Abstract
Whole exome sequencing provides unprecedented opportunities to identify causative DNA variants in rare Mendelian disorders. Finding the responsible mutation via traditional methods in families with hearing loss is difficult due to a high degree of genetic heterogeneity. In this study we combined autozygosity mapping and whole exome sequencing in a family with 3 affected children having nonsyndromic hearing loss born to consanguineous parents. Two novel missense homozygous variants, c.508C>A (p.H170N) in GIPC3 and c.1328C>T (p.T443M) in ZNF57, were identified in the same ∼6 Mb autozygous region on chromosome 19 in affected members of the family. Both variants co-segregated with the phenotype and were absent in 335 ethnicity-matched controls. Biallelic GIPC3 mutations have recently been reported to cause autosomal recessive nonsyndromic sensorineural hearing loss. Thus we conclude that the hearing loss in the family described in this report is caused by a novel missense mutation in GIPC3. Identified variant in GIPC3 had a low read depth, which was initially filtered out during the analysis leaving ZNF57 as the only potential causative gene. This study highlights some of the challenges in the analyses of whole exome data in the bid to establish the true causative variant in Mendelian disease.
Highlights
Hearing loss is one of the most common sensorial disorders in humans
After finding potential regions through autozygosity mapping we identified two novel rare variants to cause hearing loss in this study (GIPC3 p.H170N and ZNF57 p.T443M)
If GIPC3 was not known as a cause of deafness we could have concluded that the variant in ZNF57 was causative
Summary
Hearing loss is one of the most common sensorial disorders in humans. Genetic factors account for more than 50% of cases with congenital or prelingual hearing loss, with autosomal recessive (77%), autosomal dominant (22%), and X-linked inheritance (1%) [1,2]. A two step approach combining linkage analysis and whole exome sequencing based on the generation technologies have been applied previously in other studies for Mendelian disease [3,4] including deafness [5,6]. Whole exome sequencing using the generation technologies provides a new and transformational approach for identifying causative mutations in Mendelian disorders [5,7,8,9,10,11,12]. We apply this two step approach, face the challenges, and eventually uncover a novel mutation causing hereditary hearing loss in a family. This study provides some comprehensive insights which would be valuable in certain scenarios and will help minimize certain limitations in using the new whole exome sequencing technologies
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