Uniparental disomy (UPD) is defined as a condition in which both homologues of a chromosome are inherited from only one parent [1]. Maternal UPD (UPDmat) and paternal UPD (UPDpat) consist of two homologues derived from only the mother and only the father, respectively. Isodisomy refers to the inheritance of duplicated identical homologues from one parent, whereas heterodisomy refers to the inheritance of both non-identical homologues from one parent. UPD is caused by four mechanisms, namely, trisomy rescue (TR), gamete complementation (GC), monosomy rescue (MR), and post-fertilization mitotic error (PE) (Figure S1) [1]. TR-type and GC-type UPDs show heterodisomy, MR-type UPD shows full isodisomy, and PE-type UPD includes mosaic full isodisomy with normal cell lineage and segmental isodisomy. As shown in Figure S1, TR, GC, and MR types of UPDs are caused by aneuploid sperms or oocytes (aneuploid UPDs). Briefly, TR-type and GC-type UPDs are mediated by disomic oocytes in UPDmat and disomic sperms in UPDpat (Figure S1). MR-type UPD is mediated by nullisomic oocytes in UPDpat and nullisomic sperms in UPDmat (Figure S1). In this regard, TR-type and GC-type UPDmat and MR-type UPDpat are considered as aneuploid oocyte-mediated UPDs, whereas TR-type and GC-type UPDpat and MR-type UPDmat are considered as aneuploid sperm-mediated UPDs.
Imprinting disorders (IDs) are clinical syndromes caused by abnormal expression of the imprinted genes, which express in parental origin specific manner [2]. The etiologies of IDs include pathogenic variants in causative genes, structural abnormalities affecting the imprinted regions, UPD of chromosomes having imprinted genes, and aberrant methylation of the disease-responsible differential methylated regions (DMRs), i.e., epimutation [2]. The relative frequency of UPD differs among IDs (Table S1). UPD is the most frequent genetic cause of several IDs, such as transient neonatal diabetes mellitus caused by UPDpat of chromosome 6, Temple syndrome caused by UPDmat of chromosome 14 (UPD(14)mat), and Kagami-Ogata syndrome caused by UPDpat of chromosome 14 (UPD(14)pat) (Table S1).
Advanced maternal age at childbirth (≥ 35 years) is known to be a risk factor for the development of aneuploid oocytes due to chromosome segregation errors during meiosis, in particular, meiosis 1 (M1) [3, 4]. Consistent with this, several studies have shown advanced maternal age in patients with TR-type or GC-type UPDmat [5, 6] and MR-type UPD(14)pat [7] mediated by disomic and nullisomic oocytes, respectively. In addition, Nakka et al. reported that mothers of patients with UPDmat were significantly older than those of non-UPD individuals, based on the database consisting of four million individuals from the general population [8]. However, the effect of advanced paternal age on the development of aneuploid sperm and UPDpat remains to be elucidated.
Assisted reproductive technology (ART), including controlled ovarian stimulations (COS), in vitro maturation and cryopreservation of oocytes, in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), embryo culture, and embryo transfer may affect the epigenetic modification at the imprinted region during gametogenesis and embryonic development in the preimplantation stage [9]. Therefore, ART has been considered as a risk factor for the development of IDs, particularly epimutation-mediated IDs (epi-IDs). Several studies, including IDs with all genetic causes (UPD, structural abnormalities, epimutation, and variants in causative genes), showed that the frequency of ART-conceived livebirths was higher in patients with Beckwith-Wiedemann syndrome (BWS), Silver-Russell syndrome (SRS), Angelman syndrome (AS), and Prader-Willi syndrome (PWS) than in the general population [10, 11]. In our previous study focused on epi-IDs, we demonstrated that ART can be a risk factor for the development of epi-IDs, particularly BWS and SRS, in mothers aged over 30 years [12]. However, it remains controversial whether ART increases the risk for the development of aneuploid gametes and aneuploid UPD in zygotes. COS, particularly using high-dose gonadotropins, has been reported to increase the frequency of oocyte aneuploidy because of stimulated meiotic progression that leads to segregation errors [13, 14]. On the contrary, a recent retrospective study in Chinese women using anonymized data on preimplantation genetic screening for blastocysts found that gonadotropin dosage is not associated with embryonic aneuploidy [15]. In addition, molecular cytogenic analysis of early spontaneous abortions revealed that IVF and ICSI did not enhance aneuploidy rate [16]. Although a previous study assessed the risk of ART focusing on PWS due to UPDmat of chromosome 15 (UPD(15)mat) [17], there was no study which evaluated the effect of ART on the development of various aneuploid UPD-mediated IDs. Moreover, the confounding effect of advanced parental age at childbirth remains to be elucidated.
To clarify whether ART or advanced parental age at childbirth facilitates the development of aneuploid UPD-mediated IDs (UPD-IDs), we compared (1) the proportion of ART-conceived livebirths and the distribution of maternal childbearing age between patients with aneuploid UPD-IDs and that of the general population or patients with epi-IDs by utilizing previous data from our cross-sectional study [12], and (2) the proportion of ART-conceived livebirths and parental ages at childbirth between patients with UPD-IDs caused by aneuploid oocytes and those with UPD-IDs caused by aneuploid sperms.