Silver-Russell patients showing a broad range of ICR1 and ICR2 hypomethylation in different tissues

Abstract

In all known congenital imprinting disorders an association with aberrant methylation or mutations at specific loci was well established. However, several patients with transient neonatal diabetes mellitus (TNDM), Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) exhibiting multilocus hypomethylation (MLH) have meanwhile been described. Whereas TNDM patients with MLH show clinical symptoms different from carriers with isolated 6q24 aberrations, MLH carriers diagnosed as BWS or SRS present only the syndrome-specific features. Interestingly, SRS and BWS patients with nearly identical MLH patterns in leukocytes have been identified. We now report on the molecular findings in DNA in three SRS patients with hypomethylation of both 11p15 imprinted control regions (ICRs) in leukocytes. One patient was a monozygotic (MZ) twin, another was a triplet. While the hypomethylation affected both oppositely imprinted 11p15 ICRs in leukocytes, in buccal swab DNA only the ICR1 hypomethylation was visible in two of our patients. In the non-affected MZ twin of one of these patients, aberrant methylation was also present in leukocytes but neither in buccal swab DNA nor in skin fibroblasts. Despite mutation screening of several factors involved in establishment and maintenance of methylation marks including ZFP57, MBD3, DNMT1 and DNMT3L the molecular clue for the ICR1/ICR2 hypomethylation in our patients remained unclear. Furthermore, the reason for the development of the specific SRS phenotype is not obvious. In conclusion, our data reflect the broad range of epimutations in SRS and illustrate that an extensive molecular and clinical characterization of patients is necessary.

Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders

“…MEST hypomethylation in SRS-MLID has also been reported by other authors [8,19,28,31] as a distinct mechanism compared to mUPD(7), leading to GOM at this iDMR [32]. In our cases, LOM at MEST in SRS-MLID patients further sustains a key role of this iDMR in SRS.…”

Congenital imprinting disorders: Application of multilocus and high throughput methods to decipher new pathomechanisms and improve their management

“…In particular in the 11p15-associated disorders (BWS and SRS), nearly all patients with epimutations and UPD show mosaicism (for review: [13]). As a consequence of mosaicism, the molecular alterations currently often escape diagnostic detection in case of a low level mosaicism [30], an unequal distribution in different tissues [15], or an insufficient sensitivity of assays [31,32]. New diagnostic approaches therefore may analyze different tissues from the same patient as well as apply multilocus and/or deep-sequencing tests.…”

European guidance for the molecular diagnosis of pseudohypoparathyroidism not caused by point genetic variants at GNAS: an EQA study

“…19 The distribution of mosaic genetic defects can vary widely among different tissues of a patient, and similar discrepancies can also be found for methylation defects. 43 This implies that partial 'epimutations' detected in lymphocytes of PHP patients might be explained by mosaicism; thus, strict methylation cutoff values for partial GoM or LoM are not useful in this condition. Moreover, low or undetectable (epi)mutations in lymphocytes do not exclude a high percentage of mutated cells in target tissues like the proximal renal tubule.…”