Whole Exome Sequencing and Homozygosity Mapping Identify Mutation in the Cell Polarity Protein GPSM2 as the Cause of Nonsyndromic Hearing Loss DFNB82

Abstract

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 underlying hearing loss.

Disease gene identification strategies for exome sequencing

“…Hence, it is important that reliable population frequencies are obtained for variants in control data sets, as this will allow the exclusion of variants that are present at frequencies higher than the expected carrier frequency. Walsh et al 35 warned about the use of uncurated variant databases. One of the pathogenic mutations they identified was recorded in dbSNP as a known variant based on a single study.…”

Identification of OSBPL2 as a novel candidate gene for progressive nonsyndromic hearing loss by whole-exome sequencing

“…[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] It is estimated that more than 230 novel rare disease genes have been discovered to date using WES. 11 Several new NSHLcausative genes have also recently been revealed via WES, including GPSM2, DNMT1, BDP1, ELMOD3, TNC, GRXCR2, and ADCY1.…”

“…11 Several new NSHLcausative genes have also recently been revealed via WES, including GPSM2, DNMT1, BDP1, ELMOD3, TNC, GRXCR2, and ADCY1. [12][13][14][15][16][17][18] Thus, WES is a powerful approach for investigating the genetic basis of human disease.…”

Novel myosin mutations for hereditary hearing loss revealed by targeted genomic capture and massively parallel sequencing

“…3,[23][24][25] All known deafness-causing mutations in the Palestinian population were excluded, including mutations in CDH23, MYO7A, MYO15A, OTOF, PJVK, SLC26A4, TECTA, TMHS, TMPRSS3, OTOA, PTPRQ and GPSM2. 22,26,27 Massive parallel sequencing Capture libraries were created and MPS was performed, followed by bioinformatics analysis, as previously described. 28,29 Exons and the flanking 40 bp into the introns of 284 human deafness-associated genes were captured using the SureSelect Target Enrichment Solution (Agilent, Santa Clara, CA, USA) and sequenced on an Illumina HiSeq 2000 Analyzer (HT-Seq Unit, Technion, Haifa, Israel).…”