BACKGROUND AND PURPOSE:

• Whole exome sequencing (WES) can diagnose 25 to 37% of postnatal unexplained single gene disorders
  • The technique depends on obtaining good quality DNA from ‘trios’ – mother/father/affected child
• In the prenatal setting, identification of lethal prenatal genetic disorders is not always possible using the ‘trio’ approach, due to either poor quality or insufficient quantity of fetal DNA
• Stals et al. (Prenatal Diagnosis, 2017) have developed a novel technique to detect recessive single gene disorders using parental samples and saving fetal DNA where available for confirmation studies

METHODS:

• WES sequencing was performed on couples (unaffected) with at least 1 fetus affected with severe, lethal, prenatal onset disease
  • Special filtering was applied to WES data
  • Fetal DNA was saved to confirm pathogenic variants
• Potential pathogenic variants were identified using a bioinformatics pipeline that highlighted changes in disease-causing genes consistent with the clinical phenotype and autosomal recessive inheritance pattern
• Disease-causing variants were confirmed using stored fetal DNA

RESULTS:

• Exome sequencing was carried out in a consecutive series of 50 couples
• WES identified heterozygous pathogenic (or likely pathogenic) variants in 24 different genes in 26/50 couples (52%)
• A genetic diagnosis was obtained in 18/29 cases (62%) when 2 fetuses in a family were affected and in 8/21 (38%) when only 1 fetus was affected
• In 25 cases, autosomal recessive inheritance was identified and in 1 case, an X-linked recessive disorder was identified
• A diagnosis was made in 6/11 (54%) of couples who were consanguineous

CONCLUSION:

• Exome sequencing of parental samples is a powerful strategy for diagnosing lethal or prenatal-onset recessive disorders and can be applied even in the absence of large, high quality fetal samples
• The authors suggest various explanations for those cases that remained undiagnosed including
  • Disorder may not yet be associated with a known phenotype
  • Disorder may not be a monogenic (single gene), autosomal recessive disorder
• Identifying pathogenic variants may provide useful information to parents considering PGD or prenatal diagnosis in subsequent pregnancies

Learn More – Primary Sources:

Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing

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