MOLECULAR GENETICS OF HEREDITARY HEARING LOSS 
Geoffrey M. Duyk, M.D., Ph.D., Assistant Investigator 
Hearing loss is the most common form of sensory 
impairment. Profound childhood hearing loss has 
an incidence of 4-8 per 1,000 births in developed 
countries. In at least half of the cases, the likely etiol- 
ogy is a single gene mutation. It is estimated that as 
many as 5% of school-age children have unilateral 
and/or mild-to-moderate hearing loss, representing 
a potentially reversible cause of learning difficulty. 
In addition to early-onset hearing loss, progressive 
hearing loss, or presbycusis, occurs as part of the 
normal aging process. By the time we reach the age 
of 65, there is a one-in-six chance of having func- 
tionally significant hearing loss. 
While environmental causes such as acoustic 
trauma, infection, or ototoxic drugs play a signifi- 
cant causative role in auditory sensory impairment, 
underlying predisposing genetic factors are likely to 
be identified. Some types of genetic hearing loss can 
easily be distinguished, since they occur as part of a 
recognizable syndrome. Hearing loss is a major com- 
ponent in more than 100 defined genetic disorders. 
Nonsyndromic, or undifferentiated, hearing loss 
represents the second major category of hearing loss 
in which auditory sensory impairment is an isolated 
finding. Analysis of affected families is complicated 
by the difficulty in determining whether the hearing 
loss in the members is genetic or acquired. If the 
hearing loss is proved to be hereditary, analysis of 
pedigrees may be further complicated by genetic 
heterogeneity and nonassortative mating. The broad 
goal of Dr. Duyk's laboratory is to develop methods 
and resources to identify and study the genetic basis 
of nonsyndromic hearing loss. 
Genetics 
An important aspect of the laboratory's research is 
the identification of pedigrees that segregate hear- 
ing loss and are also suitable for linkage analysis. 
The genetic analysis of hearing loss in human popu- 
lations is complicated by the fact that many of these 
syndromes are not readily diff'erentiated from one 
another (genetic heterogeneity) and the fact that in- 
dividuals with profound hearing loss often inter- 
marry (nonassortative mating) . 
In collaboration with the Massachusetts Eye and 
Ear Infirmary (ME&EI), Dr. Duyk and his colleagues 
have identified two kindreds affected with an auto- 
somal dominant, progressive sensorineural hearing 
loss. The primary pathologic change appears to 
be deposition of mucopolysaccharide-containing 
ground substance in the cochlear and vestibular 
nerve channels that causes strangulation and subse- 
quent degeneration of the dendritic nerve channels. 
Julie Gastier (Department of Genetics, Harvard Med- 
ical School) and Dr. Umang Khetarpal (ME&EI) 
have initiated a study of this family, with a view to 
mapping the location of the gene and eventually 
identifying its molecular defect. 
In the study of hereditary hearing loss, pedigrees 
suitable for conventional linkage analysis are the ex- 
ception rather than the rule. To analyze families 
with nonsyndromic hearing loss that is most likely 
due to autosomal recessive loci, the alternative ap- 
proach of homozygosity mapping of affected indi- 
viduals in consanguineous pedigrees will be uti- 
lized, in conjunction with conventional linkage 
analysis of nuclear families with multiple affected 
siblings. The use of homozygosity mapping with af- 
fected offspring of first cousins is a much more effi- 
cient approach than reliance on small nuclear non- 
consanguineous pedigrees, since far fewer families 
may be expected to demonstrate linkage. This strat- 
egy involves looking for homozygosity of DNA vari- 
ants in affected children from consanguineous 
unions on the premise that the region adjacent to the 
disease locus will be homozygous by descent. Such 
approaches will identify candidate regions within 
the genome likely to encode a gene for nonsyn- 
dromic hearing loss. The feasibility and power of 
such approaches will dramatically improve with the 
increasing density of the human genetic map and 
the availability of highly informative polymerase 
chain reaction (PGR) -based short tandem-repeat 
polymorphisms (STRPs). 
Toward this end. Dr. Duyk's laboratory has devel- 
oped an efficient method (marker selection) for the 
construction of small insert genomic libraries 
highly enriched for selected classes of short tandem 
repeats (STRs). These libraries will aid in the pro- 
duction of high-resolution genetic maps composed 
of highly polymorphic, homogeneously distributed 
PCR-based markers. Members of Dr. Duyk's labora- 
tory (Jacqueline Pulido, Julie Gastier, and Wendi 
Beck) are developing STRP markers based on the 
large numbers of trinucleotide and tetranucleotide 
repeats isolated by improved versions of this 
method. In collaboration with Drs. Jeffrey Murray 
and Val Sheffield (University of Iowa), Dr. Kenneth 
Buetow (Fox Chase Cancer Center) , and Dr. James 
Weber (Marshfield Clinic), the laboratory will as- 
GENETICS 185 
