Parthenogenetic mosaicism: generation via second polar body retention and unmasking of a likely causative PER2 variant for hypersomnia

Yohei Masunaga,Takeshi Usui,Hirotomo Saitsu,Kazushi Aoto,Masayo Kagami,Maki Fukami,Fumiko Kato,Kazuo Mishima,Tsutomu Ogata,Takako Yonemoto

doi:10.1186/s13148-021-01062-0

Abstract

BackgroundParthenogenetic mosaicism is an extremely rare condition identified only in five subjects to date. The previous studies indicate that this condition is mediated by parthenogenetic activation and is free from a specific phenotype ascribed to unmaking of a maternally inherited recessive variant in the parthenogenetic cell lineage.ResultsWe examined a 28-year-old Japanese 46,XX female with Silver-Russell syndrome and idiopathic hypersomnia. The results revealed (1) predominance of maternally derived alleles for all the differentially methylated regions examined; (2) no disease-related copy-number variant; (3) two types of regions for all chromosomes, i.e., four BAF (B-allele frequency) band regions with single major microsatellite peaks of maternal origin and single minor microsatellite peaks of non-maternal (paternal) origin, and six BAF band regions with single major microsatellite peaks of maternal origin and two minor microsatellite peaks of maternal and non-maternal (paternal) origin; (4) an unmasked extremely rare PER2 variant (c.1403G>A:p.(Arg468Gln)) with high predicted pathogenicity; (5) mildly affected local structure with altered hydrogen bonds of the p.Arg468Gln-PER2 protein; and (6) nucleus-dominant subcellular distribution of the p.Arg468Gln-PER2 protein.ConclusionsThe above findings imply that the second polar body retention occurred around fertilization, resulting in the generation of the parthenogenetic cell lineage by endoreplication of a female pronucleus and the normal cell lineage by fusion of male and female pronuclei, and that the homozygous PER2 variant in the parthenogenetic cells is the likely causative factor for idiopathic hypersomnia.

Highlights

Parthenogenetic mosaicism is an extremely rare condition identified only in five subjects to date
It is inferred that the second polar retention occurred around the time of fertilization, resulting in the generation of the parthenogenetic cell lineage by endoreplication of a female pronucleus and the normal cell lineage by fusion of male and female pronuclei (Fig. 1e) [6]
Period circadian regulator 2 (PER2) is present on the four B allele frequency (BAF) band region, and the observed frequencies of the VT and WT alleles in PER2 are similar to the predicted frequencies of the VT and WT alleles in a gene on the four BAF band regions. e Protein modelling analysis

Summary

Introduction

Parthenogenetic mosaicism is an extremely rare condition identified only in five subjects to date. Other mechanisms such as retention of second polar body and failure of the paternal pronucleus to duplicate, followed by endoreplication of a female pronucleus and fusion of biparentally derived pronuclei, have been assumed [6], there is no report describing such generation mechanisms While such patients frequently exhibit growth failure with some Silver-Russell syndrome (SRS) features [2,3,4,5,6], no specific phenotype ascribed to unmasking of a recessive pathogenic variant(s) of maternal origin in the parthenogenetic cell lineage has been described, probably due to the buffering effect of a co-existing paternally derived wildtype (WT) allele or the absence of such a variant(s) in the previously reported patients.

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Conclusion