title: Challenges in whole exome sequencing: an example from hereditary deafness.
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.
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Asli
authors.initials: A
authors.lastname: Sirmaci
authors.forename: Yvonne J K
authors.initials: YJ
authors.lastname: Edwards
authors.forename: Hatice
authors.initials: H
authors.lastname: Akay
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001299:Audiometry; D001483:Base Sequence; D002352:Carrier Proteins; D002648:Child; D002877:Chromosomes, Human / Q000235:genetics; D003638:Deafness / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C452600:GIPC3 protein, human; D022821:RNA Splice Sites; D014157:Transcription Factors