Whole-exome sequencing on deceased fetuses with ultrasound anomalies: expanding our knowledge of genetic disease during fetal development

Abstract

PurposeThe aim of this study was to determine the diagnostic yield of whole-exome sequencing (WES) in fetuses with ultrasound anomalies that resulted in fetal demise or pregnancy termination. The results were also utilized to aid in the identification of candidate genes for fetal development and to expand the clinical phenotype of known genetic conditions.MethodsWES was performed on specimens from 84 deceased fetuses. Data were analyzed and final results were classified into one of four categories: positive, possible, negative, and candidate gene only. WES analysis was predominantly performed in fetus-parent trios or quads (61%, n=52).ResultsOverall, 20% (n = 17) of cases were positive, 45% (n=38) were possible, 9% (n=7) had only candidate gene variants and 26% (n = 22) tested negative. The diagnostic yield for definitive findings for trio analysis was 24% (n = 11) compared to 14% (n = 4) for singletons. The most frequently reported ultrasound anomalies were central nervous system (37%, n = 31), hydrops/edema (36%, n = 30), and cardiovascular anomalies (31%, n = 26).ConclusionOur experience supports the use of WES to identify the molecular etiology of fetal ultrasound anomalies, to identify candidate genes involved in fetal development, and to expand our knowledge of the clinical phenotype of known genetic conditions.

Prenatal diagnosis of skeletal dysplasias using a targeted skeletal gene panel

“…The molecular genetic diagnostic rates in the current study are on the higher end of prenatal yields (10/12 affected fetuses, 83%), with 8 definitive molecular diagnoses and 2 possible molecular diagnoses, confirming that proband‐only skeletal panel sequencing is highly sensitive for prenatal diagnosis in a selected group of affected fetuses with antenatal evidence of skeletal anomalies that are based on an ultrasound evaluation and who failed to receive a diagnosis with standard genetic testing (karyotyping and microarray). Recent studies recommended the utility of prenatal whole‐exome sequencing (WES) for diagnosis of structurally abnormal fetuses, with diagnostic rates varying between 6.2% and 81% . One study with a high diagnostic yield of 80% applied WES on 5 trios with very strict entry criteria .…”

Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia‐lymphedema syndrome‐1

“…Previously, targeted analysis of candidate genes using specific predetermined probes, for example, florescent in situ hybridization, was needed. This, however, requires at least a suspicion of a particular disease or candidate gene, either by family history or clinical phenotype . Unfortunately, many phenotypes discovered via fetal ultrasound, especially nonimmune hydrops, are nonspecific.…”

“…There are many case reports that describe using WES to aid in clinical diagnosis. More recent series have reported diagnostic yields of fetus and parents trios up to 24% in cases where standard genetic testing is normal . Unfortunately, WES remains limited by cost, lengthy turnaround time, diagnostic gaps, and the need for sophisticated genetic counseling .…”

A system‐based approach to the genetic etiologies of non‐immune hydrops fetalis

“…A recently published large prospective cohort study demonstrated a yield of 8.5% for diagnostic genetic variants in fetuses with a variety of structural anomalies, and the diagnostic yield specifically for the NIHF cases within this cohort was 9%. Finally, among a cohort of deceased fetuses with anomalies undergoing WES, 41% of cases with pathogenic variants, and 31% of cases with variants in candidate genes had hydrops …”