Biology Reference
In-Depth Information
10p patients can have highly variable expressivity of any or all of these find-
ings. Schuffenhaur et al. analyzed the deletions of 12 DGS2 patients, three
of whom had sensorineural hearing loss, and determined that the hearing
loss gene(s) within the DGS2 locus on 10p must reside just distal to marker
D10S1705 (Schuffenhauer et al. 1998).
2.2.3.3 Smith-Magenis Syndrome
Smith-Magenis syndrome is a contiguous gene-deletion syndrome origi-
nally described in 1982 and resulting from interstitial deletions in 17p11.2
(Fig. 5.7C). The phenotype includes brachycephaly, midface hypoplasia,
prognathism, deep hoarse voice, psychomotor and growth retardation,
and behavioral problems that include self-injurious behavior and sleep
disorders (OMIM 1999). Greenberg et al. (1996) found that 68% of
Smith-Magenis patients have hearing loss, with approximately two-thirds of
those having conductive loss and one-third having sensorineural hearing
loss.
The nonsyndromic autosomal-recessive hearing loss locus DFNB3 was
mapped to the pericentromeric region of chromosome 17 (Friedman et al.
1995) and then refined to 17p11.2, within the deletion interval for Smith-
Magenis syndrome (Liang et al. 1998). Later that same year, DFNB3 was
shown to be caused by mutations in the gene encoding the unconventional
myosin,
MYO15
(Wang et al. 1998). Interestingly, several Smith-Magenis
patients who have sensorineural hearing loss and deletion of one allele of
MYO15
also have a point mutation in the remaining allele of
MYO15
(Liang et al. 1998). Deletion of the Smith-Magenis region uncovered the
recessive mutation, making the patients hemizygous for the mutated allele.
2.3 Use of Cytogenetics to Help Identify
Candidate Genes
An extremely useful aspect of cytogenetics when studying any genetic
disease is that it can lead to identification or refinement of a disease locus.
Chromosomal rearrangements or deletions that disrupt critical genes can
be the first clue to the locus of a disease gene. This approach was success-
ful in studies of Waardenburg syndrome type 1, where linkage analyses had
been unproductive, apparently due to locus heterogeneity (Mueller, Van
Camp, and Lench, Chapter 4). In both Branchio-Oto-Renal syndrome and
X-linked mixed deafness, deletions found in the chromosomes of affected
individuals allowed refinement of the disease intervals, ultimately leading
to cloning of the genes.
2.3.1 Waardenburg Syndrome Type 1
Waardenburg syndrome is an autosomal-dominant disorder that commonly
manifests as deafness with pigmentary anomalies. Ishikiriyama et al. (1989)
reported a Japanese child with a phenotype consistent with Waardenburg
