Cell-free DNA screening positive for monosomy X: clinical evaluation and management of suspected maternal or fetal Turner syndrome.

Initially provided as an alternative to evaluation of serum analytes and nuchal translucency for the assessment of pregnancies at high risk of trisomy 21, cell-free DNA screening for fetal aneuploidy, also referred to as noninvasive prenatal screening, can now also screen for fetal sex chromosome anomalies such as monosomy X as early as 9 to 10 weeks of gestation. Early identification of Turner syndrome, a sex chromosome anomaly resulting from the complete or partial absence of the second X chromosome, allows medical interventions such as optimizing obstetrical outcomes, hormone replacement therapy, fertility preservation and support, and improved neurocognitive outcomes. However, cell-free DNA screening for sex chromosome anomalies and monosomy X in particular is associated with high false-positive rates and low positive predictive value. A cell-free DNA result positive for monosomy X may represent fetal Turner syndrome, maternal Turner syndrome, or confined placental mosaicism. A positive screen for monosomy X with discordant results of diagnostic fetal karyotype presents unique interpretation and management challenges because of potential implications for previously unrecognized maternal Turner syndrome. The current international consensus clinical practice guidelines for the care of individuals with Turner syndrome throughout the lifespan do not specifically address management of individuals with a cell-free DNA screen positive for monosomy X. This study aimed to provide context and expert-driven recommendations for maternal and/or fetal evaluation and management when cell-free DNA screening is positive for monosomy X. We highlight unique challenges of cell-free DNA screening that is incidentally positive for monosomy X, present recommendations for determining if the result is a true-positive, and discuss when diagnosis of Turner syndrome is applicable to the fetus vs the mother. Whereas we defer the subsequent management of confirmed Turner syndrome to the clinical practice guidelines, we highlight unique considerations for individuals initially identified through cell-free DNA screening.

Clinical utility and cost-effectiveness analysis of chromosome testing concomitant with chromosomal microarray of patients with constitutional disorders in a U.S. academic medical center.

Chromosomal microarray (CMA) is now widely used as first-tier testing for the detection of copy number variants (CNVs) and absence of heterozygosity (AOH) in patients with multiple congenital anomalies (MCA), autism spectrum disorder (ASD), developmental delay (DD), and/or intellectual disability (ID). Chromosome analysis is commonly used to complement CMA in the detection of balanced genomic aberrations. However, the cost-effectiveness and the impact on clinical management of chromosome analysis concomitant with CMA were not well studied, and there is no consensus on how to best utilize these two tests. To assess the clinical utility and cost-effectiveness of chromosome analysis concomitant with CMA in patients with MCA, ASD, DD, and/or ID, we retrospectively analyzed 3,360 postnatal cases for which CMA and concomitant chromosome analysis were performed in the Colorado Genetic Laboratory (CGL) at the University Of Colorado School Of Medicine. Chromosome analysis alone yielded a genetic diagnosis in two patients (0.06%) and contributed additional information to CMA results in 199 (5.92%) cases. The impact of abnormal chromosome results on patient management was primarily related to counseling for reproductive and recurrence risks assessment (101 cases, 3.01%) while a few (5 cases, 0.15%) led to changes in laboratory testing and specialist referral (25 cases, 0.74%). The incremental cost-effectiveness ratio (ICER) of combined testing demonstrated the cost of each informative chromosome finding was significantly higher for patients with clinically insignificant (CI) CMA findings versus clinically significant (CS) CMA results. Our results suggest that a stepwise approach with CMA testing with reflex to chromosome analysis on cases with CS CMA findings is a more cost-effective testing algorithm for patients with MCA, ASD, and/or DD/ID.