A gene for non-syndromic autosomal dominant progressive postlingual sensorineural hearing loss maps to chromosome 14q12-13
A gene for non-syndromic autosomal dominant progressive postlingual sensorineural hearing loss maps to chromosome 14q12-13Evangelos N. Manolis1, Naidu Yandavi2,3,4, Joseph B. Nadol Jr1, Roland D. Eavey1, Michael McKenna1, Stella Rosenbaum2, Uman Khetarpal1,+, Christopher Halpin1, Saumil N. Merchant1, Geoffrey M. Duyk2,[dagger], Calum MacRae2, Christine E. Seidman3 and J. G. Seidman2,*
1Departments of Otolaryngology, Massachusetts Eye and Ear Infirmary and Otology and Laryngology, Harvard Medical School, Boston, MA 02114, USA, 2Department of Genetics and the Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA, 3Department of Medicine and the Howard Hughes Medical Institute, Brigham and Womens Hospital and Harvard Medical School, Boston, MA 02115, USA and 4Department of Pediatrics, Medical School, Boston, MA 02115, USA
Received February 19, 1996;Revised and Accepted March 29, 1996
We report a novel locus responsible for postlingual progressive sensorineural hearing loss (designated DFNA9) that maps to chromosome 14q12-13. A large kindred with autosomal dominant transmission of non-syndromic hearing loss was clinically studied. Hearing in affected individuals deteriorated at ~20 years of age and progressed to anacusis in the fifth decade. A random genome-wide search using polymorphic short tandem repeats demonstrated linkage with D14S121 (maximum two point LOD score = 6.19, [theta] = 0). Haplotype analysis of recombination events defined a 9 cM disease interval, between D14S252 and D14S49.
Hearing loss is a common form of sensory impairment, affecting millions of individuals worldwide (1 ). Hearing loss occurs from multiple etiologies including hereditary sensorineural hearing loss (SNHL) which has an estimated incidence of ~27/1000 persons (2 ). Since up to 30% of hereditary hearing loss is syndromic, phenotypic distinction of that subpopulation is clinically feasible (3 ). However, the majority of hereditary SNHL is non-syndromic. The phenotypes and audiometric findings of individuals with hereditary SNHL are frequently indistinguishable. Yet molecular analyses of autosomal dominant, non-syndromic SNHL has demonstrated genetic heterogeneity; nearly all families map to a unique locus (4 -8 ). These findings suggest the model of hearing as a complex function, and that malfunction of dissimilar structural or regulatory processes can produce the same final clinical result of hearing loss. Further mapping and identification of mutations that cause non-syndromic SNHL will hopefully identify many as yet unknown processes required for normal audition.
We have performed genetic linkage studies in a family with non-syndromic SNHL. Clinical evaluations and temporal bone histopathologic findings of the family have been reported previously (9 -11 ). Hearing loss is inherited as an autosomal dominant trait which begins at approximately age 20 years and progresses to total deafness. Affected individuals also have a unique finding: mucopolysaccharide depositions in the neural channels of the inner ear. Our analyses demonstrate that the locus (designated DFNA9) responsible for SNHL in this family maps to chromosome 14q12-13, ~5 cM from DFNB5 (12 ).
Based on complete audiologic examinations, 16 family members were identified as affected with progressive SNHL (Fig. 1 ). Five deceased individuals were considered affected based on medical and family histories. Thus a total of 21 affected individuals (alive and deceased) were identified among family members. The age onset of hearing loss ranged from 16 to 28 years (Table 1 ; mean = 21 years). All affected individuals reported slow progressive hearing loss, with no instances of rapid change. Audiologic examination demonstrated more pronounced hearing loss in the high frequencies (see Fig. 2 a). The threshold data was consistent with initially mild SNHL that progressed to a profound loss in mid-life (Fig. 2 b). In addition to the steady loss of sensitivity, affected individuals in their third decade of life developed a precipitous drop in word recognition (data not shown), which corresponded to a sharp decrease in both communication ability and satisfaction with hearing aids. By the fifth decade of life, four affected family members required cochlear implants (Table 1 ). Although the cochlea is non-functional, sufficient nerve fibers remained to allow successful use of the implant in these four family members. Five affected individuals utilize hearing aids (Table 1 ).
