Patient G, a 5-year-old Korean boy, suffered from severe congenital non-syndromic bilateral sensorineural hearing loss (SHNL). In order to rule out the possibility of having progressive hearing loss, the physicians have ordered a whole exome sequencing(WES) test.

Upon initial examination, our team identified a heterozygous potential pathogenic variant within a gene called OTOA located in chromosome 16p12.2. OTOA gene is a causative gene responsible for profound prelingual SHNL called autosomal recessive deafness 22. NM_144672.4(OTOA):c.1765del variant located in exon 17, is predicted to result in a frameshift of NM_144672.4 transcript and cause premature termination of OTOA gene.

grand-rounds-2 symptoms

The variant has been reported in a Korean patient with SNHL previously (PMID: 25373420). However, patient G could not be diagnosed with autosomal recessive deafness 22 as there was no evidence of a second pathogenic variant. Because the disease is inherited as an autosomal recessive disorder, single heterozygous individuals are expected to be unaffected. The patients must have a second pathogenic variant to be fully diagnosed. Therefore, the patient has received an inconclusive result with single heterozygous pathogenic variant NM_144672.4(OTOA):c.1765del.

The physician who received the inconclusive results examined the patient’s phenotype and suggested that the patient’s phenotype matched well with suggestive findings and decided to look for a second variant using the whole genome sequencing (WGS) test. Because WES only sequences coding regions of genes that account for 1~2% of the whole genome, there was a chance that deep intronic variant or small copy number variant with breakpoints in the intronic/intergenic region.


The variant NM_144672.4(OTOA):c.1765del is present inside the patient’s exon22 in both WGS and WES. Note that in WES read is only converging areas near the exon while WGS is covering the entire gene. Genomic position number varies slightly as WES was mapped to hg19 and WGS was mapped to hg38

From the WGS test, no additional variants were identified from the coding region of OTOA as well as the non-coding region. However, upon examination of structural variants, we identified evidence of inversion in the chromosome 16p12.2 region which includes the 3' end of the OTOA gene. The inversion started from the intron between exons 17 and 18 of OTOA and spans across two additional genes NPIPB4, and UQCRC2, downstream of the OTOA gene.

The inversion breakpoints were each located at the deep intronic region of the OTOA and UQCRC2 gene where WES does not target. Additionally, because this was chromosomal inversion which is a balanced translocation, there was no change in gene coverage between inversion spans. Therefore, this inversion is not identifiable in WES.


The inversion can be identified using blue and cyan colored reads which is indicating that the read direction is different from expected. (visit here for more information about how to interpret read directions) Note that in WES colored reads are not present as they are not part of targeted sequences

Genetic deafness or hearing loss is one of the most genetically heterogeneous disorders. More than 100s genes are known to be related to non-syndromic hearing loss, and numbers are even higher when other syndromic features are included while more gene-disease relationships are being discovered every year. More than half of congenital sensorineural hearing loss (SHNL) have a monogenic genetic cause that follows a mendelian inheritance pattern. Therefore, hearing loss patients would highly benefit from NGS-based WES and WGS tests for a genetic diagnosis. Additionally, any patient who might have received an inconclusive result from the WES test might benefit from the WGS test as it might uncover the second variant that is necessary for the diagnosis. The second variant could be present in the deep intronic regions where WES does not sequence, or a chromosomal structural variant similar to our patient G.

If you are interested in the limitations of WGS:

For more information about autosomal recessive Deafness 22:
Deafness, autosomal recessive 22 (OMIM:607039)

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