[Application of optical genome mapping technology in the genetic diagnosis of a family with a cryptic complex chromosomal balanced translocations].

OBJECTIVES: For couples with recurrent adverse pregnancy outcomes but normal results on conventional karyotype analysis, the underlying genetic causes (such as cryptic chromosomal balanced translocations) are difficult to identify using traditional methods. These complex structure variations are often missed due to resolution limitations, posing a major challenge in clinical genetic diagnosis. This study aims to perform genetic etiological diagnosis and provide reproductive guidance for a couple with two abnormal reproductive histories, and to evaluate the application value of optical genome mapping (OGM) in the field of reproductive genetics.

METHODS: Clinical data were collected from a couple who attended the Reproductive Medicine Center, First Hospital of Lanzhou University, with two consecutive adverse pregnancy outcomes and seeking genetic diagnosis. Previous results from ultrasonography, chromosomal karyotyping, copy number variation sequencing (CNV-seq), and fluorescence in situ hybridization (FISH) were reviewed. OGM was further performed on peripheral blood samples from both partners to conduct high-resolution, genome-wide structural variation analysis, in order to assess the clinical utility of OGM in detecting cryptic chromosomal balanced translocations, particularly complex structure variations.

RESULTS: CNV-seq results from the 2 pregnancies showed del(4)(p16.3), 3.80 Mb, and dup(4)(p16.3), 3.74 Mb combined with del(22)(q13.31-q13.33), 4.64 Mb, respectively. Conventional chromosomal karyotyping of peripheral blood from both parents revealed no obvious abnormalities, suggesting the possibility of a cryptic chromosomal balanced translocation carrier. OGM analysis demonstrated that the male partner carried a cryptic complex balanced translocation involving chromosomes 1, 4, and 22. The breakpoints were located in regions consistent with the boundaries of the abnormal CNV segments identified in both fetuses. These findings confirmed that the male partner was a phenotypically normal carrier of a complex balanced translocation, and that the chromosomal abnormalities in both fetuses resulted from unbalanced segregation of derivative chromosomes during parental meiosis.

CONCLUSIONS: As a novel non-sequencing-based genomic technology characterized by high resolution, ultra-long read length, and automation, OGM is more efficient than traditional cytogenetic techniques in detecting cryptic balanced translocations.