Fetal phenotypes emerge as genetic technologies become robust

Abstract

Prenatal genomic evaluation of the fetus is available at decreasing cost and with a faster turnaround time. However, fetal genotype‐phenotype correlations are in their infancy. By comparison, pediatric and adult genotype‐phenotype databases are well established and publicly accessible. A similar system for fetal genomics is lacking. When a fetal anomaly is identified by ultrasound imaging, a genetic diagnosis provides important information. However, fetal prognostic counseling is problematic if the only available information is based on outcomes following postnatal diagnoses. The same conditions identified prenatally may have more benign or more deleterious outcomes. Also, the condition may evolve over the pregnancy itself. As genomic testing increasingly examines fetal DNA at a single nucleotide level, the concomitant in utero phenotype deserves equal attention. Often, the reports of fetal phenotype are limited. Among sonologists, an increased awareness of attaining and communicating detailed fetal phenotypes is needed. The interpretation of expanded prenatal sequencing is reliant on deeper fetal phenotyping. The information gained significantly impacts clinical care and understanding of fetal development. This case series highlights: the broad spectrum of fetal phenotypes for known genetic conditions, phenotype progression during pregnancy, and the need to supplement systematic imaging with descriptive details when assessing fetuses with malformations.

Deciphering congenital anomalies for the next generation

“…The genetic underpinnings of these more subtle anomalies, compared to severe malformations leading to fetal demise, may differ substantially. Including the entire spectrum in sequencing studies is critical, particularly as defining the full fetal phenotype of genetic syndromes associated with structural malformations is needed to interpret prenatal genetic testing results and for prenatal counseling (Gray et al 2019).…”

A prospective study on rapid exome sequencing as a diagnostic test for multiple congenital anomalies on fetal ultrasound

“…Detailed information on the phenotype is still essential for accurate interpretation of genetic data. Uncertainty about the fetal phenotype and lack of knowledge on the fetal phenotype in relation to disease-causing genes are possible, but unavoidable, obstacles to correct data interpretation 23. On the other hand, suspected diagnoses might turn out to be false.…”

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“…A major hurdle to be overcome in prenatal medicine will be the gaps in knowledge regarding the fetal clinical presentations of monogenic diseases. Fortunately, with the increased prenatal utilisation of chromosome microarrays and exome sequencing, more cases are being described in the literature that demonstrate new knowledge regarding fetal phenotypes . This should help to facilitate automated prenatal diagnoses in the future, reducing turnaround time and expanding management options.…”