Учебники / Genetics and Auditory Disorders Keats 2002

Treacher Collins E (1900) Cases with symetrical congenital notches in the outer part of each lid and defective development of the malar bones. Trans Ophthal Soc UK 20:190–192.

Usher CH (1914) On the inheritance of retinitis pigmentosa with notes of cases. R Land Opthal Hosp Res 18:130–236.

Vahava O, Morell R, Lynch ED,Weiss S, et al. (1998) Mutation in transcription factor POU4F3 associated with inherited progressive hearing loss in humans. Science 279:1950–1954.

van den Ouweland JMW, Lemkes HHPJ, Ruitenbeck W, Sandkuijl LA, et al. (1992) Mutation in mitochondrial tRNA (leu-UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nature Genet 1:368–371.

Vanderbilt University Hereditary Deafness Study Group (1968) Dominantly inherited low frequency hearing loss. Arch Otolaryng 88:242–250.

Waardenburg PJ (1951) A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and congenital deafness. Am J Hum Genet 3:195–253.

Watanabe A, Takeda K, Ploplis B, Tachibana M (1998) Epistatic relationship between Waardenburg Syndrome genes MITF and PAX3. Nat Genet 18:283–286.

Wattanasirichaigoon D, Beggs AH (1998) Molecular genetics of long-QT syndrome. Curr Opin Pediatr 10:628–634.

Wolf B, Heard GS, Weissbecker KA, McVoy JR, et al. (1985) Biotinidase deficiency: Initial clinical features and rapid diagnosis. Ann Neurol 18:614–617.

Xia JH, Liu CY, Tang BS, Pan Q, et al. (1998) Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment. Nat Genet 20:370–373.

Zelante L, Gasparini P, Estivill X, Melchionda S, et al. (1997) Connexin 26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. Hum Mol Genet 6:1605–1609.

introduced (Caspersson et al. 1970; Drets and Shaw 1971). The most common technique used today, G-banding, is shown in Figure 5.1. Each of the chromosomes can be identified by its size, shape, and characteristic banding pattern. The light and dark bands of each chromosome are numbered according to an accepted international standard (Fig. 5.2) (Mitelman 1995). By convention, the chromosomes are ordered essentially from largest to smallest, with the shorter arm of each chromosome (the p arm) positioned on top, and the longer q arm below.

When a chromosomal rearrangement such as a translocation or deletion is described, it is done according to nomenclature guidelines that cite the chromosome(s) involved and the band where the break is thought to have occurred (Mitelman 1995). For example, a deletion (del) of chromosomal material from the long arm of chromosome 14 between bands q22 and q23 is denoted as del(14)(q22q23). A translocation (t) between the short arm of chromosome 3 from band p24 to the end of the short arm (pter), and the long arm of chromosome 8 from band q13 to the end of the long arm (qter), is described as t(3;8)(p24;q13).

2.1 Cytogenetic Causes of Human Disease

Over the course of hundreds of thousands of years of evolution, the human species has come to maintain a relatively stable karyotype. Gross variation in the number or structure of human chromosomes severely reduces genetic fitness. It is estimated that the human complement of 46 chromosomes contains 50,000 to 100,000 genes, with temporal and spatial regulation of each. With few exceptions, addition or deletion of whole chromosomes (aneuploidy) is incompatible with life. Large subchromosomal deletions or duplications are similarly lethal, whereas fetuses with small deletions or duplications may be viable. A large percentage of the DNA that comprises human chromosomes does not encode proteins, but even small, submicroscopic pieces of chromosomes can contain dozens or hundreds of genes. Chromosomal rearrangements such as translocations can abrogate gene expression, resulting in multiple congenital anomalies, similar in nature to an autosomal dominant mutation.

