BACKGROUND AND PURPOSE:

• Chromosomal abnormalities are the most common cause of early pregnancy loss but role of submicroscopic copy-number variations (CNVs) remains unclear
• Wang et al. (Ultrasound in Obstetrics & Gynecology, 2019) sought to identify potential miscarriage-associated submicroscopic CNVs as well as candidate genes for miscarriage

METHODS:

• Study design
  • Over a 5-year period, fresh miscarriage specimens were analyzed using
    • Quantitative fluorescent polymerase chain reaction (qfPCR) and sequencing
    • Chromosomal microarray analysis
• Frequency of recurrent submicroscopic CNVs were compared between miscarriage cases and a published control cohort
• Potential candidate genes
  • Genes were prioritized based on whether miscarriage-associated CNVs disrupted critical gene regions

RESULTS:

• 5,180 miscarriage specimens obtained | 5,003 (96.6%) did not have significant maternal-cell contamination
  • Clinically significant chromosomal abnormalities were identified in 59.1%
    • Single aneuploidies accounted for majority of these cases (43.6%) with trisomies accounting for the biggest group  
    • Partial aneuploidies (large CNVs) were noted in 3.8% of cases
    • Microdeletions and microduplications were seen in 2.7%
  • Of these abnormal cases, 97.4% could have been detected using standard G-banding cytogenetic technique (size of abnormality >10 Mb)
• 3 recurrent submicroscopic (<10 Mb) CNVs were significantly more frequent in miscarriage cases
  • 22q11.21 | 2q37.3 | 9p24.3p24.2
• 44 critical regions of large CNVs (14 deletions and 30 duplications) appeared to recur in the miscarriage specimens
  • Large deletions were seen most commonly in chromosomes 8, 4 and 1
  • Large duplications were seen most commonly in chromosomes 8, 7 and 11
• Candidate genes: 309 genes were identified as possible miscarriage related genes based on gene-prioritization analysis

CONCLUSION:

• The authors of this study identified potential genes and CNVs associated with miscarriage
• Due to new technologies, the authors stress the importance of continuing to analyze CNVs in the study of miscarriage
• The authors state that

22q11.21 microdeletion is a miscarriage‐causing locus, and that early embryonic death could be caused by major heart malformations resulting from the 22q11.21 deletion.

Learn More – Primary Sources:

Systematic analysis of copy‐number variations associated with early pregnancy loss

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