Alterations in the frequency of trinucleotide repeat dynamic mutations in offspring conceived through assisted reproductive technology

• Published in: Human reproduction (Oxford) 2013-09, Vol.28 (9), p.2570-2580
• Main Authors: Zheng, Ying-Ming, Li, Li, Zhou, Li-Ming, Le, Fang, Cai, Li-Yi, Yu, Ping, Zhu, Yu-Rong, Liu, Xiao-Zhen, Wang, Li-Ya, Li, Le-Jun, Lou, Yi-Yun, Xu, Xiang-Rong, Lou, Hang-Ying, Zhu, Xiao-Ming, Sheng, Jian-Zhong, Huang, He-Feng, Jin, Fan
• Format: Article
• Language: English
• Subjects: Alleles; China; Chromosome Aberrations; Female; Fertilization in Vitro - adverse effects; Fetal Blood; Gene Frequency; Genomic Instability; Hospitals, Teaching; Humans; Infant, Newborn; Infertility, Female - blood; Infertility, Female - therapy; Infertility, Male - blood; Male; Mutation; Parents; Sperm Injections, Intracytoplasmic - adverse effects; Tertiary Care Centers; Trinucleotide Repeats
• ISSN: 0268-1161; 1460-2350
• DOI: 10.1093/humrep/det294

STUDY QUESTION How does the frequency of trinucleotide repeat dynamic mutations in offspring conceived through assisted reproductive technology (ART) compare with the frequency of these mutations in control offspring conceived from spontaneous pregnancies? SUMMARY ANSWER There is a slight increase in dynamic mutation instability in offspring conceived through ART compared with the naturally conceived offspring. WHAT IS KNOWN ALREADY There is evidence to suggest that ART can increase the risk of birth defects and karyotypic abnormalities. However, the accumulating evidence of an association between ART and de novo genetic aberrations is controversial. STUDY DESIGN, SIZE, DURATION A prospective clinical observational study was performed on 246 families recruited from an in vitro fertilisation (IVF) centre at a tertiary-care, university-affiliated teaching hospital from 2008 to 2012. The study included 147 ART families [75 IVF and 72 intracytoplasmic sperm injection (ICSI)] in the study group and 99 natural-conception families in the control group. PARTICIPANTS, SETTING, METHODS Parental, umbilical cord and infant peripheral blood samples were collected, and the trinucleotide repeats of the ATN1, AR, ATXN1, ATXN3, Huntington, DMPK and FMR-1 genes were investigated between the generations; these genes were chosen due to their ability to undergo dynamic mutation. The frequencies and sizes of the mutational repeats, as well as the intergenerational instability, were measured. MAIN RESULTS AND THE ROLE OF CHANCE In 2466 transmissions identified in the ART offspring, 2.11% (n = 52/2466) of the alleles were unstable upon transmission, while in the control group offspring, the frequency of dynamic mutation was 0.77% (n = 10/1300); this difference was statistically significant (P < 0.01). The unstable transmission alleles were detected in 32 (2.48%) of the 1288 alleles from the IVF offspring and in 20 (1.70%) of the 1178 alleles from the ICSI offspring; both of these frequencies were significantly different from that of naturally conceived offspring (0.77%) (P < 0.01 and P < 0.05, respectively). However, there were no significant differences in the sizes of the mutational repeats or in the rates of expansion or contraction among the three groups (P > 0.05). The repeat copy numbers of the examined genes were found to be within the normal ranges in all parents and infants. LIMITATIONS, REASONS FOR CAUTION One strength of our study is the relatively large sample size; w