title: SIX2 haploinsufficiency causes conductive hearing loss with ptosis in humans.
abstract: The ossicles represent one of the most fundamental morphological features in evolutionary biology of the mammalians. The mobile ossicular morphology abnormalities result in the severe conductive hearing loss. Development and patterning of the middle ear malformation depend on genetic and environmental causes. However, the genetic basis for the risk of congenital ossicle malformation is poorly understood. We show here nine affected individuals in a Chinese pedigree who had bilateral conductive hearing loss with ptosis. We performed whole-genome sequencing and array comparative genomic hybridization (CGH) analysis on DNA samples from the Chinese pedigree. We confirmed the presence of a novel 60 kb heterozygous deletion in size, encompassing SIX2 in our family. Mutation screening in 169 sporadic cases with external ear and middle ear malformations identified no pathogenic variant or polymorphism. We suggest SIX2 haploinsufficiency as a potential congenital factor could be attributed to developmental malformation of the middle ear ossicles and upper eyelid. To the best of our knowledge, this is the first report to provide a description of copy number variation in the SIX2 gene resulting in syndromic conductive hearing loss.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Jing
authors.identifier: http://orcid.org/0000-0002-1134-1172
authors.initials: J
authors.lastname: Guan
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Dayong
authors.initials: D
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Renqian
authors.initials: R
authors.lastname: Du
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Lan
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zong
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Ju
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Zifang
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Wang
mesh_terms: D001299:Audiometry; D001706:Biopsy; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D056726:Genetic Association Studies; D057895:Haploinsufficiency; D006314:Hearing Loss, Conductive / Q000175:diagnosis* / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011859:Radiography; D036542:Tomography, Spiral Computed
chemical_list: D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; C484762:SIX2 protein, human