When whole exome sequencing fails: Lessons learned from whole genome sequencing

Exome sequencing is an extremely efficient way to to identify disease-causing variations and increasingly used in healthcare and research. However, in certain cases, either due to the complexity or the location of the aberration, whole exome sequencing (WES) might not yield a pathogenic variant, and whole genome sequencing (WGS) may be required.

We report herein four recent cases diagnosed in our lab, which were all initially missed by WES and later resolved only by sequencing the entire genome:

1-Promoter mutation: Four patients of two unrelated families, with portal vein thrombosis and macrocephaly. WGS revealed the –270C>G homozygous mutation, located in the promoter of the PIGM gene.

2-Large deletions: Eight patients from 7 different families of Iraqi-Jewish origin with autosomal recessive intractable diarrhea of infancy. Linkage analysis with WGS enabled the detection of two overlapping deletions on chromosome 16.

3-Intronic mutation: Two siblings with PS6 syndrome without mutation in the coding sequence of the candidate gene, ARSB. WGS, revealed deep intronic mutation in the gene, which leads to insertion of a pseudo-exon.

4-Large duplication: Three female siblings of Iraqi-Jewish descent, presented with cerebellar ataxia, encephalopathy, seizures and cognitive disability. WGS with Bam file analysis identified a novel biallelic duplications in the COQ5 gene.

It is clear that WGS is a powerful tool, which can improve the rate of discovery of disease-causing mutations, especially in such challenging cases. With the falling cost of WGS, more individuals are pursuing this option, which enable to enrich the databases, and lead to better diagnosis.