Objective: To investigate the genetic burden in fetuses with isolated and severe fetal growth restriction (FGR) using Trio whole-exome sequencing (WES) with a normal chromosomal microarray.
Method: This retrospective study analyzed WES results of singleton fetuses with isolated and severe FGR, whose estimated fetal weight (EFW) was less than the third percentile by Hadlock formula, in a tertiary center between March 2016 and March 2022. Cases with abnormal chromosomal microarray analysis (CMA) and TORCH results were excluded.
Results: Fifty-one fetuses with isolated and severe FGR and negative CMA results underwent Trio-WES. Of all patients, eight (15.7%) were diagnosed with FGR at its early onset (<32 weeks) and showed pathogenic or likely pathogenic variants involving Nipped-B-like protein gene (NIPBL) (n = 3), fibroblast growth factor receptor 3 (n = 1), pyruvate dehydrogenase E1 subunit alpha 1 (n = 1), collagen, type I, alpha 1 (n = 1), superkiller viralicidic activity 2-like (n = 1), and chloride voltage-gated channel (CLCN5) (n = 1). De novo-generated variants were identified in five fetuses, of which two were novel, including c.6983C>A (p. Thr2328Lys) in NIPBL and c.934-1G>T in CLCN5. Genetic disorders involved Cornelia de Lange syndrome and metabolic and skeletal genetic diseases.
Conclusion: The present study indicates that Trio-WES can improve effectivity of prenatal diagnoses for isolated and severe FGR in cases with normal CMA results, aiding prenatal genetic counseling and pregnancy management for FGR fetuses.
Keywords: exome sequencing; genetic syndrome; isolated fetal growth restriction; prenatal diagnosis.
© 2022 International Federation of Gynecology and Obstetrics.