Genetic Studies of Inner Ear Anomalies

描述（由申请人提供）：临床意义上的听力损失在出生时至少有1.9 / 1000的婴儿存在，影响至少30%的人口在他们生命中的某个时间。据报道，通过计算机扫描或磁共振成像研究发现，多达三分之一的耳聋儿童存在内耳异常。尽管最近在确定多种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。大多数内耳异常的个体是其家庭中唯一受影响的成员（单纯性）或来自小型家庭，因此无法使用传统的位置克隆策略。近年来测序技术的进步为在个体基因组中大规模筛选DNA变异提供了前所未有的机会，并为在小型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鉴定各种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个家庭的生物样本和临床数据。10个家族存在亲本血缘关系，其中3个为多家系，为常染色体隐性遗传提供了有力证据。来自家庭的DNA样本将使用全基因组SNP阵列进行基因分型，以检测亲本亲属家庭中的自合区域，并确定潜在的致病性拷贝数变异。然后，利用Hussman人类基因组研究所（HIHG）建立的外显子组分析管道进行全外显子组测序和生物信息学分析，以发现致病变异。近亲家族的共分离纯合变异体和单一家族的新生变异体将进一步研究。Sanger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。

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.