Mol. Hum. Reprod. Advance Access published online on September 23, 2009
Molecular Human Reproduction, doi:10.1093/molehr/gap083
Genomic changes detected by array CGH in human embryos with developmental defects
1Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Child & Family Research Institute, 4480 Oak Street, Vancouver, British Columbia, V6H 3V4, Canada 2Department of Medical Genetics, UBC, Vancouver, V5Z 4H4, BC, Canada 3Cytogenetic Lab, Royal Columbian Hospital, 330 East Columbia Street, New Westminster, BC, V3L 3W7 4Department of Obstetrics and Gynecology, University of Chicago, 5841 S. Maryland Avenue (MC 2050), Chicago, IL, 60637, USA 5Ludwig Boltzmann Institute for Clinical Obstetrics and Gynecology, Donauspital im SMZ-Ost, Vienna, Austria
Corresponding author Dr Evica Rajcan-Separovic, Child & Family Research Institute, Molecular Cytogenetics and Array Lab, Room 3060 and 277, 950 West 28th Avenue, Vancouver, British Columbia, V5Z 4H4, Canada, email: eseparovic{at}cw.bc.ca phone: 604-875-3121, fax: 604-875-3601
Developmental abnormalities of human embryos can be visualized in utero using embryoscopy. Our previous embryoscopic and genetic evaluations detected developmental abnormalities in the majority of both euploid (74%) and aneuploid or polyploid (90%) miscarriages. Since we found the pattern of morphological changes to be similar in euploid and noneuploid embryos, we proposed that lethal submicroscopic changes, not detected by standard chromosome testing, may be responsible for miscarriage of euploid embryos. Whole genome oligo and bacterial artificial chromosome (BAC) array comparative genome hybridization ( CGH) was used to screen for submicroscopic chromosomal changes (DNA copy number variants or CNVs) in 17 euploid embryonic miscarriages, with a range of developmental abnormalities documented by embryoscopy. The CNV breakpoints were refined using a custom array (Agilent) with a high resolution coverage of the CNVs. Six unique CNVs, previously not reported, were identified in 5 of the 17 embryos (29% of all cases or 50% of cases studied with higher resolution arrays). All 6 unique CNVs were less than 250kb in size. Based on parental array CGH analysis, a de novo origin of a CNV was determined for one embryo (at 13q32.1) and suspected for another (at 10p15.3). Three CNVs, at Xq28, 1q25.3 and 7p14.3, were inherited and a CNV at 17p13.1 was of unknown origin. The genes contained within these unique CNVs will be discussed, with specific reference to rearrangements of syntaxin and tryptophan-aspartic acid (WD) repeat genes. Our report describes for the first time, de novo and inherited unique CNVs in euploid human embryos with specific developmental defects.
Key Words: Miscarriages/DNA copy number variants (CNVs)/array comparative genomic hybridization (array CGH)/embryonic developmental defects/embryoscopy
Submitted on May 25, 2009; resubmitted on August 22, 2009; accepted on September 22, 2009.