Genetic causes of isolated and severe fetal growth restriction in normal chromosomal microarray analysis

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.

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.

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.

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.