title: DNA sequence analysis and genotype-phenotype assessment in 71 patients with syndromic hearing loss or auditory neuropathy.
abstract: OBJECTIVE
  Aetiological assessment of 71 probands whose clinical presentation suggested a genetic syndrome or auditory neuropathy.
  
  
  METHODS
  Sanger sequencing was performed on DNA isolated from peripheral blood or lymphoblastoid cell lines. Genes were selected for sequencing based on each patient's clinical presentation and suspected diagnosis. Observed DNA sequence variations were assessed for pathogenicity by review of the scientific literature, and mutation and polymorphism databases, through the use of in silico tools including sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen), and according to the recommendations of the American College of Medical Genetics and Genomics for the interpretation of DNA sequence variations. Novel DNA sequence variations were sought in controls.
  
  
  RESULTS
  DNA sequencing of the coding and near-coding regions of genes relevant to each patient's clinical presentation revealed 37 sequence variations of known or uncertain pathogenicity in 9 genes from 25 patients. 14 novel sequence variations were discovered. Assessment of phenotypes revealed notable findings in 9 patients.
  
  
  CONCLUSIONS
  DNA sequencing in patients whose clinical presentation suggested a genetic syndrome or auditory neuropathy provided opportunities for aetiological assessment and more precise genetic counselling of patients and families. The failure to identify a genetic aetiology in many patients in this study highlights the extreme heterogeneity of genetic hearing loss, the incompleteness of current knowledge of aetiologies of hearing loss, and the limitations of conventional DNA sequencing strategies that evaluate only coding and near-coding segments of genes.
authors.affiliation: Bobby R Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Hsiao-Yuan
authors.initials: HY
authors.lastname: Tang
authors.affiliation: Medical Genetics Laboratories, Baylor College of Medicine, Houston, Texas, USA Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Fang
authors.affiliation: Bobby R Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Lin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Darilek
authors.affiliation: Bobby R Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Brooke T
authors.initials: BT
authors.lastname: Osborne
authors.affiliation: Bobby R Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Jo Ann
authors.initials: JA
authors.lastname: Haymond
authors.affiliation: Department of Otorhinolaryngology-Head & Neck Surgery, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, USA.
authors.forename: Spiros
authors.initials: S
authors.lastname: Manolidis
authors.affiliation: Myriad Genetic Laboratories, Salt Lake City, Utah, USA.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Roa
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Stanford University, Stanford, California, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Oghalai
authors.affiliation: Bobby R Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Raye L
authors.initials: RL
authors.lastname: Alford
mesh_terms: D001483:Base Sequence; D004247:DNA; D005838:Genotype; D006309:Hearing; D034381:Hearing Loss / Q000209:etiology / Q000235:genetics*; D006313:Hearing Loss, Central / Q000209:etiology / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D013577:Syndrome
chemical_list: D004247:DNA
keywords: GENETICS; OTOLARYNGOLOGY