Positive predictive values and outcomes for uninformative cell-free DNA tests: An Italian multicentric Cytogenetic and cytogenomic Audit of diagnOstic testing (ICARO study).

OBJECTIVES: To establish the positive predictive values (PPV) of cfDNA testing based on data from a nationwide survey of independent clinical cytogenetics laboratories. METHODS: Prenatal diagnostic test results obtained by Italian laboratories between 2013 and March 2020 were compiled for women with positive non-invasive prenatal tests (NIPT), without an NIPT result, and cases where there was sex discordancy between the NIPT and ultrasound. PPV and other summary data were reviewed. RESULTS: Diagnostic test results were collected for 1327 women with a positive NIPT. The highest PPVs were for Trisomy (T) 21 (624/671, 93%) and XYY (26/27, 96.3%), while rare autosomal trisomies (9/47, 19.1%) and recurrent microdeletions (8/55, 14.5%) had the lowest PPVs. PPVs for T21, T18, and T13 were significantly higher when diagnostic confirmation was carried out on chorionic villi (97.5%) compared to amniotic fluid (89.5%) (p < 0.001). In 19/139 (13.9%), of no result cases, a cytogenetic abnormality was detected. Follow-up genetic testing provided explanations for 3/6 cases with a fetal sex discordancy between NIPT and ultrasound. CONCLUSIONS: NIPT PPVs differ across the conditions screened and the tissues studied in diagnostic testing. This variability, issues associated with fetal sex discordancy, and no results, illustrate the importance of pre- and post-test counselling.

12q21 Interstitial Deletions: Seven New Syndromic Cases Detected by Array-CGH and Review of the Literature.

Interstitial deletions of the long arm of chromosome 12 are rare, with a dozen patients carrying a deletion in 12q21 being reported. Recently a critical region (CR) has been delimited and could be responsible for the more commonly described clinical features, such as developmental delay/intellectual disability, congenital genitourinary and brain malformations. Other, less frequent, clinical signs do not seem to be correlated to the proposed CR. We present seven new patients harboring non-recurrent deletions ranging from 1 to 18.5 Mb differentially scattered across 12q21. Alongside more common clinical signs, some patients have rarer features such as heart defects, hearing loss, hypotonia and dysmorphisms. The correlation of haploinsufficiency of genes outside the CR to specific signs contributes to our knowledge of the effect of the deletion of this gene-poor region of chromosome 12q. This work underlines the still important role of copy number variations in the diagnostic setting of syndromic patients and the positive reflection on management and family genetic counseling.

Prenatal detection of trisomy 8 mosaicism: Pregnancy outcome and follow up of a series of 17 consecutive cases.

OBJECTIVE: To study the outcome of a series of individuals with prenatal detection of trisomy 8 mosaicism by chorionic villus sampling (CVS) and/or amniocentesis. STUDY DESIGN: The databases of two Italian genetics units were reviewed to identify all consultations requested during pregnancy because of trisomy 8 mosaicism. To evaluate the pregnancy outcome, the regional registry of congenital malformations (including terminations of pregnancies) was consulted; additional follow-up data were collected by a telephone interview. The following outcomes were analysed: delivery, pre- and post-natal growth, psychomotor development, major malformations, other diseases/complications. RESULTS: A total of 17 consecutive cases of trisomy 8 mosaicism were identified. Fourteen cases were first detected among women undergoing prenatal diagnosis by CVS; the remaining ones were identified among women who underwent amniocentesis. In most cases diagnosed by CVS, the chromosomal anomaly was only detected in long-term cell cultures (10/14) and was not confirmed by amniocentesis (11/13). There were two terminations of pregnancy and 15 live births; no major birth defects were observed among live born infants and only a case with prenatal and postnatal growth retardation was observed (mean age at follow-up interview was 5.9 years). CONCLUSION: Our data showed an overall positive prognosis for cases with an apparent confined placental mosaicism and those with low-level mosaicism in amniotic fluid if no congenital anomalies were detected by foetal ultrasound examinations. However, larger studies are warranted to better define the associated risk of neurodevelopmental anomalies.