Environmental noise in Beirut, smoking and age are combined risk factors for hearing impairment.

Effect of smoking and environmental noise on hearing impairment was investigated in 440 people aged 21-50 years living in Beirut. Participants were divided into 4 groups: nonsmokers and smokers living in noisy areas (70-90 dBA) and non-smokers and smokers living in quiet areas (45-55 dBA). Smoking was associated with hearing loss at 8000 Hz, in both bivariate and multivariate analysis. An additive interaction at high frequencies (mostly at 8000 Hz) between smoking and noise appeared after age 40 years. At age 21-39 years, neither smoking nor environmental noise had a significant adverse effect on hearing capacity at low frequencies.

Environmental noise in Beirut, smoking and age are combined risk factors for hearing impairment

Effect of smoking and environmental noise on hearing impairment was investigated in 440 people aged 21-50 years living in Beirut. Participants were divided into 4 groups: nonsmokers and smokers living in noisy areas [70-90 dBA] and non-smokers and smokers living in quiet areas [45-55 dBA]. Smoking was associated with hearing loss at 8000 Hz, in both bivariate and multivariate analysis. An additive interaction at high frequencies [mostly at 8000 Hz] between smoking and noise appeared after age 40 years. At age 21-39 years, neither smoking nor environmental noise had a significant adverse effect on hearing capacity at low frequencies

A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness.

Using a candidate gene approach, we identified a novel human gene, OTOF, underlying an autosomal recessive, nonsyndromic prelingual deafness, DFNB9. The same nonsense mutation was detected in four unrelated affected families of Lebanese origin. OTOF is the second member of a mammalian gene family related to Caenorhabditis elegans fer-1. It encodes a predicted cytosolic protein (of 1,230 aa) with three C2 domains and a single carboxy-terminal transmembrane domain. The sequence homologies and predicted structure of otoferlin, the protein encoded by OTOF, suggest its involvement in vesicle membrane fusion. In the inner ear, the expression of the orthologous mouse gene, mainly in the sensory hair cells, indicates that such a role could apply to synaptic vesicles.

An alpha-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non-syndromic deafness, DFNB21.

In our efforts to identify new loci responsible for non-syndromic autosomal recessive forms of deafness, DFNB loci, we have pursued the analysis of large consanguineous affected families living in geographically isolated areas. Here, we report on the study of a Lebanese family comprising nine members presenting with a pre-lingual severe to profound sensorineural isolated form of deafness. Linkage analysis led to the characterization of a new locus, DFNB21, which was assigned to chromosome 11q23-25. Already mapped to this chromosomal region was TECTA. This gene encodes alpha-tectorin, a 2155 amino acid protein which is a component of the tectorial membrane. This gene recently has been shown to be responsible for a dominant form of deafness, DFNA8/12. Sequence analysis of the TECTA gene in the DFNB21-affected family revealed a G to A transition in the donor splice site (GT) of intron 9, predicted to lead to a truncated protein of 971 amino acids. This establishes that alpha-tectorin mutations can be responsible for both dominant and recessive forms of deafness. Comparison of the phenotype of the DFNB21 heterozygous carriers with that of DFNA8/12-affected individuals supports the hypothesis that the TECTA mutations which cause the dominant form of deafness have a dominant-negative effect. The present results provide genetic evidence for alpha-tectorin forming homo- or heteromeric structures.

A sensorineural progressive autosomal recessive form of isolated deafness, DFNB13, maps to chromosome 7q34-q36.

Deafness is the most frequent sensorineural defect in children. The vast majority of the prelingual forms of isolated deafness are highly genetically heterogeneous with an autosomal recessive mode of inheritance. Using linkage analysis, we have mapped the gene responsible for a severe progressive sensorineural hearing loss, DFNB13, segregating in a large consanguineous family living in an isolated region in northern Lebanon. A maximum lod score of 4.5 was detected for markers D7S661-D7S498. Recombination events and homozygosity mapping by descent define a 17 cM gene interval in the chromosome region 7q34-q36, between the markers D7S2468/D7S2505, on the proximal side, and D7S2439, on the distal side.

Map refinement of the Usher syndrome type 1B gene, MYO7A, relative to 11q13.5 microsatellite markers.

Usher syndrome (US) is clinically and genetically a heterogeneous group of disorders characterized by the association of deafness with retinitis pigmentosa. So far, eight genes responsible for US have been mapped, of which only the gene responsible for the most common form, USH1B, has been identified. The USH1B is a large gene containing 49 exons and encoding for an unconventional myosin-VIIA (MYO7A). Mutation analysis within the MYO7A gene showed a wide variety of mutations dispersed all over the gene. The present report refines the location of the MYO7A gene relative to microsatellite markers mapped to this region, thereby allowing a reliable and efficient carrier detection by linkage analysis.

The Usher syndrome in the Lebanese population and further refinement of the USH2A candidate region.

