Strong founder effect of p.P240L in CDH23 in Koreans and its significant contribution to severe-to-profound nonsyndromic hearing loss in a Korean pediatric population.
BACKGROUND
Despite the prevalence of CDH23 mutations in East Asians, its large size hinders investigation. The pathologic mutation p.P240L in CDH23 is common in East Asians. However, whether this mutation represents a common founder or a mutational hot spot is unclear. The prevalence of CDH23 mutations with prelingual severe-to-profound sporadic or autosomal recessive sensorineural hearing loss (arSNHL) is unknown in Koreans.


METHODS
From September 2010 to October 2014, children with severe-to-profound sporadic or arSNHL without phenotypic markers, and their families, were tested for mutations in connexins GJB2, GJB6 and GJB3. Sanger sequencing of CDH23 p.P240L was performed on connexin-negative samples without enlarged vestibular aqueducts (EVA), followed by targeted resequencing of 129 deafness genes, including CDH23, unless p.P240L homozygotes were detected in the first screening. Four p.P240L-allele-linked STR markers were genotyped in 40 normal-hearing control subjects, and the p.P240L carriers in the hearing-impaired cohort, to identify the haplotypes.


RESULTS
Four (3.1 %) of 128 children carried two CDH23 mutant alleles, and SLC26A4 and GJB2 accounted for 18.0 and 17.2 %, respectively. All four children showed profound nonsyndromic SNHL with minimal residual hearing. Interestingly, all had at least one p.P240L mutant allele. Analysis of p.P240L-linked STR markers in these children and other postlingual hearing-impaired adults carrying p.P240L revealed that p.P240L was mainly carried on a single haplotype.


CONCLUSIONS
p.P240L contributed significantly to Korean pediatric severe arSNHL with a strong founder effect, with implications for future phylogenetic studies. Screening for p.P240L as a first step in GJB2-negative arSNHL Koreans without EVA is recommended.
Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea. sossi81@hanmail.net.
So Young
SY
Kim
Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea. teddyepo@naver.com.
Ah Reum
AR
Kim
Samsung Genome Institute, Samsung Medical Center, Seoul, Korea. bionkdk@gmail.com.
Nayoung K D
NK
Kim
Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, 463-707, Korea. my911@paran.com.
Min Young
MY
Kim
Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, 463-707, Korea. ever0608@naver.com.
Eun-Hee
EH
Jeon
Department of Otorhinolaryngology-Head and Neck Surgery, Dankook University Hospital, Cheonan, Korea. bj_king@daum.net.
Bong Jik
BJ
Kim
Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea. 5a796@snubh.org.
Young Eun
YE
Han
Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea. caduent@gmail.com.
Mun Young
MY
Chang
Samsung Genome Institute, Samsung Medical Center, Seoul, Korea. woongyang@gmail.com.|Department of Molecular Cell Biology, School of Medicine, Sungkyunkwan University, Seoul, Korea. woongyang@gmail.com.
Woong-Yang
WY
Park
Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, 463-707, Korea. choiby@snubh.org.|Sensory Organ Research Institute, Seoul National University Medical Research Center, Seoul, Korea. choiby@snubh.org.
Byung Yoon
BY
Choi
D000483:Alleles; D044466:Asian People / Q000235:genetics*; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics*; D002648:Child; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D015331:Cohort Studies; D000072259:Connexin 26; D017630:Connexins; D003638:Deafness / Q000235:genetics; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010375:Pedigree
C442480:CDH23 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26