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