Experiences With Detection of Higher‐Copy Sex Chromosome Aneuploidy by <scp>cfDNA</scp> Screening: The Critical Role of Diagnostic Testing

Noninvasive prenatal cell-free DNA (cfDNA) screening is standard of care for detecting prenatal chromosomal aneuploidies. The positive predictive value of prenatal cfDNA screening is lower for sex chromosome aneuploidies (SCAs) compared to autosomal aneuploidies due to sex chromosome mosaicism and the potential for subclinical maternal sex chromosome aneuploidy. In some cases, these factors can result in indeterminate cfDNA results for SCAs. We present three cases which highlight higher-copy sex chromosome aneuploidies (HC SCAs; i.e., tetrasomy and pentasomy for the sex chromosomes) as one cause of an indeterminate sex chromosome prenatal cfDNA result. Timely diagnosis of HC SCAs enables informed pregnancy management and decision-making. Thus, these cases underscore the potential value of an indeterminate result by cfDNA screening and the importance of comprehensive genetic counseling and follow-up diagnostic testing when faced with indeterminate cfDNA results, particularly regarding the risk of HC SCAs.