2.1.1 Aneuploidy

The first chromosomal disorders reported to cause human pathology were aneuploidies. Lejeune et al. reported in 1959 that nine children with “mongolism” (Down syndrome, Fig. 5.3) had an additional small chromosome

(now known to be chromosome 21) (Lejeune et al. 1959). In the same year, a number of sex chromosome aneuploidies were reported, including Turner syndrome (45,X, Fig. 5.4), in which a female typically has only 45 chromosomes, with monosomy X (Ford et al. 1959), and Klinefelter syndrome

(47,XXY), in which a phenotypic male has two X chromosomes and one Y,

94 A.B. Skvorak Giersch and C.C. Morton

for a complement number of 47 instead of the usual 46 (Jacobs and Strong 1959). Additional sex chromosome aneuploidies, such as 47,XXX, 47,XYY and other combinations, were also described.

Of all cytogenetic abnormalities observed, aneuploidies are the most common. They account for greater than 90% of the chromosomally abnormal newborns and spontaneous pregnancy losses (Therman and Susman 1993). The sex chromosome aneuploidies are the only variations in total chromosome number that can yield a relatively healthy individual. Indeed, often patients with sex chromosome aneuploidies are ascertained only at puberty or in adulthood when sexual developmental or reproductive difficulties arise. Among the autosomal trisomies, only trisomy 21 is compatible with a relatively long life, but it is characterized by multiple developmental problems, both physical and mental. Trisomy 21 is the single most common cause of mental retardation, and has the highest incidence of any autosomal chromosomal aneuploidy in liveborns (Gardner and Sutherland 1996). Other autosomal trisomies, such as trisomies 13 and 18, are seen among liveborns, but these infants have severe mental and physical handicaps, and rarely survive for more than a year (Therman and Susman 1993). If these trisomies are found in a mosaic state, where only a subset of cells in the body has the abnormal number of chromosomes, the individual may live many years, though a wide spectrum of disabilities, from very mild to profound will typically be present. Other trisomies or monosomies are generally only seen in stillbirths or miscarriages, reflecting the severity of the chromosomal imbalance on fetal development.

2.1.2 Unique Chromosomal Rearrangements

A variety of chromosomal rearrangements is possible, having been seen in human karyotypes. A translocation is an exchange of genetic material between two chromosomes. Translocations can be either balanced or unbalanced. The term balanced implies an exact exchange of chromosomal material. Constitutional balanced translocations are usually without clinical significance to an individual. Approximately 1 in 500 newborns are balanced translocation carriers (Hook and Hammerton 1997). However, an apparently balanced translocation can also cause gene disruptions or fusions, resulting in an untoward outcome. For example, studies show that balanced translocations are five times more frequent in mentally retarded individuals than in the general population (Funderburk et al. 1977).

The best studied translocations are the acquired translocations found in various cancers, especially hematological disorders. Perhaps the most well known translocation in human disease is the “Philadelphia” chromosome described by Nowell and Hungerford in leukemic cells from patients with chronic myeloid leukemia (Nowell and Hungerford 1960). Named for the city in which it was discovered, the Philadelphia chromosome results from a balanced translocation between chromosomes 9 and 22, t(9;22)(q34;q11).

96 A.B. Skvorak Giersch and C.C. Morton

98 A.B. Skvorak Giersch and C.C. Morton

FIGURE 5.3. Infant with Down syndrome. Notice low-set, posteriorly rotated ears, flat facial profile and protruding tongue (Jones 1997, with permission of W.B. Saunders Co.).

It is detected in approximately 95% of CML patients. The translocation creates a fusion transcript between the BCR (break point cluster region) gene on chromosome 22 and the ABL (Abelson) gene on chromosome 9. The fusion protein is thought to create an aberrantly regulated kinase that activates a number of signal transduction proteins, leading to dysregulated cellular proliferation.

Inversions are due to breakage and reunion within the same chromosome. Inversions are of two types: pericentric, which involves a break in each arm with the centromere in between, and paracentric, in which both breaks are within the same chromosomal arm. A number of inversions, such as a small pericentric inversion involving chromosome 9, appear to be clinically insignificant, and are recognized as a chromosome polymorphism in humans. About one percent of the human population carries a chromosomal inversion without phenotypic consequence (Therman and Susman 1993). However, inversions can cause disease when a breakpoint occurs in a functional gene. Difficulty can also arise during meiosis when an inverted chromosome attempts to pair with its normal homolog. Depending on the size of the inverted region, faulty pairing and missegregation can occur, resulting in deleted or duplicated chromosomal segments.

