In Pursuit of New Imprinting Syndromes by Epimutation Screening in Idiopathic Neurodevelopmental Disorder Patients.

Sonia Mayo,Francisco Martínez,Sandra Monfort,Mónica Roselló,Carmen Orellana,Silvestre Oltra

doi:10.1155/2015/341986

Sonia Mayo, Francisco Martínez + Show 4 more

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https://doi.org/10.1155/2015/341986

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Abstract

Alterations of epigenetic mechanisms, and more specifically imprinting modifications, could be responsible of neurodevelopmental disorders such as intellectual disability (ID) or autism together with other associated clinical features in many cases. Currently only eight imprinting syndromes are defined in spite of the fact that more than 200 genes are known or predicted to be imprinted. Recent publications point out that some epimutations which cause imprinting disorders may affect simultaneously different imprinted loci, suggesting that DNA-methylation may have been altered more globally. Therefore, we hypothesised that the detection of altered methylation patterns in known imprinting loci will indirectly allow identifying new syndromes due to epimutations among patients with unexplained ID. In a screening for imprinting alterations in 412 patients with syndromic ID/autism we found five patients with altered methylation in the four genes studied: MEG3, H19, KCNQ1OT1, and SNRPN. Remarkably, the cases with partial loss of methylation in KCNQ1OT1 and SNRPN present clinical features different to those associated with the corresponding imprinting syndromes, suggesting a multilocus methylation defect in accordance with our initial hypothesis. Consequently, our results are a proof of concept that the identification of epimutations in known loci in patients with clinical features different from those associated with known syndromes will eventually lead to the definition of new imprinting disorders.

Highlights

Intellectual disability (ID) is a complex disease which affects 2% of our population
We found five cases with alteration of methylation: two alterations in the methylation pattern of MEG3 as a consequence of paternal or maternal uniparental disomy for chromosome 14, one hypermethylation of H19, one partial loss of methylation in KCNQ1OT1, and one partial loss of methylation in SNRPN
In the screening for imprinting alterations in the 412 patients with neurodevelopmental disorders we have found five cases with different alterations of methylation

Summary

Introduction

Intellectual disability (ID) is a complex disease which affects 2% of our population. It is increasingly evident that epimutations leading to imprinting disorders in some instances may affect not one but several imprinted loci throughout the genome, suggesting that imprinting-specific DNA-methylation may have been altered more globally due to unknown factors [15,16,17,18,19,20,21] Phenotypic differences of these cases with the classical imprinting syndromes may be present or not and can be attributed to abnormal DNA-methylation elsewhere. Based on these findings, we hypothesize that many of the imprinted genes of unknown clinical consequences may be responsible for neurodevelopmental disorders when epimutated, associated or not with other congenital anomalies. We found five cases with alteration of methylation: two alterations in the methylation pattern of MEG3 as a consequence of paternal or maternal uniparental disomy for chromosome 14, one hypermethylation of H19 (due to paternal 11p duplication), one partial loss of methylation in KCNQ1OT1, and one partial loss of methylation in SNRPN

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Conclusion