Incidental finding of maternal sex chromosome aneuploidy from DMD carrier screening and single‐nucleotide polymorphism (SNP)‐based prenatal cell‐free DNA screening

Abstract Prenatal cell‐free DNA (cfDNA) screening and carrier screening (CS) may have incidental findings that have implications for maternal health outside the scope of the test. We investigated outcome information for individuals with both a DMD full gene deletion/duplication on CS and a suspected maternal X chromosome abnormality on SNP‐based prenatal cfDNA screening. This retrospective analysis included de‐identified data from pregnant individuals referred for CS and prenatal cfDNA screening at a single reference laboratory (9/2019–12/2021). Maternal karyotype and/or chromosomal microarray analysis results were requested from referring clinics for individuals with both DMD full gene deletion/duplication on CS and prenatal cfDNA screening results indicating potential maternal X chromosome aneuploidy. Of 333,814 individuals screened, 144 (1 in 2318) met study criteria, and for 84 (58.3%) we obtained information on whether diagnostic testing was received following these results. Of the 84 patients with follow‐up information available, 34 (40.5%) received maternal diagnostic testing based on karyotype or chromosomal microarray analysis. At 97% ( n = 33), the majority of patients with diagnostic testing had X chromosome aneuploidies, including trisomy X ( n = 22, 64.7%), monosomy X mosaicism ( n = 8, 24.2%), monosomy X ( n = 2, 6.1%), and maternal X chromosome structural abnormality ( n = 1, 2.9%). Our study supports a high likelihood of maternal sex chromosome abnormality in the presence of an inconclusive DMD result on CS and prenatal cfDNA screening suspicious for a maternal sex chromosome abnormality. Given the implications for maternal health, follow‐up counseling, karyotype, and chromosomal microarray analysis may be recommended.