Analysis of chromosome microstructures in products of conception associated with recurrent miscarriage

Research question: The causes of almost half of all miscarriages are unknown. Genetic alterations undetectable by conventional methods may cause some cases of recurrent miscarriage. The study aimed to identify candidate genetic alterations associated with recurrent miscarriage. Design: Twenty-nine Japanese women with a history of recurrent miscarriage without any known underlying anatomical or medical causes were recruited. The products of conception were collected after miscarriage and showed either a normal karyotype or a failure of complete chromosomal Giemsa banding. Genomic DNA from the chorionic villi of the conception products was analysed using genome-wide single-nucleotide polymorphism (SNP) arrays. Results: In four cases, the products could not be analysed because of contaminating maternal-origin DNA, and chromosomal aneuploidies were observed in 10 cases. Thirty-three copy-number variations (CNV) were identified from the array data of 15 diploid cases. Causative CNV were identified by comparison with CNV observed in healthy, parous Japanese women. Twenty-four chromosomal regions with 26 CNV were identified as strong candidates for causing recurrent miscarriage, and these were all too small to detect by conventional chromosome analysis banding. Moreover, one novel CNV that caused complete deletion of a microRNA cluster region was detected. Conclusions: High-resolution genome-wide SNP arrays are effective for detecting novel genetic factors causing recurrent miscarriage. A more appropriate reference CNV list may be necessary to more effectively enrich for CNV likely to cause recurrent miscarriage. The findings confirmed one non-coding RNA cluster as a strong candidate that may contribute to unexplained miscarriages. Gene expression-regulatory mechanisms may play important roles in the pathogenesis of miscarriages.