Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG).

Carrier screening began 50 years ago with screening for conditions that have a high prevalence in defined racial/ethnic groups (e.g., Tay-Sachs disease in the Ashkenazi Jewish population; sickle cell disease in Black individuals). Cystic fibrosis was the first medical condition for which panethnic screening was recommended, followed by spinal muscular atrophy. Next-generation sequencing allows low cost and high throughput identification of sequence variants across many genes simultaneously. Since the phrase "expanded carrier screening" is nonspecific, there is a need to define carrier screening processes in a way that will allow equitable opportunity for patients to learn their reproductive risks using next-generation sequencing technology. An improved understanding of this risk allows patients to make informed reproductive decisions. Reproductive decision making is the established metric for clinical utility of population-based carrier screening. Furthermore, standardization of the screening approach will facilitate testing consistency. This practice resource reviews the current status of carrier screening, provides answers to some of the emerging questions, and recommends a consistent and equitable approach for offering carrier screening to all individuals during pregnancy or preconception.

Cell-free DNA for the detection of fetal aneuploidy.

Screening for fetal aneuploidy via cell-free DNA was described more than two decades ago and has been used clinically by obstetric providers in the United States for more than 5 years. Cell-free DNA affords excellent detection of fetal Down syndrome and other common aneuploidies and thus is sought by patients and providers. However, owing to the source of the DNA and the nature of the screening test, scenarios may arise that require expert counseling about complex issues regarding fetal and maternal health, test interpretation, and management. It is essential that infertility specialists understand the specific issues related to the strengths and limitations of this screening test, especially in light of expanded genetic testing of embryos.

Chromosomal abnormalities not currently detected by cell-free fetal DNA: a retrospective analysis at a single center.

BACKGROUND: Cell-free fetal DNA analysis is used as a screening test to identify pregnancies that are at risk for common autosomal and sex chromosome aneuploidies. OBJECTIVE: The purpose of this study was to investigate the chromosomal abnormalities that would not be detected by cell-free fetal DNA in a single medical center. STUDY DESIGN: This was a retrospective cohort analysis of 3182 consecutive invasive diagnostic procedures that were performed at Montefiore Medical Center's Division of Reproductive and Medical Genetics from January 1, 2009 to August 31, 2014. All patients underwent cytogenetic analysis; one-third of the patients (1037/3182) went through chromosomal microarray analysis. RESULTS: Clinically significant chromosomal abnormalities were detected in 220 of 3140 cases (7%) after we excluded multiple gestation pregnancies (n = 42). Of these 125 cases (57%) were diagnosed with the common autosomal trisomies that involved chromosomes 21, 18, and 13 and with sex chromosome aneuploidies. There were 23 mosaic karyotypes; 8 of them involved trisomy in chromosomes 21 and 13; 5 of them were sex chromosome mosaics, and 10 of them were other mosaic cases. Five cases of triploidy were detected. Additionally, 19 unbalanced chromosomal rearrangements, a rare autosomal trisomy, and 47 clinically significant findings on chromosomal microarray analysis were diagnosed. Based on the published detection rates of cell-free fetal DNA testing and considering the "no-results" rate, we calculated that 99 of 220 chromosomal changes (45%) could not have been detected by cell-free fetal DNA testing: 16 of the 125 common aneuploidies and sex chromosome aneuploidies, 1 of the 5 triploidy cases, 15 of the 23 mosaic cases, all cases of unbalanced chromosomal rearrangements (n = 19), rare autosomal trisomy (n = 1), and 47 clinically significant chromosomal microarray abnormalities. CONCLUSIONS: Current cell-free DNA testing could not detect up to one-half of the clinically significant chromosomal abnormalities that were found, which included clinically significant chromosomal microarray abnormalities. Among the 99 abnormal karyotypes that were not identified by cell-free DNA screening, 79% were from women with abnormal screening or abnormal ultrasound finding; 21% were from women who underwent invasive testing simply for advanced maternal age/concern, with no other risk factors or ultrasound findings. This information highlights the limitations of cell-free DNA screening and the importance of counseling patients about all prenatal screening and diagnostic procedures and about the added gain of invasive testing with karyotype and microarray.

Chromosomal microarray in prenatal diagnosis: case studies and clinical challenges.

Chromosomal microarray analysis (CMA) is a diagnostic tool used in the evaluation of pediatric patients with congenital anomalies or developmental and intellectual disability. In both the pediatric and prenatal patient population, CMA has been shown to have a higher detection rate of chromosomal abnormalities than conventional karyotype alone. Currently, the diagnostic yield of prenatal CMA is highest when applied to the evaluation of a fetus with multiple ultrasound anomalies. Challenges arise when CMA yields isolated findings not associated with a phenotype on ultrasound or variants of uncertain significance, which warrants evaluation of the risks, benefits, limitations and optimal incorporation of CMA into prenatal care. The clinical cases presented here will be used to illustrate these issues.