B2414 - Genetic Mutations causing congenital imprinting disorders mechanisms and consequences - 09/04/2015
Aim: to compare the DNA methylation (blood leukocyte) of patients with ultra-rare imprinting disorders, with that of batch-matched, averaged data from individuals within ALSPAC and similar cohorts.
Background
Humans harbour approximately 100 known imprinted genes, characterised by the epigenetic control of gene expression, often through parent-of-origin specific methylation that is applied in the germ line and conserved through subsequent development in all tissues. As yet, disruption of the methylation state at eight imprinted loci has been associated with imprinting disorders (IDs): Beckwith-Wiedemann syndrome (BWS; MIM #130659), Silver-Russell syndrome (SRS; MIM #180860), transient neonatal diabetes mellitus (TNDM; MIM #601410), Prader-Willi syndrome (PWS; MIM #176270), Angelman syndrome (AS; MIM #105830), matUPD14-like (Temple syndrome) and patUPD14-like (Wang-Kagami) syndromes, and pseudohypoparathyroidism 1B (PHP-1B; MIM #103580).
A proportion of patients with IDs have multi-locus imprinting disturbance (MLID) affecting different imprinted loci throughout the genome. MLID patients may have clinical features in addition to the 'classic' clinical presentation of IDs, such as developmental or behavioural problems, atypical growth patterns, or congenital anomalies; in some cases, clinical features may be nonspecific to any ID, obscuring a clinical diagnosis. We have developed a robust informatic approach for analysing epigenomewide DNA methylation, using the Illumina Infinium HumanMethylation450 BeadChip (henceforth referred to as 450k). The method requires analysis of 450k data from a single patient, compared with the averaged values from a group (optimally 20-40) batch-matched controls.
Accurate characterisation DNA methylation in MLID patients is valuable as it can underpin personalised management, and moreover can indicate the presence of an underlying genetic mutation. While in many cases the causes of MLID are unknown, and may be purely stochastic or environmental, in some cases we have identified genetic mutations causing MLID.