A comprehensive introduction to the genetic basis of non-syndromic hearing loss in the Saudi Arabian population

Abstract

Background: Hearing loss is a clinically and genetically heterogeneous disorder. Mutations in the DFNB1 locus have been reported to be the most common cause of autosomal recessive non-syndromic hearing loss worldwide. Apart from DFNB1, many other loci and their underlying genes have also been identified and the basis of our study was to provide a comprehensive introduction to the delineation of the molecular basis of non-syndromic hearing loss in the Saudi Arabian population. This was performed by screening DFNB1 and to initiate prioritized linkage analysis or homozygosity mapping for a pilot number of families in which DFNB1 has been excluded.

Methods: Individuals from 130 families of Saudi Arabian tribal origin diagnosed with an autosomal recessive non-syndromic sensorineural hearing loss were screened for mutations at the DFNB1 locus by direct sequencing. If negative, genome wide linkage analysis or homozygosity mapping were performed using Affymetrix GeneChip® Human Mapping 250K/6.0 Arrays to identify regions containing any known-deafness causing genes that were subsequently sequenced.

Results: Our results strongly indicate that DFNB1 only accounts for 3% of non-syndromic hearing loss in the Saudi Arabian population of ethnic ancestry. Prioritized linkage analysis or homozygosity mapping in five separate families established that their hearing loss was caused by five different known-deafness causing genes thus confirming the genetic heterogeneity of this disorder in the kingdom.

Conclusion: The overall results of this study are highly suggestive that underlying molecular basis of autosomal recessive non-syndromic deafness in Saudi Arabia is very genetically heterogeneous. In addition, we report that the preliminary results indicate that there does not seem to be any common or more prevalent loci, genes or mutations in patients with autosomal recessive non-syndromic hearing loss in patients of Saudi Arabian tribal origin.

Figure 1

Family pedigrees, linkage analysis/homozygosity mapping, and mutation data. A) Pedigrees of five Saudi families segregating with autosomal recessive prelingual profound hearing loss. B) Linkage analysis showing LOD scores of 3.3 on chromosome 17 and 2.7 on chromosome 21 for families SS16 and KT1, indicating linkage to MYO15A and TMPRSS3 genes, respectively. Homozygosity mapping with GT console is shown for TRIC and LHFPL5 as genes of interest for families TA12 and SS3, respectively. For family SS17, homozygosity mapping with CNAG shows the region of homozygosity on chromosome 9 where TMC1 resides. C) Sequencing chromatogram of wild type, heterozygous and mutant alleles of respective deafness genes for a normal control, a carrier and affected member of each of the families.

Figure 2

Schematic presentation for the genomic localization and the sequence of splice site mutation. The IVS12-1 g>c mutation (indicated by an arrow) creates a 5' cryptic acceptor site (AG boxed in red) 8 bp downstream in exon 12 instead of a normal acceptor site (ag boxed in yellow). Sequencing of the mutant transcript shows that cryptic splice site leads to a frameshift and incorporation of faulty amino acids as compared to the wild type.