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）：每1000名婴儿至少有1.9例出生时，临床上的听力损失至少有1.9，并且在他们一生中的某个时候至少影响了30％的人口。通过计算机扫描或磁共振成像研究检测到的内耳异常，已有多达三分之一的耳聋儿童据报道。尽管最近在确定确定多种形式综合征和非综合性感觉性听力丧失的基因方面取得了进展，但内耳异常的遗传发病机理仍在很大程度上未知。大多数患有内耳异常的人是其家庭中唯一受影响的成员（Simplex），或者来自避免使用传统位置克隆策略的小型家庭。 测序技术的最新进展为整个个体基因组的DNA变异进行了大规模筛查提供了前所未有的机会，并在小型家庭或单纯案例中打开了基因发现的方式。我们已成功地将该技术应用于孟德尔疾病中负责任的DNA变化。在这项研究中，我们将使用我们现有的内耳异常参与者存储库，该存储库目前包含来自203个家庭的生物样品和临床数据。父母的血统存在于10个家庭中，其中3个是多重的，为常染色体隐性遗传提供了有力的证据。 来自家族的DNA样本将使用全基因组的SNP阵列进行基因分型，以检测父母血缘家族的自卵区域，并鉴定潜在的致病拷贝数变异。 然后，将在侯斯曼人类基因组学研究所（HIHG）中使用已建立的外显子分析管道进行整个外显子组测序和生物信息学分析，以查找因果变体。将进一步研究单纯族家庭中的纯合变体的共同隔离变体。 Sanger测序和Taqman基因分型将有助于筛选其他家庭，并研究种族匹配的对照中的变异等位基因频率。 为了支持鉴定出病理生理学变化的作用，将迅速产生斑马鱼模型。 将从鼠标模型获得进一步的支持。该提案的结果将是发现人类内耳发展的新基因/途径以及临床分子诊断测试的基础，以更好地诊断和咨询内耳异常的聋人。