. ResultsNinety-nine whole-chromosome and 13 segmental UPD events were identified. Of these, 29 were associated with an imprinting disorder, and 16 were associated with a positive test result through homozygous sequence variants. Isodisomy was more commonly observed in large chromosomes along with a higher rate of homozygous pathogenic variants, while heterodisomy was more frequent in chromosomes associated with imprinting or trisomy mosaicism (14, 15, 16, 20, 22). ConclusionWhole-chromosome UPD was observed in 0.31% of cases, resulting in a diagnostic finding in 0.14%. Only three UPD-positive cases had a diagnostic finding unrelated to the UPD. Thirteen UPD events were identified in cases with prior normal SNP chromosomal microarray results, demonstrating the additional diagnostic value of UPD detection by trio ES.

Highlights

First proposed in 1980, inheritance of both copies of a chromosome from a single parent, or uniparental disomy (UPD), has been a known mechanism of disease for four decades.[1,2] The American College of Medical Genetics and Genomics (ACMG) recently published a new set of points to consider regarding prenatal and postnatal testing for UPD, a tribute to the importance of this phenomenon as a cause of genetic disease.[3]
The overall rate of whole-chromosome UPD within the cohort was 3 in 1,000; this was significantly higher than the rate of 1:2,000 previously reported within the general population (Fisher’s exact, p = 2.2E-68).[16]
We identified 58/99 probands who had received a genetic test with the potential to detect UPD, either a single-nucleotide polymorphism (SNP) microarray, targeted methylation testing, or, in one case, a prior exome test

Summary

Introduction

First proposed in 1980, inheritance of both copies of a chromosome from a single parent, or uniparental disomy (UPD), has been a known mechanism of disease for four decades.[1,2] The American College of Medical Genetics and Genomics (ACMG) recently published a new set of points to consider regarding prenatal and postnatal testing for UPD, a tribute to the importance of this phenomenon as a cause of genetic disease.[3]. UPD of six autosomes are associated with disease through parent-oforigin effects. Parent-of-origin effects are not the only mechanism by which UPD may cause disease. A pathogenic variant in a recessive disease gene may be unmasked in a region of isodisomy, and cause disease. In this way, UPD of any chromosome has the potential to result in a genetic disorder and a range of phenotypes. Uniparental disomy most commonly results from nondisjunction and subsequent trisomy rescue.[4,5,6] While the rescue event can correct the chromosome number, a persistent mosaic trisomic cell line could contribute to the phenotype. Maternal UPD16 has been reported in a patient subsequently determined to have mosaic trisomy 16, which could account for the patient’s phenotype.[7]

Methods

Results

Conclusion