BACKGROUND AND PURPOSE:

• Preconception and prenatal expanded carrier testing panels are available
• Consanguinous couples
  • 4 to 6% risk for having a child with a significant birth defect (double baseline rate of 2 to 3%)
  • Increased risk for autosomal recessive disorders
  • Often the first time couples find out about their risk is after the birth of an affected child
• Kirk et al (Genetics in Medicine 2019) screened consanguineous couples at preconception with a “clinical exome” panel as a proof of concept that broad, expanded carrier testing may be of benefit

METHODS:

• Participants
  • Consanguineous couples
  • At least 2^nd cousins and were planning further children
• Genetic screening
  • Done using a 4,813 gene panel associated with human disease
  • Approach was that of ‘couples’ testing, rather than sequential
  • Variants (for recessive) were only assessed if
    • Both partners were carriers for the same variant or
    • Each partner was a carrier for a different variant but in same gene
• X-linked disorders were included in addition to autosomal recessive
  • X-linked included due to impact on offspring, not because of increased risk in consanguineous couples

RESULTS:

• 15 couples were sequenced
• 4 couples were found to be at risk of autosomal recessive disorders
  • One couple: Poretti-Boltshauser syndrome (and already had a child with this disorder, undiagnosed until this study)
  • One couple: β-globin variant – previously known
  • Two couples: New information for the family
    • Gene C5orf42: Associated with Joubert syndrome and orofaciodigital syndrome
    • Gene GYS2: Associated with glycogen synthase deficiency
• There was one known variant that was not detected but could not be picked up using the technology used in this study (single exon deletion)

CONCLUSION:

• The authors claim
  • Only ¼ variants would have been detected with current available panels (β-globin variant)
  • Broad preconception screening would detect more at-risk couples than current targeted approaches
  • Preconception screening for recessive and X-linked disorders in consanguineous couples is of benefit
  • By screening and combining data from both partners, rather than sequential testing, the number of variants that needed to be assessed was greatly reduced

Learn more – Primary Sources:

Beyond the panel: preconception screening in consanguineous couples using the TruSight One “clinical exome”

Related ObG Topics:

ISPD, SMFM and PQF Release a Joint Position Statement on Fetal Genome-Wide Sequencing

The Exome and Whole Exome Sequencing: Prenatal Testing Recommendations

Can Whole Exome Sequencing Explain Prenatal Loss With Insufficient Fetal DNA?

ACOG Opinion on Expanded Carrier Screening

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