title: Resolving the genetic heterogeneity of prelingual hearing loss within one family: Performance comparison and application of two targeted next generation sequencing approaches.
abstract: Here, we report an unconventional Chinese pedigree consisting of three branches all segregating prelingual hearing loss (HL) with unclear inheritance pattern. After identifying the cause of one branch as maternally inherited aminoglycoside-induced HL, targeted next generation sequencing (NGS) was applied to identify the genetic causes for the other two branches. One affected subject from each branch was subject to targeted NGS whose genomic DNA was enriched either by whole-exome capture (Agilent SureSelect All Exon 50 Mb) or by candidate genes capture (Agilent SureSelect custom kit). By NGS analysis, we identified that patients from Branch A were compound heterozygous for p.E1006K and p.D1663V in the CDH23 (DFNB12) gene; and patients from Branch B were homozygous for IVS7-2A>G in the SLC26A4 (DFNB4) gene. Both CDH23 mutations altered conserved calcium binding sites of the extracellular cadherin domains. The co-occurrence of three different genetic causes in this family was exceedingly rare but fully compatible with the mutation spectrum of HL. Our study has also raised several technical and analytical issues when applying the NGS technique to genetic testing.
authors.affiliation: Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lu
authors.affiliation: 1] MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing, China [2] Department of Psychiatry, The University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Xueya
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Otolaryngology, Chinese PLA Air Force General Hospital, Beijing, China.
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Shen
authors.affiliation: Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Ji
authors.affiliation: MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing, China.
authors.forename: Liyang
authors.initials: L
authors.lastname: Liu
authors.affiliation: MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing, China.
authors.forename: Xuegong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 1] MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing, China [2] MCB, Center for Systems Biology, The University of Texas at Dallas, Richardson, TX, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Zhang
authors.affiliation: 1] Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, China [2] CUHK-University of Utrecht Joint Centre for Language, Mind and Brain, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Dongyi
authors.initials: D
authors.lastname: Han
authors.affiliation: 1] Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, China [2] CUHK-University of Utrecht Joint Centre for Language, Mind and Brain, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, China.
authors.forename: KwongWai
authors.initials: K
authors.lastname: Choy
authors.affiliation: Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Yuan
mesh_terms: D000293:Adolescent; D000328:Adult; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics; D005192:Family Health; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D012335:RNA, Ribosomal / Q000235:genetics; D015203:Reproducibility of Results; D000076988:Sulfate Transporters; D055815:Young Adult
chemical_list: C442480:CDH23 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D026901:Membrane Transport Proteins; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters