Genetic Studies of Inner Ear Anomalies

内耳异常的遗传学研究

• 批准号: 8422463
• 负责人: MUSTAFA TEKIN
• 金额: $ 64.89万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8422463
• 关键词: Affect; American; Animal Model; Animals; Bioinformatics; Biological; Birth; Candidate Disease Gene; Child; Clinic; Clinical; Clinical Data; Cochlea; Collaborations; Consanguinity; Counseling; DNA; Data; Development; Diagnosis; Diagnostic; Dideoxy Chain Termination DNA Sequencing; Disease; Ear; Embryonic Development; Ethnic Origin; Family; Family Sizes; Family member; Fishes; Foundations; Functional disorder; Gene Expression Regulation; Gene Frequency; Genes; Genetic; Genetic Counseling; Genome; Genomics; Genotype; Goals; Health; Hearing Impaired Persons; Hereditary Disease; Heterogeneity; Human; Individual; Infant; Institutes; International; Knowledge; Labyrinth; Lead; Magnetic Resonance Imaging; Maps; Measures; Modeling; Molecular; Molecular Diagnostic Testing; Mus; Mutation; Orthologous Gene; Outcome; Parents; Participant; Pathogenesis; Pathway interactions; Population; Quality Control; Recruitment Activity; Reporting; Research Personnel; Resources; Role; Sampling; Scanning; Sensorineural Hearing Loss; Sensory; Severities; Siblings; Syndrome; Technology; Time; Tissues; Universities; Variant; Zebrafish; base; clinically significant; computerized; deafness; disorder prevention; exome; exome sequencing; gene discovery; genetic pedigree; genome-wide; hearing impairment; improved; knock-down; member; mouse model; novel; positional cloning; prevent; repository; screening; segregation; tool

DESCRIPTION (provided by applicant): Clinically significant hearing loss is present in at least 1.9 per 1,000 infants at birth and affects at least 30% of the population at some time in their lives. Inner ear anomalies, detected by a computerized scan or magnetic resonance imaging study, have been reported in up to one third of children with deafness. Despite recent progress in identifying genes that determine many forms of syndromic and non-syndromic sensorineural hearing loss, the genetic pathogenesis of inner ear anomalies has remained largely unknown. Most of the individuals with inner ear anomalies are the only affected members of their families (simplex) or come from small-sized families preventing the usage of traditional positional cloning strategies. Recent advances in sequencing technology have provided unprecedented opportunities for the large scale screening of DNA variation throughout individual genomes and opened the way of gene discovery in small-sized families or in simplex cases. We have successfully applied this technology to identification of responsible DNA changes in various Mendelian disorders. In this study we will use our existing Repository of participants with inner ear anomalies that currently contains biological samples and clinical data from 203 families. Parental consanguinity is present in 10 families, 3 of which are multiplex, providing strong evidence for autosomal recessive inheritance. DNA samples from families will undergo genotyping with genomewide SNP arrays to detect autozygous regions in families with parental consanguinity and to identify potential pathogenic copy number variants. Then, whole exome sequencing and bioinformatics analysis with an established exome analysis pipeline at the Hussman Institute for Human Genomics (HIHG) will be applied to find causative variants. Co- segregating homozygous variants in consanguineous families and de novo variants in simplex families will be further investigated. Sanger sequencing and TaqMan genotyping will serve to screen additional families, and to study variant allele frequencies in ethnicity-matched controls. To support the role of identified changes in pathophysiology, zebrafish models will be rapidly produced. Further support will be obtained from mouse models. The outcomes of this proposal will be discoveries of new genes/pathways involved in the development of the inner ear in humans and foundation of clinical molecular diagnostic tests for better diagnosis and counseling of deaf individuals with inner ear anomalies.

描述(由申请人提供)：在出生时，每1000名婴儿中至少有1.9人出现临床上严重的听力损失，在他们一生中的某个时候，至少有30%的人受到影响。据报道，通过电脑扫描或磁共振成像研究发现的内耳异常，在多达三分之一的耳聋儿童中存在。尽管最近在识别决定多种形式的综合征性和非综合征性感音神经性耳聋的基因方面取得了进展，但内耳畸形的遗传发病机制仍然很大程度上是未知的。大多数患有内耳畸形的人是他们家庭中唯一受影响的成员(单纯性)或来自阻止使用传统位置克隆策略的小家庭。最近测序技术的进步为大规模筛选个体基因组中的DNA变异提供了前所未有的机会，并为在小家庭或单纯性病例中发现基因开辟了道路。我们已经成功地将这项技术应用于识别各种孟德尔疾病的负责任的DNA变化。在这项研究中，我们将使用我们现有的内耳畸形参与者资料库，其中目前包含来自203个家庭的生物样本和临床数据。10个家系中有亲缘关系，其中3个家系为复合家系，为常染色体隐性遗传提供了有力证据。来自家庭的DNA样本将通过全基因组SNP阵列进行基因分型，以检测有父母血缘关系的家庭中的纯合子区域，并确定潜在的致病拷贝数变异。然后，整个外显子组测序和生物信息学分析将利用在赫斯曼人类基因组研究所(Hihg)建立的外显子组分析管道来寻找致病变异。在近亲家庭中共分离纯合子变异和在单纯型家庭中的从头变异将被进一步研究。Sanger测序和TaqMan基因分型将用于筛选更多的家系，并研究种族匹配对照中的变异等位基因频率。 为了支持已确定的变化在病理生理学中的作用，将迅速制作斑马鱼模型。将从老鼠模型中获得进一步的支持。这项建议的结果将是发现与人类内耳发育有关的新基因/途径，并为更好地诊断和咨询患有内耳异常的聋人奠定临床分子诊断测试的基础。