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.
The goals of the project are to identify new genes for deafness associated with inner ear anomalies and to establish a resource for research on inner ear anomalies including biological samples and clinical data from large numbers of affected families. The outcome of this proposal will expand the scientific knowledge on the genomic basis of inner ear anomalies and provide molecular diagnostic tools to the affected families.