2.1.3 Deletion Syndromes

Chromosomal deletions are usually associated with a constellation of clinical findings. A number of well known chromosomal deletion and

FIGURE 5.4. Girl with Turner syndrome at ages 2 and 4 years. Notice large, prominent ears, webbed neck, and short staure (Jones 1997, with permission of W.B. Saunders Co.).

microdeletion syndromes exist that give rise to recognizable genetic disorders. Among these are the DiGeorge/velocardiofacial syndromes, which usually result from a deletion in chromosome 22 in band q11, and the Prader-Willi/Angelman syndromes, which are most often caused by deletions of chromosome 15 in bands q11-q13. Deletions in some disorders are large enough to be seen on a routine karyotype, but molecular techniques such as fluorescence in situ hybridization (FISH), where fluorescently labeled DNA probes are hybridized to chromosome spreads, have become the standard for diagnosis of these disorders.

The clinical phenotype resulting from a chromosomal deletion can be due to loss of one critical gene, or to a set of contiguous genes. For example, Alagille syndrome is characterized by ocular, skeletal and cardiac defects in association with loss of intrahepatic bile ducts. Additional anomalies may also be present. A large deletion of chromosome 20p12 is observed in several families with Alagille syndrome; however, point mutations in the gene Jagged1 (JAG1), which maps to this locus, also cause the same syndrome (Li et al. 1997; Oda et al. 1997), suggesting deletion of only this one gene is sufficient to cause the syndrome. In contrast, Miller-Dieker syn-

100 A.B. Skvorak Giersch and C.C. Morton

drome is caused by the deletion of multiple genes. Miller-Dieker patients have lissencephaly, severe mental retardation, and a characteristic facial appearance. They may also have growth retardation, heart defects, and seizures (Dobyns et al. 1991). Ninety percent of Miller-Dieker patients have deletions in chromosome 17p13. More than one gene must be involved in the syndrome because mutations in the LIS1 gene at this locus cause isolated lissencephaly, without the other features characteristic of MillerDieker syndrome (Chong et al. 1997). Presumably, deletion of genes in addition to LIS1 at 17p13 contribute to the full spectrum of anomalies.

Miller-Dieker syndrome illustrates how analysis of individual genes within a critical deletion region can help establish which gene is responsible for a specific feature of a syndrome. Collections of overlapping deletions are used to narrow the critical region, allowing identification and analysis of individual genes and the role they play in the pathobiology of the disease.

Alternatively, chromosomal deletions may cause disease by unmasking recessive alleles on the sister chromosome. This mechanism may be the etiology for the hearing loss associated with Smith-Magenis syndrome (Greenberg et al. 1996).

2.2 Cytogenetics and Hearing Loss

Hearing loss is a component of a number of chromosomal syndromes. Aneuploidies, translocations, inversions, duplications, and deletions have each been found that cause hearing loss. However, cytogenetics has not been a traditional technique used in investigations of genetic deafness. No large scale cytogenetic studies of patients with isolated hearing loss have been reported.

In the next sections, some of the syndromes and isolated cases of chromosomal rearrangement in which hearing loss has been found are reviewed.

Cytogenetic studies may complement molecular investigations, allowing a better understanding of a syndrome and the gene(s) that cause it. Three specific examples in which cytogenetic findings facilitated gene discovery are discussed below.

2.2.1 Aneuploidy and Hearing Loss

Depending on the missing or additional chromosome, individuals with chromosome aneuploidies can have a wide spectrum of physical and mental handicaps, reflecting developmental disorders at various stages of fetal life.

Generally, the more complex organ systems or structures appear to be affected most profoundly. Thus, among autosomal aneuploidies, the brain is uniformly abnormal, and physical anomalies, especially craniofacial, are typical. Heart, genitourinary system, eyes, hands and feet are also often involved (Therman and Susman 1993). It is of no surprise that hearing loss or deafness is found in several of the human aneuploidies.