Genomic study of severe fetal anomalies and discovery of GREB1L mutations in renal agenesis

Abstract

Our study opens a window on the distinctive genetic landscape associated with fetal anomalies and highlights the power-but also the challenges-of WES in prenatal diagnosis.

Is prenatal genomic testing ready for prime time?

“…To date, the highest diagnostic yield for prenatal WES has been in fetuses with multiple anomalies or specific types of anomalies, such as structural brain malformations, 7,8 with diagnostic rates that are similar to those reported in the study by Boissel et al 5 Furthermore, trio testing has a slightly higher diagnostic yield compared with proband-only testing, particularly for sporadic fetal findings in the absence of parental consanguinity or a family history of similar findings. Such cases are highly selected with a greater a priori risk that the fetus has a single-gene condition.…”

“…Unlike the initial implementation of targeted chromosomal microarray into prenatal testing, it may be more difficult to target genomic testing to solely known pathogenic variants in known disease-causing genes. This will certainly decrease diagnostic yield, particularly for those conditions caused by pathogenic missense variants that have not been reported previously or pathogenic variants in novel disease genes, such as Boissel et al 5 found with GREB1L.…”

“…The article by Boissel et al 5 entitled "Genomic Study of Severe Fetal Anomalies and Discovery of GREB1L Mutations in Renal Agenesis" in this issue of Genetics in Medicine explores the clinical utility of whole-exome sequencing (WES) when applied to 101 stillborn or terminated fetuses with congenital anomalies (at least two major malformations; a structural brain malformation and/or severe ventriculomegaly; or an anomaly in which postnatal lethality is likely). The authors hypothesize that de novo pathogenic variants account for a substantial proportion of severe fetal phenotypes that may not be represented in postnatal populations due to the serious nature of the findings.…”

“…In the situation of either an incomplete phenotype or a phenotype that diverges from the classic syndrome, diagnostic accuracy may be lost. In the study by Boissel et al 5 a fetus with a de novo pathogenic EP300 truncating variant had spina bifida and postaxial polydactyly on ultrasound with the dysmorphic features of Rubenstein-Taybi syndrome (RTS) identified at autopsy. Without being able to assess for the recognizable facial and limb findings of RTS, a clinician who receives this result in a prenatal setting may not know how to counsel the family and would be concerned that the fetus might have a secondary diagnosis that explains the malformations in addition to RTS.…”

Retrospective analysis of fetal vertebral defects: Associated anomalies, etiologies, and outcome

“…FKPB8 was proposed as a candidate gene based on the reported phenotype of FKBP8 −/− mice which includes VD and scoliosis (Shirane, Ogawa, Motoyama, & Nakayama, ). Two fetuses whose VD had been identified on postmortem skeletal survey were diagnosed with the following syndromes: Raine syndrome (a lethal hyperostosis syndrome) and Currarino syndrome (which associates partial sacral agenesis, a presacral mass, and anorectal malformation; Boissel et al, ). Medical genetics referral is therefore indicated to look for non‐chromosomal causes, especially for non‐isolated cases.…”