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Grand Rounds

Can Whole-Exome Sequencing Help Diagnose Otherwise Unexplained Fetal Structural Anomalies?

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BACKGROUND AND PURPOSE: 

  • For decades, routine chromosome analysis was used to analyze amniocentesis and CVS samples, however technique was limited as karyotyping could not assess smaller microdeletions  
  • Microarray analysis is now recommended in the presence of fetal structural abnormalities 
  • Microarrays can detect small, submicroscopic changes, but cannot identify smaller base pair mutations which may be associated with single gene disorders  
  • Petrovski et al. (The Lancet, 2019) sought to determine the incremental diagnostic yield of whole-exome sequencing (WES) following uninformative results of karyotype testing and chromosomal microarray

METHODS: 

  • Prospective cohort study of parents of anomalous fetuses identified on ultrasound  
    • Fetuses with known chromosomal or microdeletion were excluded   
  • Among fetuses and parents (parent-fetus trios) WES was performed and ‘qualifying’ variants were classified as either Tier 1 or Tier 2 
    • Tier 1: Highly penetrant | Absent in the parents and controls 
    • Tier 2: Previously categorized as ‘likely pathogenic” or protein truncating variant where protein-truncation is a known mechanism of disease  
  • Variant classification followed ACMG guidelines and also used previously published bioinformatic approaches  
  • Primary outcome: Detection of disease causing variants that could explain the fetal anatomical abnormalities  
  • Secondary outcomes 
    • Frequency of fetuses with a diagnostic genetic variant comparing  
      • Cultured vs direct sampling 
      • Single versus multiple anomalies

RESULTS: 

  • 517 women anomalous fetuses were screened for eligibility  
    • 71 (14%) couples declined testing 
    • 87 (17%) trios were missing at least one DNA sample (from either parent or the fetus) 
    • 69 (13%) trios had a clinically relevant abnormal karyotype or chromosomal microarray finding 
    • 51 (10%) couples did not consent to WES or withdrew consent 
    • 5 (1%) samples were not of good enough quality for analysis 
  • DNA samples from 234 (45%) eligible trios were included in the study  
    • Known genetic variants were identified in 24 (10%) families  
    • Mutations indicative of pathogenicity but with insufficient evidence to be considered diagnostic were identified in another 46 (20%) of the families 
      • Under ACMG guidelines, 15 would have been considered pathogenic   
  • There was no difference between cultured and direct samples  
  • Frequency of genetic diagnoses based on fetal anomaly were highest in the following 
    • Lymphatic or effusion (24%) 
    • Skeletal (24%) 
    • CNS (22%) 
    • Renal (16%)  
  • Lowest frequency of genetic diagnoses: Cardiac anomalies (5%)

CONCLUSION: 

  • WES can provide important additional genetic diagnostic information in the setting of structural anomalies following a negative karyotype and microarray

Learn More – Primary Sources: 

Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study

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Related ObG Topics:

The Exome and Exome Sequencing: Prenatal Testing Recommendations
Can Whole Exome Sequencing Explain Prenatal Loss With Insufficient Fetal DNA?
The Genome and Whole Genome Sequencing

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