KAPLAN_USMLE_STEP_1_LECTURE_NOTES_2018_BIOCHEMISTRY_and_GENETICS

Translocations

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Note

Alternate and adjacent segregation are diagrams (Figure II-3-4, upper right) used to predict the possible gametes produced by a translocation carrier.

•Adjacent segregation: chromosomes from adjacent quadrants (next to each other) enter a gamete

•Alternate segregation: chromosomes from alternate (diagonally opposed) quadrants enter a gamete

Figure II-3-3. A Reciprocal Translocation

In a translocation carrier, during gametogenesis and meiosis, unbalanced genetic material can be transmitted to the offspring, causing partial trisomies and partial monosomies typically resulting in pregnancy loss. During meiosis 1, the translocated chromosomes may segregate as chromosome 8 or as chromosome 2, producing a variety of possible gametes with respect to these chromosomes.

For example, see Figure II-3-4, which depicts a man who is a translocation carrier mating with a normal woman. The diagram in the upper right is used to depict the possible sperm the father can produce. It acknowledges that the translocated chromosomes can potentially pair with either of the two homologs (2 or 8) during meiosis.

Sperm that contain balanced chromosomal material (labeled alternate segregation in the diagram) produce either a normal diploid conception or another translocation carrier. Both are likely to be live births.

Sperm that contain unbalanced chromosomal material (labeled adjacent segregation in the diagram) produce conceptions that have partial monosomies and partial trisomies. These conceptions are likely to result in pregnancy loss.

Fertilization with normal egg

Figure II-3-4. Consequences of a Reciprocal

Translocation (Illustrated with Male)

Reciprocal Translocations After Birth. Reciprocal translocations may occur by chance at the somatic cell level throughout life. Because these translocations involve only a single cell and the genetic material is balanced, there is often no consequence. Rarely, however, a reciprocal translocation may alter the expression or structure of an oncogene or a tumor suppressor gene, conferring an abnormal growth advantage to the cell.

Chapter 3 ● Cytogenetics

Note

Reciprocal Translocations and

Pregnancy Loss

When one parent is a reciprocal translocation carrier:

•Adjacent segregation produces unbalanced genetic material and most likely loss of pregnancy.

•Alternate segregation produces a normal haploid gamete (and diploid conception) or a liveborn who is a phenotypically normal translocation carrier.

Part II ● Medical Genetics

Bridge to Pathology

Translocations Involving Oncogenes

Translocations are seen in a variety of cancers. Important examples include:

•t(9;22) chronic myelogenous leukemia (c-abl)

•t(15;17) acute myelogenous leukemia (retinoid receptor-α)

•t(14;18) follicular lymphomas (bcl-2 that inhibits apoptosis)

•t(8;14) Burkitt lymphoma (c-myc)

•t(11;14) mantle cell lymphoma (cyclin D)

Chronic Myelogenous Leukemia and the Philadelphia

Chromosome

Although most of our discussion deals with inherited chromosome alterations, rearrangements in somatic cells can lead to the formation of cancers by altering the genetic control of cellular proliferation. A classic example is a reciprocal translocation of the long arms of chromosomes 9 and 22, termed the Philadelphia chromosome. This translocation alters the activity of the abl proto-oncogene (proto-oncogenes can lead to cancer). When this alteration occurs in hematopoietic cells, it can result in chronic myelogenous leukemia. More than 100 different chromosome rearrangements involving nearly every chromosome have been observed in more than 40 types of cancer.

Robertsonian translocations

These translocations are much more common than reciprocal translocations and are estimated to occur in approximately 1 in 1,000 live births. They occur only in the acrocentric chromosomes (13, 14, 15, 21, and 22) and involve the loss of the short arms of two of the chromosomes and subsequent fusion of the long arms. An example of a Robertsonian translocation involving chromosomes 14 and 21 is shown in Figure II-3-5. The karyotype of this (male) translocation carrier is designated 45,XY,–14,–21,+t(14q;21q). Because the short arms of the acrocentric chromosomes contain no essential genetic material, their loss produces no clinical consequences, and the translocation carrier is not clinically affected.

Figure II-3-5. A Robertsonian Translocation

Part II ● Medical Genetics

Note

Robertsonian Translocations

When one parent is a Robertsonian translocation carrier:

•Adjacent segregation produces unbalanced genetic material and most likely loss of pregnancy. Important exception: Down syndrome: 46,XX or 46XY,–14 +t(14q;21q)

•Alternate segregation produces a normal haploid gamete (and diploid conception) or a liveborn who is a phenotypically normal translocation carrier.

One can determine the mechanism leading to Down syndrome by examining the karyotype. Trisomy 21 due to nondisjunction during meiosis (95% of Down syndrome cases) has the karyotype 47,XX,+21 or 47,XY,+21. In the 5% of cases where Down syndrome is due to a Robertsonian translocation in a parent, the karyotype will be 46,XX,-14,+t(14q;21q) or 46,XY,–14,+t(14q;21q). The key difference is 47 versus 46 chromosomes in the individual with Down syndrome.

Although the recurrence risk for trisomy 21 due to nondisjunction during meiosis is very low, the recurrence risk for offspring of the Robertsonian translocation carrier parent is significantly higher. The recurrence risk (determined empirically) for female translocation carriers is 10–15%, and that for male translocation carriers is 1–2%.

The reason for the difference between males and females is not well understood. The elevated recurrence risk for translocation carriers versus noncarriers underscores the importance of ordering a chromosome study when Down syndrome is suspected in a newborn.

Deletions

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Part II ● Medical Genetics

Note

Structural Abnormalities

•Translocations (Robertsonian and reciprocal)

•Deletions and duplications

•Inversions (pericentric and paracentric)

•Ring chromosomes

•Isochromosomes

OTHER CHROMOSOME ABNORMALITIES

Several other types of structural abnormalities are seen in human karyotypes. In general, their frequency and clinical consequences tend to be less severe than those of translocations and deletions.

Inversions

Inversions occur when the chromosome segment between two breaks is reinserted in the same location but in reverse order. Inversions that include the centromere are termed pericentric, whereas those that do not include the centromere are termed paracentric. The karyotype of the inversion shown in Figure II-3-8, extending from 3p21 to 3q13 is 46,XY,inv(3)(p21;q13). Inversion carriers still retain all of their genetic material, so they are usually unaffected (although an inversion may interrupt or otherwise affect a specific gene and thus cause disease). Because homologous chromosomes must line up during meiosis, inverted chromosomes will form loops that, through recombination, may result in a gamete that contains a deletion or a duplication, which may then be transmitted to the offspring.

Pericentric Inversion of Chromosome 16

A male infant, the product of a full-term pregnancy, was born with hypospadias and ambiguous genitalia. He had a poor sucking reflex, fed poorly, and had slow weight gain. He had wide-set eyes, a depressed nasal bridge, and microcephaly. The father stated that several members of his family, including his brother, had an abnormal chromosome 16. His brother had two children, both healthy, and the father assumed that he would also have normal children. Karyotype analysis confirmed that the father had a pericentric inversion of chromosome 16 and that his infant son had a duplication of material on 16q, causing a small partial trisomy.