Biology Reference
In-Depth Information
Waardenburg (1951), Pendred (1896), Usher (1914), Treacher Collins
(1900), Jervelle and Lange-Nielsen (1957) and Nance (1971), Mendelian
transmission is well established and has allowed the mapping, demon-
stration of heterogeneity and/or cloning of more than 20 relevant genes.
Distinctive audiologic or otolaryngologic characteristics, such as low-
frequency (Vanderbilt University Hereditary Deafness Study Group 1968),
high-frequency (Nance and McConnell 1974), or progressive hearing loss
(Cremers 1979), or the presence of distinctive vestibular, cochlear or
ossicular abnormalities, can also be used to characterize different forms of
genetic deafness.
3.2 Non-Syndromic Deafness
Dramatic advances have also been made during the past decade in mapping
and cloning human genes for nonsyndromic deafness (Mueller, VanCamp,
and Lench, Chapter 4). Many factors have contributed to this progress.
These include the availability of increasingly dense maps of highly poly-
morphic markers, and knowledge of mouse homologs for comparative
gene mapping. In addition, sophisticated methodologies and linkage pro-
grams have been developed which exploit data on sib pairs (Penrose 1935;
Kruglyak and Lander 1995), consanguineous probands (Lander and
Botstein 1987), large multiplex families (Lathrop et al. 1984) identity by
descent (Haseman and Elston 1972), inbred isolates (Guilford et al. 1994)
and linkage disequilibrium (Friedman et al. 1994; Blanton et al. 1999).
The recognition of the value of deaf subjects from consanguineous mar-
riages for homozygosity mapping has played a major role in the successful
localization of many genes for recessive nonsyndromic deafness. Individu-
als of this type can be assumed to have inherited two copies of same reces-
sive mutation carried by one of their common ancestors. The disease gene,
along with closely linked markers are autozygous, or identical by descent.
The mapping strategy involves typing the consanguineous deaf offspring
and searching for chromosomal regions in which closely linked polymor-
phic markers are homozygous. Many of the markers now available are so
polymorphic that it is unusual to observe homozygosity. In these circum-
stances, the observation of even a few deaf offspring of consanguineous
marriages who are homozygous for alleles at the same locus may be suffi-
cient to map the gene. When Lander and Botstein (1987) first called atten-
tion to the power of this mapping strategy, they advocated the use of
isolated probands from consanguineous marriages and showed that as few
as six to eight could be sufficient to map a locus. In practice, though,
successful examples of homozygosity mapping have usually involved the
analysis of multiple affected individuals in large consanguineous kindreds.
However, the technique can be used successfully with isolated consan-
guineous probands, as was shown for biotinidase deficiency. Biotinidase
deficiency is a recessively transmitted defect in the recycling of the vitamin
