Strategy for Use of Genome-Wide Non-Invasive Prenatal Testing for Rare Autosomal Aneuploidies and Unbalanced Structural Chromosomal Anomalies.

Atypical fetal chromosomal anomalies are more frequent than previously recognized and can affect fetal development. We propose a screening strategy for a genome-wide non-invasive prenatal test (NIPT) to detect these atypical chromosomal anomalies (ACAs). Two sample cohorts were tested. Assay performances were determined using Cohort A, which consisted of 192 biobanked plasma samples-42 with ACAs, and 150 without. The rate of additional invasive diagnostic procedures was determined using Cohort B, which consisted of 3097 pregnant women referred for routine NIPT. Of the 192 samples in Cohort A, there were four initial test failures and six discordant calls; overall sensitivity was 88.1% (37/42; CI 75.00-94.81) and specificity was 99.3% (145/146; CI 96.22-99.88). In Cohort B, there were 90 first-pass failures (2.9%). The rate of positive results indicating an anomaly was 1.2% (36/3007) and 0.57% (17/3007) when limited to significant unbalanced chromosomal anomalies and trisomies 8, 9, 12, 14, 15, 16, and 22. These results show that genome-wide NIPT can screen for ACAs with an acceptable sensitivity and a small increase in invasive testing, particularly for women with increased risk following maternal serum screening and by limiting screening to structural anomalies and the most clinically meaningful trisomies.

A French multicenter study of over 700 patients with 22q11 deletions diagnosed using FISH or aCGH.

Although 22q11.2 deletion syndrome (22q11.2DS) is the most recurrent human microdeletion syndrome associated with a highly variable phenotype, little is known about the condition's true incidence and the phenotype at diagnosis. We performed a multicenter, retrospective analysis of postnatally diagnosed patients recruited by members of the Association des Cytogénéticiens de Langue Française (the French-Speaking Cytogeneticists Association). Clinical and cytogenetic data on 749 cases diagnosed between 1995 and 2013 were collected by 31 French cytogenetics laboratories. The most frequent reasons for referral of postnatally diagnosed cases were a congenital heart defect (CHD, 48.6%), facial dysmorphism (49.7%) and developmental delay (40.7%). Since 2007 (the year in which array comparative genomic hybridization (aCGH) was introduced for the routine screening of patients with intellectual disability), almost all cases have been diagnosed using FISH (96.1%). Only 15 cases (all with an atypical phenotype) were diagnosed with aCGH; the deletion size ranged from 745 to 2904 kb. The deletion was inherited in 15.0% of cases and was of maternal origin in 85.5% of the latter. This is the largest yet documented cohort of patients with 22q11.2DS (the most commonly diagnosed microdeletion) from the same population. French cytogenetics laboratories diagnosed at least 108 affected patients (including fetuses) per year from among a national population of ∼66 million. As observed for prenatal diagnoses, CHDs were the most frequently detected malformation in postnatal diagnoses. The most common CHD in postnatal diagnoses was an isolated septal defect.

Mosaic trisomy 16 in a fetus: the complex relationship between phenotype and genetic mechanisms.

OBJECTIVES: This study was undertaken to discuss the workup of trisomy 16 pregnancies. STUDY DESIGN: This case study reports the prenatal detection and postnatal confirmation of mosaic trisomy 16, associated with uniparental disomy (UPD) 16, in a 34-year-old woman who showed elevated maternal serum alpha-fetoprotein and beta-HCG at a gestational age (GA) of 15.5 weeks. RESULTS: Amniotic fluid (AF) karyotyping at different GAs revealed various levels of trisomy 16 mosaicism (0 to level III). UPD studies at 21 weeks of gestation revealed maternal heterodisomy 16. Serial fetal ultrasonography showed fetal abnormalities: intrauterine growth restriction (IUGR), dilated digestive tract, and gallbladder agenesis. Postmortem examination confirmed the prenatal findings and revealed additional anomalies, such as hypoplastic cerebellum with abnormal gyration of the vermis. CONCLUSIONS: Workup following prenatal detection of trisomy 16 mosaicism in chorionic villi must include AF karyotyping and serial ultrasound examination of the fetus in order to approach postnatal developmental prognosis.