title: GJB2-associated hearing loss undetected by hearing screening of newborns.
abstract: The hearing loss caused by GJB2 mutations is usually congenital in onset, moderate to profound in degree, and non-progressive. The objective of this study was to study genotype/phenotype correlations and to document 14 children with biallelic GJB2 mutations who passed newborn hearing screening (NHS). Genetic testing for GJB2 mutations by direct sequencing was performed on 924 individuals (810 families) with hearing loss, and 204 patients (175 families) were found to carry biallelic GJB2 mutations. NHS results were obtained through medical records. A total of 18 pathological mutations were identified, which were subclassified as eight inactivating and 10 non-inactivating mutations. p.I128M and p.H73Y were identified as novel missense GJB2 mutations. Of the 14 children with biallelic GJB2 mutations who passed NHS, eight were compound heterozygotes and 3 were homozygous for the c.235delC mutation in GJB2, and the other three combinations of non-c.235delC mutations identified were p.Y136X-p.G45E/p.V37I heterozygous, c.512ins4/p.R143W heterozygous, and p.V37I/p.R143W heterozygous. These 14 cases demonstrate that the current NHS does not identify all infants with biallelic GJB2 mutations. They suggest that the frequency of non-penetrance at birth is approximately 6.9% or higher in DFNB1 patients and provide further evidence that GJB2 hearing loss may not always be congenital in onset.
authors.affiliation: Department of Otolaryngology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan; Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
authors.forename: Shujiro B
authors.initials: SB
authors.lastname: Minami
authors.forename: Hideki
authors.initials: H
authors.lastname: Mutai
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nakano
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Arimoto
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Taiji
authors.forename: Noriko
authors.initials: N
authors.lastname: Morimoto
authors.forename: Hideaki
authors.initials: H
authors.lastname: Sakata
authors.forename: Nodoka
authors.initials: N
authors.lastname: Adachi
authors.forename: Sawako
authors.initials: S
authors.lastname: Masuda
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Haruo
authors.initials: H
authors.lastname: Yoshida
authors.forename: Fujinobu
authors.initials: F
authors.lastname: Tanaka
authors.forename: Noriko
authors.initials: N
authors.lastname: Morita
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sugiuchi
authors.forename: Kimitaka
authors.initials: K
authors.lastname: Kaga
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Matsunaga
mesh_terms: D000595:Amino Acid Sequence; D002675:Child, Preschool; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D056726:Genetic Association Studies; D034381:Hearing Loss / Q000175:diagnosis* / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D009154:Mutation; D015997:Neonatal Screening / Q000379:methods*
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26
keywords: AABR; ABR; AOAE; Connexin 26; Cx26; DFNB1; HI; Hereditary hearing loss; I/I; I/NI; NHS; NI/NI; Newborn hearing screening; PolyPhen-2; auditory brainstem-evoked response; automated auditory brainstem response; automated otoacoustic emissions; biallelic inactivating; biallelic non-inactivating; compound heterozygous inactivating/non-inactivating; connexin 26; hearing impairment; newborn hearing screening; polymorphism phenotyping v2