GENOMIC ANALYSES IDENTIFY NEW LOCUS AND GENE IN NON-SYNDROMIC MICROTIA
Maria Alexandra Artunduaga, MD1, Maria de Lourdes Quintanilla-Dieck, MD2, Microtia Research Group1, Roland D. Eavey, MD, SM3, Christine E. Seidman, MD4, Jonathan G. Seidman, PhD1.
1Department of Genetics, Harvard Medical School, Boston, MA, USA, 2Department of Otolaryngology-Head and Neck Surgery, Oregon Health & Science University, Portland, OR, USA, 3Vanderbilt Bill Wilkerson Center for Otolaryngology and Communication Sciences, Vanderbilt University School of Medicine, Department of Otolaryngology, Nashville, TN, USA, 4Howard Hughes Medical Institute, Boston, MA, USA.
BACKGROUND: Microtia is a major congenital anomaly of the external and middle ear that co-associates with conductive hearing loss (80%) and with hemifacial microsomia (40%), the second most common craniofacial malformation after cleft lip and cleft palate. Although twin and family-based studies have suggested a significant genetic basis for non-syndromic microtia, no specific genetic defect has been yet identified. We hypothesized that some isolated microtia cases might reflect mutations that alter gene dosage of molecules that are required for ear development.
METHODS: To assess whether copy number variants (CNVs) contribute to its etiology we surveyed 41 family trios (microtia cases and their unaffected parents) using the Affymetrix Human 6.0 SNP Chip array. Deep sequence analyses of gene expression (DSAGE) were used to determine levels of expression of identified candidate genes in microtic and normal ear cartilage. High-through massively parallel sequencing in 48 microtia cases and 48 healthy controls using a filter-based subgenome capture strategy was used to detect genetic variants within the same candidate genes.
RESULTS: We identified one de novo (i.e. non-heritable) CNV that was absent in 2,099 controls (p =0.019; OR > 100). The finding was further reconfirmed by multiplex ligation-dependent probe amplification (MLPA). The CNV is a duplication located at chromosome 1q32.1 and encompasses three candidate genes. Gene expression analyses of human auricular cartilage, showed significantly increased levels of RNA encoding one of the candidate genes. The application of filter-based hybridization capture on microtia subjects and healthy controls detected two non-synonymous variants that produce non-conservative AA changes in the same candidate gene.
CONCLUSIONS: A novel locus and gene for non-syndromic microtia have been identified in chromosome 1q32.1. The candidate gene encodes a protein that has transcriptional repression properties from histone demethylation, which suggests that microtia may result from post-translational events that occur early in embryogenesis.
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