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

J Med Genet. 2018 Jul;55(7):497-504. doi: 10.1136/jmedgenet-2017-105190. Epub 2018 Mar 24.


Background: Genomic 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.

Methods: Whole-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.

Results: We 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.

Conclusion: The 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.

Keywords: Beckwith-Wiedemann syndrome; NLRP2; NLRP5; NLRP7; PADI6; Silver-Russell syndrome; genomic imprinting; multi-locus imprinting disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Apoptosis Regulatory Proteins
  • Beckwith-Wiedemann Syndrome / genetics*
  • Beckwith-Wiedemann Syndrome / pathology
  • Chromosomes, Human, Pair 11 / genetics
  • DNA Methylation / genetics
  • Female
  • Genomic Imprinting / genetics
  • Germ-Line Mutation / genetics
  • Humans
  • Infant, Newborn
  • Infant, Newborn, Diseases / genetics
  • Infant, Newborn, Diseases / physiopathology
  • Maternal Inheritance
  • Pedigree
  • Pregnancy
  • Protein-Arginine Deiminase Type 6
  • Protein-Arginine Deiminases / genetics*
  • Silver-Russell Syndrome / genetics*
  • Silver-Russell Syndrome / physiopathology


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • NLRP2 protein, human
  • NLRP7 protein, human
  • PADI6 protein, human
  • Protein-Arginine Deiminase Type 6
  • Protein-Arginine Deiminases