Multi-locus imprinting disturbance (MLID): interim joint statement for clinical and molecular diagnosis

Abstract

Background: Imprinting disorders are rare diseases resulting from altered expression of imprinted genes, which exhibit parent-of-origin-specific expression patterns regulated through differential DNA methylation. A subgroup of patients with imprinting disorders have DNA methylation changes at multiple imprinted loci, a condition referred to as multi-locus imprinting disturbance (MLID). MLID is recognised in most but not all imprinting disorders and is also found in individuals with atypical clinical features; the presence of MLID often alters the management or prognosis of the affected person. Some cases of MLID are caused by trans-acting genetic variants, frequently not in the patients but their mothers, which have counselling implications. There is currently no consensus on the definition of MLID, clinical indications prompting testing, molecular procedures and methods for epigenetic and genetic diagnosis, recommendations for laboratory reporting, considerations for counselling, and implications for prognosis and management. The purpose of this study is thus to cover this unmet need.

Methods: A comprehensive literature search was conducted resulting in identification of more than 100 articles which formed the basis of discussions by two working groups focusing on clinical diagnosis (n = 12 members) and molecular testing (n = 19 members). Following eight months of preparations and regular online discussions, the experts from 11 countries compiled the preliminary documentation and determined the questions to be addressed during a face-to-face meeting which was held with the attendance of the experts together with four representatives of patient advocacy organisations.

Results: In light of available evidence and expert consensus, we formulated 16 propositions and 8 recommendations as interim guidance for the clinical and molecular diagnosis of MLID.

Conclusions: MLID is a molecular designation, and for patients with MLID and atypical phenotypes, we propose the alternative term multi-locus imprinting syndrome. Due to the intrinsic variability of MLID, the guidelines underscore the importance of involving experts from various fields to ensure a confident approach to diagnosis, counselling, and care. The authors advocate for global, collaborative efforts in both basic and translational research to tackle numerous crucial questions that currently lack answers, and suggest reconvening within the next 3-5 years to evaluate the research advancements and update this guidance as needed.

Keywords: Clinical diagnosis; DMR; Differentially methylated regions; Imprinting disorder; MLID; Molecular diagnosis; Multi-locus imprinting disturbance.

Fig. 1

Flow chart for investigation of MLID in the context of imprinting disorder diagnosis. Solid black lines are followed when clinical suspicion of an imprinting disorder prompts testing as per consensus guidelines, and subsequent expert evaluation prompts second-line MLID testing (Sect. “Second-line testing for MLID following molecular diagnosis of an imprinting disorder”). When suspicion of MLID prompts expert referral for first-line testing of clinically associated differentially methylated regions (CA-DMRs), dashed black lines are normally followed. Dashed green lines are followed when diagnosis of MLID prompts further investigation in an expert centre or research setting, such as epigenome-wide DNA methylation analysis (Sect. “Molecular testing for MLID as a first-line test”), or genetic testing (Sect. “Genetic testing in MLID”). 1, Imprinting disturbances relevant for MLID include disorders and disturbances indicated in Table 2 and include any MLID detected during first-line multi-locus testing; P, proposition; HCP, health care professional