Prenatal risk assessment of Xp21.1 duplication involving theDMDgene by optical genome mapping

Abstract

Structural variants (SVs) of unknown significance are great challenges for prenatal risk assessment, especially when involving dose-sensitive genes such asDMD. The pathogenicities of 5′-terminalDMDduplications in the database remain controversial. Four prenatal cases with Xp21.1 duplications were identified by routine prenatal genomic testing, encompassing the 5′-UTR to exons 1–2 in family 1 and family 2, and to exons 1–9 in family 3. The duplication in family 4 was non-contiguous covering the 5′-UTR to exon 1 and exons 3–7. All were traced to unaffected males in the family pedigrees. A new genome-wide approach of optical genome mapping was performed in families 1, 2, and 3 to delineate the breakpoints and orientation of the duplicated fragments. The extra copies were tandemly inserted into the upstream ofDMD, preserving the integrity of ORF from the second copy. The pathogenicities were thus reclassified as likely benign. Our data highlight the importance of structural delineation by optical genome mapping in prenatal risk assessment of incidentally identified SVs involvingDMDand other similar large dose-sensitive genes.