非综合性耳聋.pdfVIP

REPORT Whole Exome Sequencing and Homozygosity Mapping Identify Mutation in the Cell Polarity Protein GPSM2 as the Cause of Nonsyndromic Hearing Loss DFNB82 Tom Walsh,1,4,* Hashem Shahin,2,4 Tal Elkan-Miller,3 Ming K. Lee,1 Anne M. Thornton,1 Wendy Roeb,1 Amal Abu Rayyan,2 Suheir Loulus,2 Karen B. Avraham,3 Mary-Claire King,1 and Moien Kanaan2,* Massively parallel sequencing of targeted regions, exomes, and complete genomes has begun to dramatically increase the pace of discovery of genes responsible for human disorders. Here we describe how exome sequencing in conjunction with homozygosity mapping led to rapid identification of the causative allele for nonsyndromic hearing loss DFNB82 in a consanguineous Palestinian family. After filtering out worldwide and population-specific polymorphisms from the whole exome sequence, only a single deleterious mutation remained in the homozygous region linked to DFNB82 . The nonsense mutation leads to an early truncation of the G protein signaling modulator GPSM2, a protein that is essential for maintenance of cell polarity and spindle orientation. In the mouse inner ear, GPSM2 is localized to apical surfaces of hair cells and supporting cells and is most highly expressed during embryonic development. Identification of GPSM2 as essential to the development of normal hearing suggests dysregulation of cell polarity as a mechanism under- lying hearing loss. Homozygosity mapping in consanguineous kindreds with was hybridized to biotinylated cRNA oligonucleotide baits nonsyndromic hearing loss has led to the discovery of from the SureSelect Human All Exon kit (Agilent Technol- more than 50 recessive deafness loci.1 Genomic regions ogies), purified by streptavidin-bound magnetic beads, linked to hearing loss by homozygosity mapping are gener-