DNA Methylation in the Diagnosis of Monogenic Diseases

Abstract

DNA methylation in the human genome is largely programmed and shaped by transcription factor binding and interaction between DNA methyltransferases and histone marks during gamete and embryo development. Normal methylation profiles can be modified at single or multiple loci, more frequently as consequences of genetic variants acting in cis or in trans, or in some cases stochastically or through interaction with environmental factors. For many developmental disorders, specific methylation patterns or signatures can be detected in blood DNA. The recent use of high-throughput assays investigating the whole genome has largely increased the number of diseases for which DNA methylation analysis provides information for their diagnosis. Here, we review the methylation abnormalities that have been associated with mono/oligogenic diseases, their relationship with genotype and phenotype and relevance for diagnosis, as well as the limitations in their use and interpretation of results.

Neonatal hyperinsulinemic hypoglycemia: case report of kabuki syndrome due to a novel KMT2D splicing-site mutation

“…KMT2D and KDM6A are large, enzymatically active scaffold proteins (histone methyltransferases and chromatin-bound protein), that form the core of nuclear regulatory structures of COMPASS complex (complex of protein associated with Set-1) like family, that enhance gene expression of specific loci via the targeted modification of histone-3 tail residues, promoting active euchromatic conformations and interacting with other receptors (transcription promoting enhanceosomes). Other key COMPASS complex genes than KMT2D and KDM6A, have been linked to human congenital syndromes with postnatal growth restriction as Rubinstein-Taybi type 1 (CBP) and type 2 (EP300) and Kleefstra syndrome type 2 (KMT2C), whereas other DNA methylation defects have been described up to 100% of several mono/oligogenic diseases responsible for constitutional neurodevelopmental disorders as Fragile X syndrome, Sotos syndrome, Tatton-Brown-Rahman syndrome and Kagami-Ogata syndrome [22,23]. Furthermore, a homologue of KDM6A called KDM6C (UTY; MIM# 400009), another H3K27 demethylase, is located on the Y-chromosome [24] and constitutes a possible candidate gene for KS in male individuals [18].…”

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

“…During human development, genomic DNA methylation signatures are established in early development by two consecutive waves of nearly global demethylation, followed by targeted re-methylation [ 85 , 86 ]. NDD mutations have often been found to underlie errors in methylation during these early time points [ 87 , 88 ]. Consequently, altered methylation signatures during early development may be passed on across all cell lineages and can thus affect multiple tissues.…”

Maternal Uniparental Disomy of Chromosome 20 (UPD(20)mat) as Differential Diagnosis of Silver Russell Syndrome: Identification of Three New Cases

“…Clinical diagnosis of SRS is currently based on the Netchine–Harbison clinical scoring system (NH-CSS), a combination of six recurrent characteristic features: pre- and postnatal growth failure, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties [ 1 ]. Patients with at least four (out of six) criteria are defined as “clinical SRS”, even if no molecular anomaly is detected: however, molecular testing is recommended in patients with ≥3/6 criteria [ 1 , 2 ].…”