Autosomal dominant SNHL has been linked to several loci on chromosomes 1p32 (4 ), 4p15.3 (5 ), 5q31 (6 ), 13q12 (7 ) and 19q13 (8 ). Our data further elucidate the genetic heterogeneity of SNHL and demonstrate a locus (DFNA9) on chromosome 14q12-13. One gene defect responsible for congenital recessive hearing loss (DFNB5) has been mapped previously to chromosome 14 (12 ). However, DFNB5 is telomeric of D14S80 (12 ) while DFNA9 must be centromeric of D14S80 and is most likely centromeric of D14S252 (Fig. 3 ). Therefore, the disease intervals for these clinically distinct disorders have no overlap, and we conclude that DFNB5 and DFNA9 are not allelic, but are distinct hearing loci. DFNA9 does not co-map to any other previously described SNHL locus.
Despite the clinical similarities in phenotype among some of the unrelated families with SNHL, genetic analyses have demonstrated that there are many different defects that cause deafness. Identification of all SNHL genes should improve the diagnostic classification of hearing loss and may further define mechanisms of normal audition.
The temporal bone histopathology material available from two affected members of the family described here demonstrated unusual structural findings. The main pathologic observation was the deposition of mucopolysaccharide-laden substance in the channels of the cochlear and vestibular nerves, causing strangulation and degeneration of dendritic fibers (10 ,11 ). Deposits of mucopolysaccharides have been observed in the inner ears of patients with Hurler's syndrome (16 ) which maps to chromosome 4 (3 ). Such temporal bone deposits are an uncommon feature of pathologic material obtained from individuals with environmentally acquired, idiopathic, and/or other inherited forms of SNHL. We suspect that these deposits may be responsible for degeneration of sensory and neural elements, and thereby produce deafness in affected members of this family.
The progressive characteristic of this type of SNHL is of potential significance for much of the human population, since the most prevalent type of SNHL is late-onset and expressed in the elderly as presbycusis. Although at the present time there are no good candidate genes in the DFNA9 disease interval, we expect that mapping of the DFNA9 locus will eventually lead to the identification of the disease gene. Identification of the DFNA9 disease gene should further improve our understanding of one type of progressive SNHL and may offer future opportunities for intervention with rational therapy to mitigate further hearing loss.
This study was reviewed by and conducted in accordance with the Institutional Review Board of the Massachusetts Eye and Ear Infirmary. Family members from three generations were evaluated with a standard questionnaire and complete clinical examination including clinical vestibular testing. Fourteen family members were evaluated by one of us (C.C.H.) and two family members were evaluated by outside clinics. Audiologic evaluation took place in an ANSI standard clinical sound room. Hearing thresholds were found by air and bone conduction for 250-8000 Hz and word recognition was determined using 50-item CID W-22 lists on Compact Disk (Q/MASS Vol. 1). The level for word recognition testing was set to a region of maximum performance as predicted by the Articulation Index (13 ,14 ) and was never less than 70 dBHL. Family members with progressive sensorineural hearing loss beginning approximately at age 20 years and having no plausible alternative etiology were diagnosed as affected. Family members >30 years of age with normal audiometry findings were considered unaffected.
Peripheral blood samples obtained from each family member were used to produce Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (15 ), from which genomic DNA was isolated. Short tandem repeat polymorphisms located throughout the genomes were amplified using the polymerase chain reaction (PCR) with published primer nucleotide sequences and analyzed by polyacrylamide gel electrophoresis as described previously(15 ).
Two-point LOD (logarithm of the odds) scores were calculated using the MLINK (version 5.1) program assuming a penetrance of 0.95 and allele frequencies derived from unrelated individuals. Disease localization was refined using haplotype analysis of critical recombinants within the family.
We thank Mohammad Miri for help in transformation of cell lines. This work was supported in part by grants from the Howard Hughes Medical Institute to C.E.S. and J.G.S.
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*To whom correspondence should be addressed
+Present address: SUNY Health Science Center, Syracuse, NY 13210, USA
{Present address: Millenium Pharmaceuticals, Cambridge, MA 02138, USA
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