title: A novel frameshift variant of COCH supports the hypothesis that haploinsufficiency is not a cause of autosomal dominant nonsyndromic deafness 9.
abstract: COCH (coagulation factor C homology) encodes cochlin, and certain mutations of COCH cause autosomal dominant nonsyndromic deafness 9 (DFNA9). Hearing loss due to COCH mutation begins in adulthood, and 17 missense mutations and two in-frame mutations have been reported. Studies with animal and cellular models have suggested that the underlying biological mechanism of DFNA9 is the dominant-negative effect of mutated COCH and not haploinsufficiency. However, no human cases of DFNA9 that support this hypothesis have been reported. The proband of the present case was an 18-year-old male with congenital or infantile hearing loss. Targeted next-generation sequencing analysis detected a heterozygous novel frameshift mutation of COCH (c.146dupT, p.C50LfsX8) in the proband, whose hearing loss began earlier than what is typical for DFNA9. His mother also carried the mutation but had normal hearing. Consequently, the mutation was not considered to be the cause of the proband's hearing loss. This family is the first case of a truncating COCH variant and supports the hypothesis that COCH haploinsufficiency is not the cause of hearing loss in humans.
authors.affiliation: Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka Meguro-ku, Tokyo 152-8902, Japan; Department of Otolaryngology, School of Medicine, Kyorin University, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan. Electronic address: masoeur13@mac.com.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Masuda
authors.affiliation: Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka Meguro-ku, Tokyo 152-8902, Japan. Electronic address: mutaihideki@kankakuki.go.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Mutai
authors.affiliation: Department of Otolaryngology, Chiba Children's Hospital, 579-1 Hetacho, Midori-ku, Chiba-shi, Chiba 266-0007, Japan. Electronic address: y.armt1@pref.chiba.lg.jp.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Arimoto
authors.affiliation: Department of Otolaryngology, Chiba Children's Hospital, 579-1 Hetacho, Midori-ku, Chiba-shi, Chiba 266-0007, Japan. Electronic address: a.nkn@pref.chiba.lg.jp.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nakano
authors.affiliation: Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka Meguro-ku, Tokyo 152-8902, Japan; Medical Genetics Center, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka Meguro-ku, Tokyo 152-8902, Japan. Electronic address: matsunagatatsuo@kankakuki.go.jp.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Matsunaga
mesh_terms: D000293:Adolescent; D000328:Adult; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D016368:Frameshift Mutation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D057895:Haploinsufficiency / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: C110668:COCH protein, human; D016326:Extracellular Matrix Proteins
keywords: COCH; DFNA9; Frameshift variant; Haploinsufficiency; Hearing loss; ISO7029; International Organization for Standardization 7029; NGS; autosomal dominant nonsyndromic deafness 9; coagulation factor C homology; next-generation sequencing