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Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans.

ABSTRACT: Human-imprinting disorders are congenital disorders of growth, development and metabolism, associated with disturbance of parent of origin-specific DNA methylation at imprinted loci across the genome. Some imprinting disorders have higher than expected prevalence of monozygotic twinning, of assisted reproductive technology among parents, and of disturbance of multiple imprinted loci, for which few causative trans-acting mutations have been found. Here we report mutations in NLRP5 in five mothers of individuals affected by multilocus imprinting disturbance. Maternal-effect mutations of other human NLRP genes, NLRP7 and NLRP2, cause familial biparental hydatidiform mole and multilocus imprinting disturbance, respectively. Offspring of mothers with NLRP5 mutations have heterogenous clinical and epigenetic features, but cases include a discordant monozygotic twin pair, individuals with idiopathic developmental delay and autism, and families affected by infertility and reproductive wastage. NLRP5 mutations suggest connections between maternal reproductive fitness, early zygotic development and genomic imprinting.

SUBMITTER: Docherty LE

PROVIDER: S-EPMC4568303 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans.

Docherty Louise E LE Rezwan Faisal I FI Poole Rebecca L RL Turner Claire L S CL Kivuva Emma E Maher Eamonn R ER Smithson Sarah F SF Hamilton-Shield Julian P JP Patalan Michal M Gizewska Maria M Peregud-Pogorzelski Jaroslaw J Beygo Jasmin J Buiting Karin K Horsthemke Bernhard B Soellner Lukas L Begemann Matthias M Eggermann Thomas T Baple Emma E Mansour Sahar S Temple I Karen IK Mackay Deborah J G DJ

Nature communications 20150901

Human-imprinting disorders are congenital disorders of growth, development and metabolism, associated with disturbance of parent of origin-specific DNA methylation at imprinted loci across the genome. Some imprinting disorders have higher than expected prevalence of monozygotic twinning, of assisted reproductive technology among parents, and of disturbance of multiple imprinted loci, for which few causative trans-acting mutations have been found. Here we report mutations in NLRP5 in five mothers ...[more]

PMID: 26323243

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Project description:BackgroundA subset of individuals affected by imprinting disorders displays multi-locus imprinting disturbances (MLID). MLID has been associated with maternal-effect variants that alter the maintenance of methylation at germline-derived differentially methylated regions (gDMRs) in early embryogenesis. Pedigrees of individuals with MLID also include siblings with healthy phenotype. However, it is unknown if these healthy individuals have MLID themselves or if their methylation patterns differ from those associated with imprinting disorders, and in general, if MLID affects the clinical phenotype.MethodsWe have investigated gDMR methylation by locus-specific and whole-genome analyses in a family with multiple pregnancy losses, a child with Beckwith-Wiedemann syndrome (BWS) and a further child with no clinical diagnosis of imprinting disorder or other pathologies.ResultsWe detected MLID with different methylation profiles in the BWS-affected and healthy siblings. Whole-exome sequencing demonstrated the presence of novel loss-of-function variants of NLRP5 in compound heterozygosity in the mother. The methylation profiles of the two siblings were compared with those of other cases with MLID and control groups by principal component analysis and unsupervised hierarchical clustering, but while their patterns were clearly separated from those of controls, we were unable to cluster those associated with specific clinical phenotypes among the MLID cases.ConclusionThe identification of two novel maternal-effect variants of NLRP5 associated with poly-abortivity and MLID adds further evidence to the role of this gene in the maintenance of genomic imprinting in early embryos. Furthermore, our results demonstrate that within these pedigrees, MLID can also be present in the progeny with healthy phenotype, indicating that some sort of compensation occurs between altered imprinted loci in these individuals. The analysis of larger cohorts of patients with MLID is needed to formulate more accurate epigenotype-phenotype correlations.

Project description:BackgroundEpidemiological studies suggest that singletons born from assisted reproductive technologies (ART) have a high risk of adverse perinatal outcomes, specifically for imprinting disorders. Because ART processes take place at times when epigenetic reprogramming/imprinting are occurring, there is concern that ART can affect genomic imprints. However, little is currently known about the risk of imprinting defects according to the type of ART or the type of underlying female infertility. From the French national health database, a cohort of 3,501,495 singletons born over a 5-year period (2013-2017) following fresh embryo or frozen embryo transfers (fresh-ET or FET from in vitro fertilization), intrauterine insemination, or natural conception was followed up to early childhood. Based on clinical features, several syndromes/diseases involving imprinted genes were monitored. The effects of ART conception and the underlying cause of female infertility were assessed.ResultsCompared with infants conceived naturally, children born after fresh-ET had a higher prevalence of imprinting-related diseases, with an aOR of 1.43 [95% CI 1.13-1.81, p = 0.003]. Namely, we observed an increased risk of neonatal diabetes mellitus (1.96 aOR [95% CI 1.43-2.70], p < 0.001). There was an overall independent increase in risk of imprinting diseases for children with mothers diagnosed with endometriosis (1.38 aOR [95% CI 1.06-1.80], p = 0.02). Young and advanced maternal age, primiparity, obesity, smoking, and history of high blood pressure or diabetes were also associated with high global risk.ConclusionsThis prospective epidemiological study showed that the risk of clinically diagnosed imprinting-related diseases is increased in children conceived after fresh embryo transfers or from mothers with endometriosis. The increased perturbations in genomic imprinting could be caused by controlled ovarian hyperstimulation and potentially endometriosis through the impairment of endometrial receptivity and placentation, leading to epigenetic feto-placental changes. Further studies are now needed to improve understanding of the underlying molecular mechanisms (i.e. genetic or epigenetic causes).

Dataset Information

Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans.

Publications

Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans.

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