Molecular characterisation of 36 multilocus imprinting disturbance (MLID) patients: a comprehensive approach

Bilo, Larissa; Ochoa, Eguzkine; Lee, Sunwoo; Dey, Daniela; Kurth, Ingo; Kraft, Florian; Rodger, Fay; Docquier, France; Toribio, Ana Luisa; Bottolo, Leonardo; Binder, Gerhard; Fekete, György; Elbracht, Miriam; Begemann, Matthias; Eggermann, Thomas

doi:10.1186/s13148-023-01453-5

Cited by 5 publications

(1 citation statement)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Genetic testing for maternal effect variants is a specific situation. In fact, the pathogenic potential of SCMC variants is meanwhile accepted for families with a massive history of recurrent miscarriages, children with ImpDefs and/or aneuploidies carrying maternal effect variants [69]. However, prediction of the recurrence risk for the aforementioned reproductive issues is not possible, and oocyte donation has been suggested as a therapeutic option [70].…”

Section: Diagnostic Testing For Impdis In a Reproductive Contextmentioning

confidence: 99%

Human Reproduction and Disturbed Genomic Imprinting

Eggermann

2024

Genes

Self Cite

View full text Add to dashboard Cite

Genomic imprinting is a specific mode of gene regulation which particularly accounts for the factors involved in development. Its disturbance affects the fetus, the course of pregnancy and even the health of the mother. In children, aberrant imprinting signatures are associated with imprinting disorders (ImpDis). These alterations also affect the function of the placenta, which has consequences for the course of the pregnancy. The molecular causes of ImpDis comprise changes at the DNA level and methylation disturbances (imprinting defects/ImpDefs), and there is an increasing number of reports of both pathogenic fetal and maternal DNA variants causing ImpDefs. These ImpDefs can be inherited, but prediction of the pregnancy complications caused is difficult, as they can cause miscarriages, aneuploidies, health issues for the mother and ImpDis in the child. Due to the complexity of imprinting regulation, each pregnancy or patient with suspected altered genomic imprinting requires a specific workup to identify the precise molecular cause and also careful clinical documentation. This review will cover the current knowledge on the molecular causes of aberrant imprinting signatures and illustrate the need to identify this basis as the prerequisite for personalized genetic and reproductive counselling of families.

show abstract

Section: Diagnostic Testing For Impdis In a Reproductive Contextmentioning

confidence: 99%

Human Reproduction and Disturbed Genomic Imprinting

Eggermann

2024

Genes

Self Cite

View full text Add to dashboard Cite

show abstract

Whole-exome sequencing reveals causative genetic variants for several overgrowth syndromes in molecularly negative Beckwith-Wiedemann spectrum

Higashimoto,

Sun,

Imagawa

et al. 2024

J Med Genet

View full text Add to dashboard Cite

BackgroundBeckwith-Wiedemann syndrome (BWS) is an imprinting disorder caused by (epi)genetic alterations at 11p15. Because approximately 20% of patients test negative via molecular testing of peripheral blood leukocytes, the concept of Beckwith-Wiedemann spectrum (BWSp) was established to encompass a broader cohort with diverse and overlapping phenotypes. The prevalence of other overgrowth syndromes concealed within molecularly negative BWSp remains unexplored.MethodsWe conducted whole-exome sequencing (WES) on 69 singleton patients exhibiting molecularly negative BWSp. Variants were confirmed by Sanger sequencing or quantitative genomic PCR. We compared BWSp scores and clinical features between groups with classical BWS (cBWS), atypical BWS or isolated lateralised overgrowth (aBWS+ILO) and overgrowth syndromes identified via WES.ResultsTen patients, one classified as aBWS and nine as cBWS, showed causative gene variants for Simpson-Golabi-Behmel syndrome (five patients), Sotos syndrome (two), Imagawa-Matsumoto syndrome (one), glycosylphosphatidylinositol biosynthesis defect 11 (one) or 8q duplication/9p deletion (one). BWSp scores did not distinguish between cBWS and other overgrowth syndromes. Birth weight and height in other overgrowth syndromes were significantly larger than in aBWS+ILO and cBWS, with varying intergroup frequencies of clinical features.ConclusionMolecularly negative BWSp encapsulates other syndromes, and considering both WES and clinical features may facilitate accurate diagnosis.

show abstract

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

Mackay,

Gazdagh,

Monk

et al. 2024

Clin Epigenet

View full text Add to dashboard Cite

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.

show abstract

Molecular characterisation of 36 multilocus imprinting disturbance (MLID) patients: a comprehensive approach

Cited by 5 publications

References 47 publications

Human Reproduction and Disturbed Genomic Imprinting

Human Reproduction and Disturbed Genomic Imprinting

Whole-exome sequencing reveals causative genetic variants for several overgrowth syndromes in molecularly negative Beckwith-Wiedemann spectrum

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

Contact Info

Product

Resources

About