Abstract

Background: International databases with information on copy number variation of the human genome are an important reference for laboratories using high resolution whole genome screening. Genomic deletions or duplications which have been detected in the healthy population and thus marked as normal copy number variants (CNVs) can be filtered out using these databases when searching for pathogenic copy number changes in patients. However, a potential pitfall of this strategy is that reported normal CNVs often do not elicit further investigation, and thus may remain unrecognised when they are present in a (pathogenic) homozygous state. The impact on disease of CNVs in the homozygous state may thus remain undetected and underestimated.

Methods and results: In a patient with syndromic hearing loss, array comparative genomic hybridisation (array CGH) and multiple ligation dependent probe amplification (MLPA) revealed a homozygous deletion on 15q15.3 of a CNV, inherited from hemizygous carrier parents. The deletion is about 90 kilobases and contains four genes including the STRC gene, which is involved in autosomal recessive deafness (DFNB16). By screening healthy control individuals and review of publicly available CNV data we estimated the frequency of hemizygous deletion carriers to be about 1.6%.

Conclusion: We characterised a homozygous deletion of a CNV region causing syndromic hearing loss by a panel of molecular tools. Together with the estimated frequency of the hemizygous deletion, these results emphasise the role of the 15q15.3 locus in patients with (syndromic) hearing impairment. Furthermore, this case illustrates the importance of not automatically eliminating registered CNVs from further analysis.