Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles

Abstract

Recurrent hydatidiform moles (RHM) are aberrant human pregnancies characterized by absence of, or abnormal, embryonic development, hydropic degeneration of chorionic villi, and hyperproliferation of the trophoblast. Biallelic mutations in two maternal-effect genes, NLRP7 and KHDC3L, underlie the causation of RHM in 60% of patients. We performed exome sequencing on a patient with six pregnancy losses, two miscarriages and four HM, and found no variants that affect the functions of the known genes. We found biallelic missense variants that affect conserved amino acids in PADI6 and segregate with the disease phenotype in the family. PADI6 is another maternal-effect gene and a member of the subcortical maternal complex that has been shown to have recessive variants that affect the gene function in four unrelated women with infertility who also experienced early embryonic arrest during preimplantation development after IVF. We demonstrated that PADI6 co-localizes with NLRP7 in human oocytes and preimplantation embryos and reviewed the morphology and genotypes of four products of conception from our patient. Our data expand the involvement of PADI6 to other forms of reproductive loss and highlight the commonality between infertility, miscarriages, and molar pregnancies, in some cases.

Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance

“…Human PADI6 variants have been associated with female infertility and hydatidiform mole [13,[16][17][18][19]. It is possible that the reproductive outcome is correlated with the severity of the PADI6 variants.…”

“…PADI6 is the only PAD for which no enzymatic activity has been detected in vitro [11]. Mouse and human studies demonstrate that PADI6 is highly expressed in oocytes and early embryos, where it colocalizes with the other components of the SCMC [12,13]. PADI6 is required for the formation of the oocyte lattices that are believed to work as ribosomal storage for early embryo [14].…”

Gene-based analyses of the maternal genome implicate maternal effect genes as risk factors for conotruncal heart defects

“…Although MEGs have not previously been implicated as potential maternal risk factors for CTDs, studies in model systems demonstrate that mutations in MEGs can have a range of consequences for offspring, including embryonic lethality, developmental delay, and congenital malformations [11][12][13]. Similarly, women carrying a MEG mutation (e.g., NLRP5, NLRP7, and PADI6) experience a range of reproductive outcomes, including hydatidiform moles, periods of infertility, reproductive loss, offspring with multi-locus imprinting disorders, and unaffected children [43][44][45][46]. Although somewhat anecdotal, it is of interest that one (of five) woman with an NLRP5 mutation, ascertained following the birth of a child with a multi-locus imprinting disorder, also had a child with an isolated (i.e., apparently non-syndromic) CHD (atrial septal and ventricular defects) [43].…”

Connecting links between genetic factors defining ovarian reserve and recurrent miscarriages

“…The maternal effect proteins can interact together to form a large multiprotein complex known as sub-cortical maternal complex (SCMC), which are uniquely expressed in oocytes and in early embryos. Studies conducted on mice model with mutations in genes encoding these maternally provided proteins and multi-component complexes showed impaired early embryonic development and hence leads to RM [94][95][96][97][98][99][100]. In a recent publication, the authors have identified human SCMC homologous genes (NLRP5, OOEP, TLE6, and KHDC3L) to be specifically expressed in the oocytes of human fetal ovaries and concluded that the human SCMC and its regulators may too have similar central role in early embryonic development.…”

“…Investigating these oocyte-specific genes can thus provide answer for many unresolved RM cases [101]. In this context, various oocyte-specific transcription factors like FIGLA, NOBOX, SOHLH1, and SOHLH2 have been found to regulate the expression of important MEG like PADI6, KHDC3L, NLRP gene family, Pou5f1 [97,[102][103][104][105][106][107][108][109]. The same oocytespecific transcriptional factors have been identified to have established role in controlling the expression of genes involved follicular development also [105][106][107][108][110][111][112].…”