Identification of rare de novo epigenetic variations in congenital disorders

Abstract

Certain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. However, even after whole-genome sequencing (WGS), a substantial fraction of such disorders remain unexplained. We hypothesize that some cases of ND–CA are caused by aberrant DNA methylation leading to dysregulated genome function. Comparing DNA methylation profiles from 489 individuals with ND–CAs against 1534 controls, we identify epivariations as a frequent occurrence in the human genome. De novo epivariations are significantly enriched in cases, while RNAseq analysis shows that epivariations often have an impact on gene expression comparable to loss-of-function mutations. Additionally, we detect and replicate an enrichment of rare sequence mutations overlapping CTCF binding sites close to epivariations, providing a rationale for interpreting non-coding variation. We propose that epivariations contribute to the pathogenesis of some patients with unexplained ND–CAs, and as such likely have diagnostic relevance.

DNA methylation outlier burden, health, and ageing in Generation Scotland and the Lothian Birth Cohorts of 1921 and 1936

“…It is possible that for several disease outcomes, there was insufficient statistical power to detect associations with DNA methylation outlier burden due to limited observations. While other work has linked extreme DNA methylation patterns to congenital abnormalities [9] and low birth weight [18], the findings of the present study do not support strong links between DNA methylation outlier burden and agerelated health outcomes.…”

“…DNA methylation outliers occur when the DNA methylation level at a specific site in an individual's genome differs greatly from that of the majority of the population at this locus. It is known that abnormal methylation patterns can lead to aberrant gene expression, and DNA methylation outliers have been shown to be associated with the development of certain cancers [7,8] or neurodevelopmental disorders and congenital anomalies [9].…”

The etiology of VACTERL association: Current knowledge and hypotheses

“…In one study of 489 patients with neurodevelopmental disorders or congenital anomalies, the affected patients were found to be significantly enriched for de novo epivariations. Of these patients, 65% had multiple congenital anomalies (including congenital heart defects) in addition to neurodevelopmental anomalies (Barbosa et al, ). This study is tantalizing for a number of reasons.…”

Directly Transmitted 12.3-Mb Deletion with a Consistent Phenotype in the Variable 11q21q22.3 Region

“…Alternative causes of the features found in this family have not been excluded by, for instance, whole-genome sequencing [Lindstrand et al, 2019] or epigenetic analysis [Barbosa et al, 2018]. However, the relatively consistent phenotypes in the present family together with the common features among patients with overlapping deletions may provide the basis for a characteristic phenotype for this region with YAP1 , CNTN5 , and GRI4 as possible candidate genes for some of the observed features.…”