Testing a more extensive number of imprinted loci therefore may blur the boundaries between individual IDs which may have overlapping phenotypes. There is some evidence that individuals with MLID may exhibit a more diverse phenotype than cases with isolated imprinting errors (Poole et al., 2013). There is currently no standardized protocol for MLID diagnosis, nor has the impact of a positive diagnosis on clinical management been formally defined (Eggermann et al., 2014). It is therefore probable that cases of MLID, whether or not associated with classical phenotypes, are going undetected. Firstly, it is almost always mosaic, which complicates clinical diagnosis secondly, its heterogeneous phenotype means that patients may not meet the clinical criteria for molecular testing, thus escaping diagnosis thirdly, comprehensive epigenomic analysis is not routinely performed in individuals with molecular imprinting disturbance, so MLID may be missed. Implicated instead are environmental, iatrogenic, and trans‐acting genetic factors affecting oocyte development or early developmental epigenetic reprogramming, including trans‐acting mutations found either in the affected person or their mother (Begemann et al., 2018 Mackay et al., 2008 Sanchez‐Delgado et al., 2016).ĭetermining the prevalence of MLID across IDs is challenging.

In MLID, cis‐acting genetic changes are not found (Elbracht et al., 2020). However, a subset of affected individuals has methylation abnormalities at multiple imprinted loci (multilocus imprinting disturbance ). Imprinting disorders (IDs) may be caused by cis‐acting genetic (copy number variants, uniparental disomy, chromosomal rearrangement) or epigenetic errors of disease‐associated loci. Disturbances to this process are associated with deleterious developmental effects in pregnancy and beyond, including disturbance of pre‐ and postnatal growth, development, metabolism, and behavior.

Imprinting is a phenomenon by which epigenetic markers such as DNA methylation are maintained from one generation to another, ensuring parent of origin‐specific monoallelic expression of genes critical for growth, development, and metabolism (Mackay & Temple, 2017 Monk et al., 2019).

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