title: Alterations in the frequency of trinucleotide repeat dynamic mutations in offspring conceived through assisted reproductive technology.
abstract: OBJECTIVE
  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?
  
  
  CONCLUSIONS
  There is a slight increase in dynamic mutation instability in offspring conceived through ART compared with the naturally conceived offspring.
  
  
  BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  One strength of our study is the relatively large sample size; we were able to detect mutations in seven common dynamic genes, and this large sample size allowed us to detect unstable alleles. Although we observed a clear alteration in the frequency of dynamic mutation in the ART offspring compared with controls, further studies are urgently needed to confirm this observation and determine the cause of this phenomenon.
  
  
  CONCLUSIONS
  DNA microsatellite analysis provides an important tool to assess genomic instability. In this study, we report an association between ART and the frequency of dynamic mutation. The instability could be a reflection of the core infertility problem, the controlled ovarian hyperstimulation and/or the in vitro culture conditions.
authors.affiliation: Department of Reproductive Endocrinology, Zhejiang University School of Medicine, Zhejiang, China.
authors.forename: Ying-Ming
authors.initials: YM
authors.lastname: Zheng
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Zhou
authors.forename: Fang
authors.initials: F
authors.lastname: Le
authors.forename: Li-Yi
authors.initials: LY
authors.lastname: Cai
authors.forename: Ping
authors.initials: P
authors.lastname: Yu
authors.forename: Yu-Rong
authors.initials: YR
authors.lastname: Zhu
authors.forename: Xiao-Zhen
authors.initials: XZ
authors.lastname: Liu
authors.forename: Li-Ya
authors.initials: LY
authors.lastname: Wang
authors.forename: Le-Jun
authors.initials: LJ
authors.lastname: Li
authors.forename: Yi-Yun
authors.initials: YY
authors.lastname: Lou
authors.forename: Xiang-Rong
authors.initials: XR
authors.lastname: Xu
authors.forename: Hang-Ying
authors.initials: HY
authors.lastname: Lou
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Zhu
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Sheng
authors.forename: He-Feng
authors.initials: HF
authors.lastname: Huang
authors.forename: Fan
authors.initials: F
authors.lastname: Jin
mesh_terms: D000483:Alleles; D002681:China; D002869:Chromosome Aberrations; D005260:Female; D005307:Fertilization in Vitro / Q000009:adverse effects*; D005312:Fetal Blood; D005787:Gene Frequency; D042822:Genomic Instability; D006784:Hospitals, Teaching; D006801:Humans; D007231:Infant, Newborn; D007247:Infertility, Female / Q000097:blood / Q000628:therapy; D007248:Infertility, Male / Q000097:blood; D008297:Male; D009154:Mutation; D010290:Parents; D020554:Sperm Injections, Intracytoplasmic / Q000009:adverse effects; D062606:Tertiary Care Centers; D018911:Trinucleotide Repeats
keywords: assisted reproductive technology; dynamic mutation; offspring; trinucleotide repeat