Microarray and RASopathy‐disorder testing in fetuses with increased nuchal translucency

Abstract

Objectives To determine the incidence of chromosomal abnormalities, submicroscopic chromosomal abnormalities and RASopathy‐disorder (RD) pathogenic variants in a cohort of pregnancies with nuchal translucency thickness (NT) ≥ 3.5 mm, and to propose a clinical protocol for surveillance of this group of patients. Methods This was a retrospective chart review of patients referred to The Prenatal Diagnosis and Medical Genetics Program at Mount Sinai Hospital between January 2013 and December 2015, due to NT ≥ 3.5 mm, who underwent chorionic villus sampling or amniocentesis. Patients underwent extensive genetic counseling prior to invasive procedures and testing. Quantitative fluorescence polymerase chain reaction (QF‐PCR) was performed as the first‐line test for aneuploidy. If the result was negative, patients underwent karyotyping and/or chromosomal microarray analysis (CMA), and if the findings were normal, they had testing for RD pathogenic variants, which included nine known genes. Patients also underwent detailed fetal ultrasound examinations and echocardiography, performed by expert operators. Results A total of 226 eligible patients were identified. In 116/226 (51.3%) patients, QF‐PCR identified a chromosomal aneuploidy. The remaining 110/226 (48.7%) patients had further genetic testing. Karyotyping/CMA detected an abnormal/pathogenic cytogenetic result in 9/110 (8.2%) patients, as well as five variants of unknown significance (VOUS). RD testing yielded three pathogenic variants (3/103), giving a detection rate of 2.9%, and one VOUS. The optimal NT cut‐off for RD screening was 7.9 mm in this population. In 92/110 (83.6%) patients, the genetic investigations were normal. Of these pregnancies, an early (14–16 weeks' gestation) detailed fetal ultrasound examination identified a structural abnormality in 24 (26.1%), 15 (16.3%) had an abnormal detailed ultrasound examination at 18–22 weeks' gestation and fetal echocardiography showed a cardiac abnormality in nine (9.8%). The birth outcome in the 83 pregnancies that had normal genetic investigations and known outcome included seven (8.4%) cases of termination of pregnancy, seven (8.4%) cases of intrauterine fetal death and 69 (83.1%) cases of live birth. Nine (9.8%) patients were lost to follow‐up. Conclusions Both CMA and molecular testing for RD are important investigations in pregnancies with NT ≥ 3.5 mm. The use of genetic testing combined with fetal ultrasound examination provides valuable information that can influence pregnancy outcome, and provide recurrence risks, in this patient population. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

First‐trimester absent nasal bone: is it a predictive factor for pathogenic CNVs in the low‐risk population?

“…12 In our cohort, the overall rate of CNVs in the group of fetuses with absent NB and NT≥99th centile was 9.4%, in line with other studies reporting a diagnostic yield of CMA in the range of 7% to 9% for nonisolated NT ≥99th centile. [15][16][17][18] The second relevant finding is that major fetal aneuploidies were found in more than 50% of fetuses with NT between the 95 and 99th centile and absent NB, suggesting that in this specific subgroup, an invasive test for fetal karyotype should be proposed as a first-line procedure.…”

Prenatal Diagnosis of Fetuses With Increased Nuchal Translucency by Genome Sequencing Analysis

“…Detection of fetuses with increased nuchal translucency (NT) in routine first-trimester ultrasound screening has been widely used as a sensitive indication for fetal chromosomal abnormalities and/or fetal structural anomalies, such as congenital heart disorders or neurodevelopmental anomalies detected in later gestations (Leung et al, 2011; Huang et al, 2014; Socolov et al, 2017; Sinajon et al, 2019). Fetuses with increased NT and structural malformations are frequently contributed by genetic abnormalities and have poor prognoses.…”

Increased nuchal translucency: diagnostic value of RASopathy‐disorder testing

“…We read with interest the study of Sinajon et al 1 on chromosomal microarray analysis (CMA) and RASopathydisorder (RD) testing in fetuses with nuchal translucency (NT) thickness ≥ 3.5 mm. The authors determined the incidence of chromosomal abnormalities, submicroscopic chromosomal abnormalities and RD pathogenic variants in a total of 226 fetuses over a 3-year period.…”

“…We read with interest the study of Sinajon et al . on chromosomal microarray analysis (CMA) and RASopathy‐disorder (RD) testing in fetuses with nuchal translucency (NT) thickness ≥ 3.5 mm.…”