Whole-exome sequencing increases the diagnostic rate for prenatal fetal structural anomalies

Prenatal whole-exome sequencing (WES) is becoming increasingly used when karyotype and microarray tests are not diagnostic of fetal malformations. Although the value of WES clearly emerges in terms of higher diagnostic rates, the limitations of prenatal phenotyping together with the counseling challenges for variants of uncertain significance and incidental results suggest that the routine application of prenatal WES is not yet easy.

Structurally abnormal fetuses with a mean gestational age of 24 weeks (range 13-38 weeks) were recruited from the Chong Qing Health Center for Women and Children. We performed a retrospective WES investigation in 85 fetuses, using DNA from amniotic fluid (66 samples, 77.6%), umbilical cord blood (10 samples, 11.8%), and fetal tissues (9 samples, 10.6%). Parental DNA was extracted from peripheral blood.

Molecular diagnosis was obtained in 16 of the 85 fetuses (18.8%). According to the variant segregation mode and family history, 7 fetuses (43.75%) were affected by an autosomal dominant condition (6 variants were de novo and 1 variant was inherited from an unknowingly affected father), 7 fetuses (43.75%) had an autosomal recessive syndrome always associated with compound heterozygosity, and 2 fetuses (12.5%) had an X-linked condition (one mother was a carrier). In addition, the highest diagnostic rate was observed in fetuses with multisystem abnormalities (38.9%, 7/18). A variant of uncertain significance was detected in 16 samples (18.8%, 16/85).

Our study confirms that prenatal WES is an efficient tool for studying fetal abnormalities, although further improvements are needed to establish stronger fetal genotype-phenotype correlations.