Further studies on the spectrum, prevalence rates, and functional effect of sequence variants in the TMIE gene in other populations should demonstrate the true importance of this gene as a cause of hearing impairment. The prevalence of functional TMIE variants in Pakistani families is 1.7%. Conservation and potential functionality of previously published mutations were also examined. The c.92A>G (p.E31G) variant occurred at a residue that is conserved in the mouse and is predicted to be extracellular. Two novel variants, c.92A>G (p.E31G) and the splice site mutation c.212–2A>C, were identified in one Pakistani and one Jordanian family, respectively. The previously reported c.241C>T (p.R81C) variant was observed in two Pakistani families. Of seven families that were screened for TMIE, putatively functional sequence variants were found to segregate with hearing impairment in four families but were not seen in not less than 110 ethnically matched control chromosomes. The evolutionary conservation and location in predicted protein domains of amino acid residues where sequence variants occurred were studied to elucidate the possible effects of these sequence variants on function. Two-point and multipoint parametric linkage analyses were performed, and families with logarithmic odds (LOD) scores of 1.0 or greater within the TMIE region underwent further DNA sequencing. To determine putatively functional sequence variants in the transmembrane inner ear ( TMIE) gene in Pakistani and Jordanian families with autosomal recessive (AR) NSHI, four Jordanian and 168 Pakistani families with ARNSHI that is not due to GJB2 (CX26) were submitted to a genome scan. Identifying the functional sequence variants within these genes and knowing their population-specific frequencies is of public health value, in particular for genetic screening for NSHI. To date, 37 genes have been identified for nonsyndromic hearing impairment (NSHI).
El-Shanti, Hatem Sikandar, Shaheen Lee, Kwanghyuk Bhatti, Attya Yan, Kai Chahrour, Maria H. Novel sequence variants in the TMIE gene in families with autosomal recessive nonsyndromic hearing impairment
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