Prenatal exome sequencing in fetuses with callosal anomalies

Abstract

Objective:We aimed to investigate the value of exome sequencing (ES) in fetuses with callosal anomalies (CA) with or without other structural anomalies, but with normal findings by karyotyping and chromosome microarray analysis (CMA).Methods: Cases with CA with or without other structural anomalies were screened for eligibility. Fetuses with abnormal karyotyping or CMA results were excluded.We performed ES on DNA samples from eligible fetus-parental trios and identified diagnostic genetic variants based on the ultrasonographic features.Results: A total of 50 eligible fetus-parental trios were successfully analyzed by ES.We found 17 likely pathogenic or pathogenic variants in 14 genes from 17 fetuses, with a total proportion of diagnostic genetic variants equal to 34.0% (17/50). Of the 17 cases with a diagnosis, 10 (29.4%, 10/35) were isolated and 7 (43.8%, 7/15) were non-isolated. Pregnancy outcome data showed that 70.0% (7/10) of the surviving isolated CA fetuses with negative ES results had a good prognosis in early childhood.Conclusions: Our study used ES prenatally for CA and showed that ES can be used diagnostically to define the molecular defects that underlie unexplained CA. Most subjects with isolated CA with negative results for genetic causes will have a favorable prognosis in early childhood.

Fetal central nervous system anomalies: When should we offer exome sequencing?

“…ES for prenatally detected CNS anomalies yields a genetic diagnosis in almost 14% of pregnancies that have had a negative genetic workup through traditional karyotype and chromosomal microarray. When a CNS anomaly is found in isolation, exome sequencing reveals an overall genetic diagnosis in approximately 7% of fetuses with higher rates in some isolated findings such as mild ventriculomegaly or ACC similar to rates found by others 23, 26 …”

“…Our finding that 30% of cases with isolated agenesis of the corpus callosum had a pathogenic, causative variant on ES is higher than one previous literature report, 23 but in keeping with the report from Lei and colleagues who reported pathogenic variants in 29% of cases with isolated ACC. 26 In the series looking at 65 fetuses with agenesis of the corpus callosum, 15% of fetuses with isolated ACC had pathogenic variants on ES compared to 42% of fetuses with nonisolated ACC. 23 Of note, in this series, almost 15% of fetuses that were initially diagnosed with isolated ACC subsequently had additional anomalies diagnosed.…”

“…When a CNS anomaly is found in isolation, exome sequencing reveals an overall genetic diagnosis in approximately 7% of fetuses with higher rates in some isolated findings such as mild ventriculomegaly or ACC similar to rates found by others. 23,26 Securing a genetic diagnosis helps families understand the current pathology and prognosis as well as facilitates planning for future pregnancies. Although limitations remain, including cumbersome interpretation of results and time and cost restraints, ES adds utility to the workup of anomalous pregnancies.…”

Prenatal exomes and genomes – so much new and so much more to learn

“…These authors also show that trio pES yielded pathogenic (P) and likely pathogenic (LP) variants in 13% of cases with isolated mild ventriculomegaly and in 30% of cases with isolated agenesis of the corpus callosum (ACC), higher than many might have expected 9 . The results for ACC align well with data from Lei and colleagues in a different population with callosal anomalies, where pES yielded diagnostic findings in 34% 10 . Such information changes counseling, since standard testing with CMA has lower yield for these diagnoses and also highlights the importance of collaboration and combining data from multiple cohorts.…”

“…9 The results for ACC align well with data from Lei and colleagues in a different population with callosal anomalies, where pES yielded diagnostic findings in 34%. 10 Such information changes counseling, since standard testing with CMA has lower yield for these diagnoses and also highlights the importance of collaboration and combining data from multiple cohorts. Other series from around the world are included in the second special issue to be published in June, and report sequencing yield for a variety indications of including hydrops, cardiac defects and renal anomalies, [11][12][13][14][15][16] again showing significant incremental diagnostic yields.…”