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Whole Exome Sequencing and Homozygosity Mapping Identify Mutation in the Cell Polarity Protein GPSM2

Summary: 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
nonsyndromic hearing loss has led to the discovery of
more than 50 recessive deafness loci.1
Genomic regions
linked to hearing loss by homozygosity mapping are gener-


Source: Avraham, Karen - Department of Human Genetics and Molecular Medicine, Tel Aviv University


Collections: Biology and Medicine