ABNORMALITIES IN CHROMOSOME STRUCTURE
Structural alterations in chromosomes are less common than numerical alterations. Structural abnormalities that affect reproduction occur in 0.2% of the population.
A deletion occurs when a portion of a chromosome seg-ment is lost (Table 7.2). In a terminal deletion, the miss-ing portion of the chromosome is appended to the end of the long or short arm. If the missing portion of the chro-mosome is appended to both the long and short arms of the same chromosome, a ring chromosome can result. An interstitial deletion occurs when the deleted portion lacks a centromere, or in cases involving chromosomal breakage. Insertions occur when the portion of an inter-stitially deleted segment is inserted into a nonhomologous chromosome.
An inversion is the result of faulty repair of a chro-mosomal breakage. The broken portion is inserted into the chromosome in an inverted fashion. A paracentricinversion occurs when both breaks occur on one arm ofa chromosome. These types of inversions do not include the centromere, the region where the chromosome pairs are joined. Paracentric inversions cannot be iden-tified by a traditional karyotype because the arms appear to be of normal length. Fluorescence in situ hybridization (FISH) [see p. X] with locus-specific probes is used to detect this type of abnormality. A pericentric inver-sion involves a break in each arm. The centromere isincluded and a notable gain or loss of genetic material can be identified on a karyotype. For a parent with an inversion, the risk of having an abnormal child depends on the method of detection, the chromosome involved, and the size of the inversion. The observed risk is approx-imately 5% to 10% if the inversion is identified after the birth of an abnormal child, and 1% to 3% if identified at some other time. An exception is pericentric inversion of chromosome 9, which is not associated with genetic defects in offspring.
A translocation involves the transfer of two chro-mosome segments, usually between nonhomologous (non-paired) chromosomes. They are the most common form of structural rearrangements in humans. A translocation is described as balanced when equal amounts of genetic material are exchanged between chromosomes, and unbal-anced when the chromosomes receive unequal amountsof genetic material. Two types of translocations are pos-sible. A Robertsonian translocation only occurs in acro-centric chromosomes—those in which the centromere is located very near one end (chromosomes 13, 14, 15, 21, and 22). A person with a Robertsonian translocation is phenotypically normal, but the gametes they produce may be unbalanced. Whether the unbalanced gametes will result in abnormal offspring depends on the type of translocation, the chromosomes involved, and the sex of the carrier parent. The most clinically important Robertsonian translocations are those involving chromo-some 21 and another acrocentric chromosome, most commonly chromosome 14. Carriers of these transloca-tions are at increased risk of having a child with trisomy
The risk of trisomy 21 is 15% if the translocation is maternal and 2% or less if it is paternal.
Balanced reciprocal translocations may involve anychromosome and are the result of a reciprocal exchange of chromosome material between two or more chromosomes. Like those with Robertsonian translocations, individuals with a balanced reciprocal translocation are also phenotyp-ically normal but may produce gametes with unbalanced chromosomes. The observed risk for a chromosomal abnormality in an offspring is less than the theoretical risk, because some of these gametes result in nonviable concep-tions. In general, carriers of chromosome translocations identified after the birth of an abnormal child have a 5% to 30% risk of having unbalanced offspring. Children with an unbalanced chromosome translocation are at increased risk for mental retardation, neurodevelopmental delay, and other congenital abnormalities.
Single-gene (Mendelian) disorders display predictablepatterns of inheritance related to the location of the gene (autosomal or X-linked) and the expression of the pheno-type (dominant or recessive). Although Mendelian disor-ders were the first type of genetic disorders described, it is now known that there are many genetic and environmental factors that modify these genes, making true single-gene disorders relatively rare. Health care providers should be aware that many single-gene disorders are discovered each year and may be tracked using Internet databases, such as Online Mendelian Inheritance in Man (http :/ /www.nslij-genetics .org/ search_omim. html).