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Recording

Oral Plenary Session I and Late-Breaking

Oral Plenary Sessions

(1) Multicenter, prospective cohort of genome sequencing in 750 fetal structural anomalies

Monday, February 12, 2024
3:45 PM – 4:00 PM  
Location: Potomac Ballroom, Ballroom Level
Objective: The incremental value of exome sequencing (ES) over chromosomal microarray (CMA) in the evaluation of fetal structural anomalies has been demonstrated. Genome sequencing (GS) is now utilized for postnatal genomic diagnostic evaluation given GS has a higher yield over other technologies (ES, CMA). We prospectively evaluated the diagnostic yield of trio GS in pregnancies with major structural fetal anomalies referred to five tertiary care centers.

Study Design: From August 2019 to July 2023, pregnancies < 36 weeks with major fetal structural anomalies, isolated fetal growth restriction < 5th percentile identified < 24 weeks, and/or an elevated nuchal translucency of ≥ 3.5mm were screened for eligibility into this five-center prospective cohort study. Exclusions included an explanatory CMA/karyotype and planned termination based on imaging findings. Prenatal diagnosis by either CVS or amniocentesis and consent of both parents was required. GS was performed at 1 of 4 diagnostic laboratories using local bioinformatic tools. Pathogenic (P), likely pathogenic (LP), and uncertain variants (VUS) related to the phenotype meeting specific study protocol criteria were reported. 

Results: 5495 pregnancies with anomalies were screened; 2147 were eligible and 750 (34.9%) were enrolled. The main reasons for ineligibility were > 36 weeks (16.4%) and planned termination or fetal demise (16.2%). A P/LP finding causative of the phenotype was identified in 117 (15.6%) and a VUS related to the phenotype was found in 21 (2.8%). There were causative P/LP findings in 41 (9.5%) cases with a single organ system involved and in 76 (23.8%) cases with multiple organ system involvement (table). Recurrent diagnoses included PTPN11 (8), NIPBL (5), CHD7 (5), MYRF (4), PIEZO1 (4). Notably, no case with NT >= 3.5 mm to < 4.5 mm without evidence of cystic hygroma had a GS finding. The positivity rate for findings related to the phenotype was not significantly different between the 4 labs (p=0.09).

Conclusion: Prenatal trio GS provides incremental diagnostic information in pregnancies with fetal structural anomalies and a non-causal CMA.