A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort.
The aim of the study was to determine the actual GJB2 and GJB6 mutation frequencies in North America after several years of generalized testing for autosomal recessive nonsyndromic sensorineural hearing loss to help guide diagnostic testing algorithms, especially in light of molecular diagnostic follow-up to universal newborn hearing screening.



Mutation types, frequencies, ethnic distributions, and genotype-phenotype correlations for GJB2 and GJB6 were assessed in a very large North American cohort.



GJB2 variants were identified in 1796 (24.3%) of the 7401 individuals examined, with 399 (5.4%) homozygous and 429 (5.8%) compound heterozygous. GJB6 deletion testing was performed in 12.0% (888/7401) of all cases. The >300-kb deletion was identified in only nine individuals (1.0%), all of whom were compound heterozygous for mutations in GJB2 and GJB6. Among a total of 139 GJB2 variants identified, 53 (38.1%) were previously unreported, presumably representing novel pathogenic or benign variants.



The frequency and distribution of sequence changes in GJB2 and GJB6 in North America differ from those previously reported, suggesting a considerable role for loci other than GJB2 and GJB6 in the etiology of autosomal recessive nonsyndromic sensorineural hearing loss, with minimal prevalence of the GJB6 deletion.
Putcha
Girish V
GV
Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
Bejjani
Bassem A
BA
Bleoo
Stacey
S
Booker
Jessica K
JK
Carey
John C
JC
Carson
Nancy
N
Das
Soma
S
Dempsey
Melissa A
MA
Gastier-Foster
Julie M
JM
Greinwald
John H
JH
Hoffmann
Marcy L
ML
Jeng
Linda Jo Bone
LJ
Kenna
Margaret A
MA
Khababa
Ishrag
I
Lilley
Margaret
M
Mao
Rong
R
Muralidharan
Kasinathan
K
Otani
Iris M
IM
Rehm
Heidi L
HL
Schaefer
Fred
F
Seltzer
William K
WK
Spector
Elaine B
EB
Springer
Michelle A
MA
Weck
Karen E
KE
Wenstrup
Richard J
RJ
Withrow
Stacey
S
Wu
Bai-Lin
BL
Zariwala
Maimoona A
MA
Schrijver
Iris
I
D002170:Canada; D000072259:Connexin 26; D000075302:Connexin 30; D017630:Connexins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D030342:Genetic Diseases, Inborn / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D034381:Hearing Loss / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008137:Longitudinal Studies; D008297:Male; D009154:Mutation; D040641:Quantitative Trait Loci; D014481:United States
D000075302:Connexin 30; D017630:Connexins; C000607042:GJB2 protein, human; C491020:GJB6 protein, human; D000072259:Connexin 26