Monozygotic Triplets Discordant for Cardiac Neonatal Lupus Erythematosus: Case Report and Epigenetic Pilot Study

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Objectives Infants born to anti-Ro/La antibody positive mothers are at risk of neonatal lupus erythematosus (NLE). These maternal antibodies are necessary but not sufficient to cause NLE, indicating other risk factors contribute to NLE development. Here we present the first recorded case of monozygotic (MZ) triplets discordant for cardiac NLE. We hypothesize that epigenetic changes contribute to the development of cardiac NLE. We also conducted an epigenetic study of infants with and without cardiac NLE, to evaluate the association between epigenetics and cardiac NLE. Methods We conducted a retrospective chart review of the triplets referred to the Hospital for Sick Children. Peripheral blood DNA of the triplets, as well as unrelated infants with and without cardiac NLE, was run on Infinium methylation EPIC array (at 850,000 methylation sites) analysis. We identified 39 infants seen in the SickKids NLE clinic with and without cardiac NLE, matched for sex, gestational age (GA) at birth, and age at blood sampling. Differential methylation between infants with and without cardiac NLE was performed and methylation changes were visualized using principal component analyses (PCA) and heatmaps. Results The MZ female triplets were identified at 18 weeks GA. Triplet A had endocardial fibroelastosis (EFE), a non-nodal manifestation associated with cardiac NLE. Triplet B was healthy, and triplet C had complete heart block (CHB) and EFE. The triplets (blood sampling at 24 days of life) demonstrated segregation on a heatmap based on methylation patterns concordant with cardiac NLE status. The subsequent study included 39 infants (12 cardiac NLE) born to high titer anti-Ro positive mothers, with a mean 37 weeks GA at birth. Ten infants had CHB, 1 had EFE, and 1 had both. PCAs and heatmaps demonstrated segregation of the cardiac NLE infants from those without cardiac manifestations (Figure). The triplets’ methylation patterns were not concordant with methylation segregation patterns observed in the unrelated infants, which may have been a consequence of age differences. Figure. Differential genome wide DNA methylation differentiating infants with cardiac NLE from those without cardiac NLE Conclusion We present the first recorded case of MZ triplets discordant for cardiac NLE and observed differences in methylation profiles between the triplets with and without cardiac NLE. In an epigenetic study of cardiac NLE, we observed segregated methylation profiles between infants with cardiac NLE and healthy infants. We acknowledge that sample collection following cardiac NLE manifestations and treatment may impact results. Further research is required to investigate and validate our findings.

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