Usher syndrome (USH) is an autosomal-recessive disease characterized by neurosensory deafness and progressive retinitis pigmentosa. So far, three clinical types of Usher syndrome have been defined, and are caused by defects at more than eight loci. We report the linkage analysis of seven Lebanese families with Usher syndrome, two with type I (USH1) and five with type II (USH2). We demonstrate that one family is linked to the USH1C locus, a rare form of USH1 only reported in the French Acadian population. Linkage analysis of the five USH2 families with recently mapped loci allowed us to reduce the USH2A candidate region to a very small interval flanked by D1S2646/D1S2629 and D1S2827. Furthermore, haplotype comparison between the different families suggests a founder effect for the USH2A mutation among the different Lebanese ethnic groups, while a genetic heterogeneity is noted for Usher syndrome type I.

Identification of a locus on chromosome 7q31, DFNB14, responsible for prelingual sensorineural non-syndromic deafness.

In our efforts to identify new loci responsible for non-syndromic autosomal recessive forms of deafness, DFNB loci, we have pursued the analysis of large consanguineous affected families living in geographically isolated areas. Here, we report on the study of a Lebanese family affected with a prelingual profound sensorineural isolated form of deafness. Segregation analysis resulted in a linkage with locus D7S554 to locus D7S2459 on 7q31, with a maximum lod score of 6.3. The causative gene was mapped to a 15 cM interval extending from D7S527 to D7S3074 (on the telomeric side). The distal limit of this interval could be located between D7S496 and D7S3074 which are the closest polymorphic loci flanking the gene underlying Pendred syndrome (PDS) on the centromeric and on the telomeric sides, respectively. To eliminate PDS as a candidate gene, its 21 exons were sequenced. No mutation was detected. This study therefore reports the identification of a novel locus, DFNB14, on chromosome 7q31, in a position proximal to PDS.

Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene.

Prelingual non-syndromic (isolated) deafness is the most frequent hereditary sensory defect. In >80% of the cases, the mode of transmission is autosomal recessive. To date, 14 loci have been identified for the recessive forms (DFNB loci). For two of them, DFNB1 and DFNB2, the genes responsible have been characterized; they encode connexin 26 and myosin VIIA, respectively. In order to evaluate the extent to which the connexin 26 gene (Cx26) contributes to prelingual deafness, we searched for mutations in this gene in 65 affected Caucasian families originating from various countries, mainly tunisia, France, New Zealand and the UK. Six of these families are consanguineous, and deafness was shown to be linked to the DFNB1 locus, 10 are small non consanguineous families in which the segregation of the trait has been found to be compatible with the involvement of DFNB1, and in the remaining 49 families no linkage analysis has been performed. A total of 62 mutant alleles in 39 families were identified. Therefore, mutations in Cx26 represent a major cause of recessively inherited prelingual deafness since according to the present results they would underlie approximately half of the cases. In addition, one specific mutation, 30delG, accounts for the majority (approximately 70%) of the Cx26 mutant alleles. It is therefore one of the most frequent disease mutations so far identified. Several lines of evidence indicate that the high prevalence of the 30delG mutation arises from a mutation hot spot rather than from a founder effect. Genetic counseling for prelingual deafness has been so far considerably impaired by the difficulty in distinguishing genetic and non genetic deafness in families presenting with a single deaf child. Based on the results presented here, the development of a simple molecular test could be designed which should be of considerable help.

Mapping of DFNB12, a gene for a non-syndromal autosomal recessive deafness, to chromosome 10q21-22.

We report here, the localization of a new recessive non-syndromal deafness gene (DFNB12) to 10q21-22 by linkage analysis, of a Sunni family. Affected individuals suffer from congenital profound sensorineural hearing loss. A maximum LOD score of 6.40 (theta = 0.00) was obtained with locus D10S535. Analysis of patients carrying recombinations mapped the gene distal to D10S529 and proximal to D10S532, delineating an interval between 11 and 15 cM. Three deaf mouse mutants Jackson circler (jc), Waltzer (v) and Ames waltzer (av) have been localized to the homologous murine region on chromosome 10. Each of these mouse mutants is a candidate mouse model for the DFNB12-associated hearing impairment.

A gene responsible for a sensorineural nonsyndromic recessive deafness maps to chromosome 2p22-23.

The recessive mode of transmission accounts for approximately 75% of inherited non syndromic deafness cases. We have previously designed the conditions for linkage studies of this highly heterogeneous disorder [Guilford et al. (1994) Nature Genet. 6, 24-28]. Here, using a similar approach, we have studied the segregation of a gene responsible for congenital, profound and fully penetrant sensorineural deafness in a consanguineous family living in an isolated region of Lebanon. A maximum lod score of 8.03 (theta = 0.00) was detected with a new polymorphic marker, AFMa052yb5 (D2S2144). Observed recombinants and homozygosity mapping define a maximum interval of 2 cM for this gene, DFNB6, which lies between AFMb346ye5 (a new polymorphic marker) (D2S2303) and AFM254vc9 (D2S174) on chromosome 2p22-23.