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Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance.
- Source :
-
Clinical epigenetics [Clin Epigenetics] 2020 Sep 14; Vol. 12 (1), pp. 139. Date of Electronic Publication: 2020 Sep 14. - Publication Year :
- 2020
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Abstract
- Background: PADI6 is a component of the subcortical maternal complex, a group of proteins that is abundantly expressed in the oocyte cytoplasm, but is required for the correct development of early embryo. Maternal-effect variants of the subcortical maternal complex proteins are associated with heterogeneous diseases, including female infertility, hydatidiform mole, and imprinting disorders with multi-locus imprinting disturbance. While the involvement of PADI6 in infertility is well demonstrated, its role in imprinting disorders is less well established.<br />Results: We have identified by whole-exome sequencing analysis four cases of Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance whose mothers are carriers of PADI6 variants. In silico analysis indicates that these variants result in loss of function, and segregation analysis suggests they act as either recessive or dominant-negative maternal-effect mutations. Genome-wide methylation analysis revealed heterogeneous and extensively altered methylation profiles of imprinted loci in the patients, including two affected sisters, but not in their healthy siblings.<br />Conclusion: Our results firmly establish the role of PADI6 in imprinting disorders. We report loss-of-function maternal-effect variants of PADI6 that are associated with heterogeneous multi-locus imprinting disturbances in the progeny. The rare finding of two siblings affected by Beckwith-Wiedemann syndrome suggests that in some cases, familial recurrence risk of these variants may be high. However, the heterogeneous phenotypes of the other pedigrees suggest that altered oocyte PADI6 function results in stochastic maintenance of methylation imprinting with unpredictable consequences on early embryo health.
- Subjects :
- Adolescent
Adult
Beckwith-Wiedemann Syndrome diagnosis
Child, Preschool
Female
Genomic Imprinting genetics
Heterozygote
Humans
Hydatidiform Mole epidemiology
Hydatidiform Mole genetics
Infant
Infertility, Female epidemiology
Infertility, Female genetics
Male
Mutation
Oocytes metabolism
Pedigree
Phenotype
Pregnancy
Siblings
Exome Sequencing methods
Beckwith-Wiedemann Syndrome genetics
DNA Methylation genetics
Maternal Inheritance genetics
Protein-Arginine Deiminase Type 6 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1868-7083
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Clinical epigenetics
- Publication Type :
- Academic Journal
- Accession number :
- 32928291
- Full Text :
- https://doi.org/10.1186/s13148-020-00925-2