title: Identification of a novel GATA3 mutation in a deaf Taiwanese family by massively parallel sequencing.
abstract: Recent studies have confirmed the utility of massively parallel sequencing (MPS) in addressing genetically heterogeneous hereditary hearing impairment. By applying a MPS diagnostic panel targeting 129 known deafness genes, we identified a novel frameshift GATA3 mutation, c.149delT (p.Phe51LeufsX144), in a hearing-impaired family compatible with autosomal dominant inheritance. The GATA3 haploinsufficiency is thought to be associated with the hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome. The pathogenicity of GATA3 c.149delT was supported by its absence in the 5400 NHLBI exomes, 1000 Genomes, and the 100 normal hearing controls of the present study; the co-segregation of c.149delT heterozygosity with hearing impairment in 9 affected members of the family; as well as the nonsense-mediated mRNA decay of the mutant allele in in vitro functional studies. The phenotypes in this family appeared relatively mild, as most affected members presented no signs of hypoparathyroidism or renal abnormalities, including the proband. To our knowledge, this is the first report of genetic diagnosis of HDR syndrome before the clinical diagnosis. Genetic examination for multiple deafness genes with MPS might be helpful in identifying certain types of syndromic hearing loss such as HDR syndrome, contributing to earlier diagnosis and treatment of the affected individuals.
authors.affiliation: Department of Otolaryngology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan; Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Yin-Hung
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Department of Otolaryngology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan; Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chen-Chi
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Department of Otolaryngology, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Tun-Yen
authors.initials: TY
authors.lastname: Hsu
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Wei-Yih
authors.initials: WY
authors.lastname: Chiu
authors.affiliation: Department of Otolaryngology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan; Department of Otolaryngology, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taiwan. Electronic address: cjhsu@ntu.edu.tw.
authors.forename: Chuan-Jen
authors.initials: CJ
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: paylong@ntu.edu.tw.
authors.forename: Pei-Lung
authors.initials: PL
authors.lastname: Chen
mesh_terms: D000328:Adult; D000483:Alleles; D005190:Family; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics*; D015894:Genome, Human; D057895:Haploinsufficiency; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007011:Hypoparathyroidism / Q000235:genetics*; D008297:Male; D009401:Nephrosis / Q000235:genetics*; D010375:Pedigree; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D013624:Taiwan
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D012333:RNA, Messenger
keywords: Deafness; Genetic diagnosis; HDR syndrome; Massively parallel sequencing