Trans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences

Area of Science:

• Genetics
• Developmental Biology
• Reproductive Medicine

Background:

• Imprinting disorders arise from molecular alterations in differentially methylated regions (DMRs).
• Multilocus imprinting disturbances (MLID) affect multiple DMRs, presenting complex clinical features.
• Existing literature on MLID is fragmented, necessitating a comprehensive review.

Purpose of the Study:

• To review and consolidate molecular and clinical data of MLID families.
• To identify pathogenic variants in maternal effect and candidate genes associated with MLID.
• To enhance understanding of MLID pathogenesis and clinical implications.

Main Methods:

• Systematic review of molecular and clinical data from 55 MLID families.
• Analysis of variants in maternal effect genes (NLRP2, NLRP5, NLRP7, KHDC3L, OOEP, PADI6) and candidate genes (ZFP57, ARID4A, ZAR1, UHRF1, ZNF445).
• Correlation of identified variants with clinical diagnoses and reproductive history.

Main Results:

• Identified 68 distinct pathogenic variants across 55 families.
• Variants were found in NLRP2, NLRP5, NLRP7, PADI6, ZFP57, ARID4A, ZAR1, OOEP, UHRF1, KHDC3L, and ZNF445.
• Clinical outcomes included imprinting disorder spectra (e.g., Beckwith-Wiedemann, Silver-Russell syndromes), neonatal diabetes, and recurrent pregnancy loss.

Conclusions:

• MLID variants provide insights into imprinting cycle mechanisms and early development.
• Further research on MLID families can clarify links between reproductive issues and offspring aneuploidy.
• Current findings support improved reproductive and genetic counseling for MLID cases.