Risk assessment of assisted reproductive technology and parental age at childbirth for the development of uniparental disomy-mediated imprinting disorders caused by aneuploid gametes

Kaori Hara-Isono; Keiko Matsubara; Akie Nakamura; Shinichiro Sano; Takanobu Inoue; Sayaka Kawashima; Tomoko Fuke; Kazuki Yamazawa; Maki Fukami; Tsutomu Ogata; Masayo Kagami

doi:10.1186/s13148-023-01494-w

Risk assessment of assisted reproductive technology and parental age at childbirth for the development of uniparental disomy-mediated imprinting disorders caused by aneuploid gametes

Clin Epigenetics. 2023 May 6;15(1):78. doi: 10.1186/s13148-023-01494-w.

Authors

Kaori Hara-Isono^{1

2}, Keiko Matsubara¹, Akie Nakamura^{1

3}, Shinichiro Sano^{1

4}, Takanobu Inoue¹, Sayaka Kawashima¹, Tomoko Fuke¹, Kazuki Yamazawa^{1

5}, Maki Fukami¹, Tsutomu Ogata^{1

6

7}, Masayo Kagami⁸

Affiliations

¹ Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-Ku, Tokyo, 157-8535, Japan.
² Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan.
³ Department of Pediatrics, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-Ku, Sapporo, 060-8648, Japan.
⁴ Department of Endocrinology and Metabolism, Shizuoka Children's Hospital, 860 Urushiyama, Aoi-Ku, Shizuoka, 420-8660, Japan.
⁵ Medical Genetics Center, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-Ku, Tokyo, 152-8902, Japan.
⁶ Department of Biochemistry, Hamamatsu University School of Medicine, 1‑20‑1 Handayama, Higashi‑ku, Hamamatsu, 431‑3192, Japan.
⁷ Department of Pediatrics, Hamamatsu Medical Center, 328 Tomizuka Cho, Naka-Ku, Hamamatsu, 432-8580, Japan.
⁸ Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-Ku, Tokyo, 157-8535, Japan. kagami-ms@ncchd.go.jp.

Abstract

Background: Our previous study suggested that assisted reproductive technology (ART) may be a possible risk factor for the development of epimutation-mediated imprinting disorders (epi-IDs) for mothers aged ≥ 30 years. However, whether ART or advanced parental age facilitates the development of uniparental disomy-mediated IDs (UPD-IDs) has not yet been investigated.

Results: We enrolled 130 patients with aneuploid UPD-IDs including various IDs confirmed by molecular studies and obtained ART data of the general population and patients with epi-IDs from a robust nationwide database and our previous report, respectively. We compared the proportion of ART-conceived livebirths and maternal childbearing age between patients with UPD-IDs and the general population or patients with epi-IDs. The proportion of ART-conceived livebirths in patients with aneuploid UPD-IDs was consistent with that in the general population of maternal age ≥ 30 years and was lower than that in the patients with epi-IDs, although there was no significant difference. The maternal childbearing age of patients with aneuploid UPD-IDs was skewed to the increased ages with several cases exceeding the 97.5th percentile of maternal childbearing age of the general population and significantly higher than that of patients with epi-IDs (P < 0.001). In addition, we compared the proportion of ART-conceived livebirths and parental age at childbirth between patients with UPD-IDs caused by aneuploid oocytes (oUPD-IDs) and that by aneuploid sperm (sUPD-IDs). Almost all ART-conceived livebirths were identified in patients with oUPD-IDs, and both maternal age and paternal age at childbirth were significantly higher in patients with oUPD-IDs than in patients with sUPD-IDs. Because maternal age and paternal age were strongly correlated (r_s = 0.637, P < 0.001), higher paternal age in oUPD-IDs was explained by the higher maternal age in this group.

Conclusions: Different from the case of epi-IDs, ART itself is not likely to facilitate the development of aneuploid UPD-IDs. We demonstrated that advanced maternal age can be a risk factor for the development of aneuploid UPD-IDs, particularly oUPD-IDs.

Keywords: Assisted reproductive technology; Imprinting disorders; Maternal age; Risk factors; Uniparental disomy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aneuploidy
DNA Methylation
Female
Genomic Imprinting*
Humans
Male
Mothers
Oocytes
Pregnancy
Reproductive Techniques, Assisted / adverse effects
Risk Assessment
Semen
Uniparental Disomy* / genetics