Optical genome mapping identifies cryptic balanced chromosomal rearrangements in karyotypically normal couples with recurrent pregnancy loss or adverse pregnancy history.

Cryptic balanced translocations below karyotype resolution, detected by optical genome mapping

Recurrent pregnancy loss affects 1% to 2% of reproductive-aged couples, with chromosomal abnormalities accounting for 40% to 60% of cases, yet balanced translocations with fragments smaller than karyotype resolution are often missed. The authors used results from 586 families who underwent preimplantation genetic testing for aneuploidy for recurrent pregnancy loss or adverse pregnancy history, and validated by optical genome mapping the cryptic balanced translocations undetectable by conventional karyotyping. The prevalence of these cryptic translocations was 1.19% in the cohort (7 of 586, 95% CI 0.58% to 2.45%). The method also resolved a complex chromosomal rearrangement involving four chromosomes and six breakpoints, and elucidated the genetic basis of two exome-negative monogenic disorders by demonstrating pathogenic disruptions of EXT1 and PITX2. The authors propose the technique as a second-line test after karyotyping and CNV-seq, since detecting a rearrangement switches management from preimplantation testing for aneuploidy to testing for structural rearrangements.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Seven couples out of 586, or 1.19%, looks small, but each of them was pursuing an inappropriate assisted reproduction strategy — the individual benefit is major even if overall yield is low. The paper's strongest argument lies elsewhere: two monogenic diagnoses recovered after a negative exome through disruption of EXT1 and PITX2, a reminder that balanced structural rearrangements are the blind spot of short-read sequencing. The cost per additional diagnosis still needs to be quantified before recommending this strategy in routine practice.

Analysis by Dr Thibaut Benquey