Diagnostic utility of novel combined arrays for genome-wide simultaneous detection of aneuploidy and uniparental isodisomy in losses of pregnancy

Abstract

BackgroundThis proof-of-principle study demonstrates the usefulness and robustness of a novel array based method for the elucidation of genetic causes underlying early pregnancy loss. A combined microarray utilizing comparative genomic hybridization and single nucleotide polymorphism detection (CGH + SNP) was used for parallel genome-wide identification of copy number and heterozygosity status of 70 products of conception. Results of samples with previously determined aneuploidies were juxtaposed to those of a second cohort appearing normal after routine genetic diagnostics.ResultsAll chromosomal imbalances were confirmed, in one sample of the aneuploid panel additional monosomy X was discovered. Genome-wide uniparental disomy causing a complete hydatidiform mole was identified in another sample. No specimen featured microaberrations of obvious clinical relevance. Among cases with presumable euploidy, one microdeletion and a single region of homozygosity were assigned unclear clinical significance.ConclusionsThe results prove the utility of combined imbalance and homozygosity mapping for routine workup of these challenging specimens. Moreover parallel screening at submicroscopic resolution facilitates the detection of novel genetic alterations underlying spontaneous abortion.

Clinical application of SNP array analysis in first‐trimester pregnancy loss: a prospective study

“…This technology can detect aneuploidy, polyploidy, microdeletion/microduplication and loss of heterozygosity (LOH) at the genome-wide level, and has been applied as the first-tier test in most pediatric and prenatal genetic diagnosis. CMA is increasingly being applied for analysis of miscarriage specimens (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). However, most CMA studies have been performed retrospectively, with the exception of a few small prospective studies (10,16).…”

Traditional and molecular chromosomal abnormality analysis of products of conception in spontaneous and recurrent miscarriage

“…A summary of studies on the accuracy of aCGH compared with conventional karyotyping of POC samples from miscarriages is shown in Table S5 . The pooled failure rate of aCGH was only 2.7% (95% CI 0.0–9.0%), much lower than in conventional karyotyping.…”

“…A summary of studies on the accuracy of aCGH compared with conventional karyotyping of POC samples from miscarriages is shown in Table S5. 5,[29][30][31][32] The pooled failure rate of aCGH was only 2.7% (95% CI 0.0-9.0%), much lower than in conventional karyotyping. Approximately 9% of all abnormalities were missed by karyotyping, but they were detected by aCGH.…”

First trimester pregnancy loss: Clinical implications of genetic testing

“…In around 5% of miscarriages, sub‐microscopic abnormalities missed by conventional karyotyping were detected by array‐CGH . However, the clinical significance of some of these abnormalities is unknown, while others may be benign, making the interpretation of the results challenging . Furthermore, female polyploidies, tetraploidies and balanced changes remain undetected and other methods are needed (e.g.…”

“…45 However, the clinical significance of some of these abnormalities is unknown, while others may be benign, making the interpretation of the results challenging. 46 Furthermore, female polyploidies, tetraploidies and balanced changes remain undetected and other methods are needed (e.g. flow cytometry for polyploidy detection).…”