Genetic Studies of Inner Ear Anomalies

描述（由申请人提供）：每1,000名婴儿中至少有1.9名在出生时存在临床显著的听力损失，并且在其生命中的某个时间影响至少30%的人口。据报道，通过计算机扫描或磁共振成像研究发现的内耳异常发生在多达三分之一的耳聋儿童中。尽管最近在鉴定决定许多形式的综合征和非综合征感音神经性听力损失的基因方面取得了进展，但内耳异常的遗传发病机制在很大程度上仍然未知。大多数患有内耳异常的个体是其家族中唯一受影响的成员（单纯型），或者来自阻止使用传统定位克隆策略的小规模家族。 测序技术的最新进展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，并为小规模家庭或单纯病例的基因发现开辟了道路。我们已经成功地将这项技术应用于鉴定各种孟德尔疾病中负责的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库，该库目前包含来自203个家庭的生物样本和临床数据。10个家系存在双亲血缘关系，其中3个为多重血缘，为常染色体隐性遗传提供了有力证据。 来自家庭的DNA样本将使用全基因组SNP阵列进行基因分型，以检测具有父母血缘关系的家庭中的纯合子区域，并鉴定潜在的致病性拷贝数变异。 然后，在Hussman人类基因组学研究所（HIHG）建立的外显子组分析管道的全外显子组测序和生物信息学分析将被应用于发现致病变异。共分离纯合变异的血缘关系的家庭和新的变异在单纯的家庭将进一步调查。桑格测序和TaqMan基因分型将用于筛选其他家族，并研究种族匹配对照中的变异等位基因频率。 为了支持已确定的病理生理学变化的作用，将迅速制作斑马鱼模型。 将从小鼠模型中获得进一步的支持。该提案的成果将是发现与人类内耳发育有关的新基因/途径，并建立临床分子诊断测试，以更好地诊断和咨询患有内耳异常的聋人。

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.