Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring

Abstract

BackgroundGenomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders by whole-exome sequencing in families with one or more members affected by multilocus imprinting disturbance.MethodsWhole-exome sequencing was performed in 38 pedigrees where probands had multilocus imprinting disturbance, in five of whom maternal variants in NLRP5 have previously been found.ResultsWe now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, including NLRP2, NLRP7 and PADI6. As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss.ConclusionThe identification of 20 putative maternal effect variants in 38 families affected by multilocus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.

Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders

“…These genes are generally considered to have a ‘maternal effect’ since they have a key role during the early embryonic stages before full zygotic genome activation. Maternally derived mutations of these genes cause impaired or delayed preimplantation development and have been associated to MLID development through oocyte-stored transcripts [37]. Nevertheless, our data do not sustain this hypothesis, since the paternally-derived NLRP2 mutation could impair methylation, suggesting a function of NLRP2 occurring after embryonic-genome activation rather than via oocyte-stored transcripts.…”

“…Overall, the absence of MLID and phenotypic effect in both carrier fathers may be explained by incomplete penetrance, as already reported for NLRP2 [21,37] and ZFP57 mutations [40]. Defining and proving the pathogenic effect of MLID-associated mutations is, indeed, challenging, given the poorly established mechanism of transmission and lack of information about the roles of analyzed factors in methylation.…”

Mutations in NLRP2 and NLRP5 cause female infertility characterised by early embryonic arrest

“…Recently, additional rare variants in the maternal NLRP2 gene were shown to be associated with MLID in the offspring 27. In that study, six probands from five families diagnosed with multilocus imprinting disturbance (MLID) whose mothers carried NLRP2 mutations were identified.…”

Search for cis-acting factors and maternal effect variants in Silver-Russell patients with ICR1 hypomethylation and their mothers

“…Maternal-effect variants in all three genes have been postulated to be associated with reproductive problems, including pregnancy losses, infertility, and MLID in liveborn children. As mentioned before, MLID is present in a significant number of patients with SRS and BWS, and in fact children born to mothers with NLPR2, NLRP5, and NLRP7 maternal effect variants often exhibit features of these imprinting disorders [15][16][17][18].…”

“…refs. [17,18,22]). In case clinical data were provided, clinical scoring for SRS was performed by applying the Netchine-Harbison (NH) scoring system [1].…”