Abstract
The molecular basis of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome remains largely unknown. Pathogenic variants in WNT4 and HNF1B have been confirmed in a small percent of individuals. A variety of copy number variants have been reported, but causal gene(s) remain to be identified. We hypothesized that rare structural variants (SVs) would be present in some individuals with MRKH, which could explain the genetic basis of the syndrome. Large molecular weight DNA was extracted from lymphoblastoid cells from 87 individuals with MRKH and available parents. Optical genome mapping (OGM) was performed to identify SVs, which were confirmed by another method (quantitative PCR, chromosomal microarray, karyotype, or fluorescent in situ hybridization) when possible. Thirty-four SVs that overlapped coding regions of genes with potential involvement in MRKH were identified, 14 of which were confirmed by a second method. These 14 SVs were present in 17/87 (19.5%) of probands with MRKH and included seven deletions, three duplications, one new translocation in 5/50 cells—t(7;14)(q32;q32), confirmation of a previously identified translocation—t(3;16)(p22.3;p13.3), and two aneuploidies. Of interest, three cases of mosaicism (3.4% of probands) were identified—25% mosaicism for trisomy 12, 45,X(75%)/46,XX (25%), and 10% mosaicism for a 7;14 translocation. Our study constitutes the first systematic investigation of SVs by OGM in individuals with MRKH. We propose that OGM is a promising method that enables a comprehensive investigation of a variety of SVs in a single assay including cryptic translocations and mosaic aneuploidies. These observations suggest that mosaicism could play a role in the genesis of MRKH.
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Data availability
The datasets generated during and analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We would like to acknowledge Dr. James Knight at the Yale Center for Genome Analysis Bioinformatics Core.
Funding
This work was funded by Combined Intramural Grant Program at MCG/AU (S. Brakta) and NICHD 1R01 HD092505 (L.C. Layman).
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All authors contributed to this manuscript. The study was funded by SB and LL. Samples were collected and lymphoblastoid cells were grown for DNA extraction by ZH and LC. Optical genome mapping was performed by NS and RK. Confirmation of selected variants and analysis of data was performed by SB, ZH, NS, DK, H-GK, LC, JP, RK, LL. Statistical analysis was performed by HX. The manuscript was written by SB and LL, but all authors read and approved the final manuscript.
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Ravindra Kolhe has received honoraria, and/or travel funding, and/or research support from Illumina, Asuragen, QIAGEN, Perkin Elmer Inc, Bionano Genomics, Agena, Agendia, PGDx, Thermo Fisher Scientific, Cepheid, and BMS. Nikhil Sahajpal owns limited number of personal stocks of Bionano Genomics Inc. However, no members of Bionano were involved in this study. The rest of the authors have no relevant financial or non-financial interests to disclose.
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Brakta, S., Hawkins, Z.A., Sahajpal, N. et al. Rare structural variants, aneuploidies, and mosaicism in individuals with Mullerian aplasia detected by optical genome mapping. Hum Genet 142, 483–494 (2023). https://doi.org/10.1007/s00439-023-02522-8
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DOI: https://doi.org/10.1007/s00439-023-02522-8