Handbook of Genetic Counseling/Ring Chromosome 22

Ring Chromosome 22

Introduction and contracting

 * Could you explain to me in your own words why you were referred to genetics?
 * What is your understanding of the chromosome results?
 * What are your main questions or concerns?
 * Outline session
 * Explain chromosome results
 * Take family history (ask standard questions i.e.) miscarriage, MR, learning disabilities, birth defects, etc.)
 * Dr. will examine him and may ask more questions about his medical history
 * We will discuss what we know and answer questions if we can

Explain results

 * Briefly explain chromosomes and genes
 * He has 46 chromosomes including an X and Y which indicates what we already knew that he is a boy
 * He also has part of an extra chromosome that has formed a ring
 * The ring contains part of chromosome 22 (show ideogram)
 * a ring usually forms when the ends of a chromosome break off leaving "sticky ends" that then connect.
 * We don't really know why rings form
 * We also don't know where the extra piece of chromosome originally came from
 * The presence of extra chromosomal material can change the way our bodies grow and develop
 * There are no reports in the literature of individuals with an extra ring chromosome 22 that is exactly like the one found in _______.
 * Therefore it makes it difficult to give you a clear idea of what to expect
 * Especially since there are two things we are considering, the extra genetic material and the fact that it is present in a ring form
 * However, we can tell you about what we do know from reports in the literature that are similar in some ways
 * I'd like to address your main concerns the best I can so please jump in with questions

Possibilities with ring chromosomes

 * Extra ring chromosomes have been passed on from parent to child (a case of grandfather, father and son all with extra ring 22 that is much small then _____'s ring)
 * When the ring chromosome is copied before cells divide sometimes there is difficulty separating them and this can result in the ring being altered (new break points or duplication of some of the material)
 * It is thought that if they can't separate the cell dies
 * It tends to be more common to have ring chromosomes present in a certain percentage of a person's cells and not all of them
 * When this is the case the cells with the extra ring are thought to die (evidence for this comes from the fact that sometimes when these individuals are retested there are no longer rings present or they are found in a smaller percentage of cells.)

Discussion

 * It seems that _____ is doing better than nearly all of the individuals that have been reported to have a duplication of all or even part of chromosome 22 in the literature
 * If individuals have an entire extra copy of chromosome 22 (that is not a ring) they generally die before birth or soon after. They also usually have a number of birth defects and characteristic physical features.
 * Individuals with partial deletions have been reported with a number of physical characteristics and health concerns that ______ does not seem to have.

Phenotype seen in other cases

 * Complete trisomy 22 syndrome, der(22) syndrome, and cat eye syndrome (CES) all have some overlapping characteristics (see charts from articles describing characteristics with complete and mosaic trisomy 22 and see chart listing features of CES)

CES

 * Typically associated with supernumerary bisatellited marker chromosome (inv dup 22pter-22q11.2) resulting in 4 copies of that region
 * Highly variable phenotype (same marker results in different phenotype in different generations)
 * 3 copies have been enough to result in CES phenotype (Reiss et al. 1985 and Knoll et al. 1994)
 * Criteria for diagnosis of CES include;
 * Ocular coloboma of the iris and or retina
 * Anal atresia (with or without fistula)
 * Preauricular skin tags and pits
 * Heart defects (especially total anomalous pulmonary venous return
 * Dysmorphic features (hypertelorism, down-slanting palpegral fissures, urogenital defects, mild to moderater MR

Minute supernumerary ring chromosome 22 associated with CES

 * 3 generations had the minute ring derived from 22q11.2
 * ring present in 90% of blood cells over the three generations
 * individual affected with CES has 4 copies of this region in each cell (unaffected father and grandfather have 3 copies)
 * father and paternal grandfather had no clinical features
 * may have been derivative of a dicentric marker chromosome

Case of duplication of 22q11.2-q13.1 and pericentric inversion (Prasher VP et al. 1995)

 * Limited communication skills
 * Persistent self injury
 * Poor mobility
 * Colobomata (common in cat eye syndrome)
 * Prominent forehead
 * Low posterior hairline
 * Prognathism of lower jaw
 * Tongue protrusion
 * Poor vision
 * Needed help with daily living skills
 * Short hands and fingers
 * Moderate thoracic kyphosis
 * Small penis and testes
 * Bilateral single transverse palmar crease

Shares features of another case with duplication of 22q11.1 to q13

 * Absence of speech
 * Persistent self-injury
 * Lack of daily living skills
 * very poor vision

Case of de novo direct duplication of 22q11-q12

 * Milder phenotype than complete trisomy 22 and der(22)t(11:22)
 * Similar in type and severity of cat eye syndrome (CES)

Other case of 22q11.2-q13.1 de novo duplication

 * Minor physical anomalies
 * Bilateral preauricular pits
 * Failure to thrive
 * Highly arched palate
 * Bilateral hydronephrosis
 * Delayed gross motor skills

Mechanisms of ring formation

 * By two DNA breaks, one in each arm of the same chromosome, followed by fusion of the proximal broken ends. The causes of these DNA breaks are usually unknown and so is the mechanism behind ligation of the ends. It is possible that the non-homologous end-joining machinery plays a role in this process (Smith et al. 2001). A ring can also be formed by fusion at two breakpoints in the same chromosome arm. However, only few examples of such rings have been described. Most probably, this is because they are acentric and will lack attachment point for the cell division machinery. Unless there is a different anchorage sequence for the kinetochore complex they will be lost in subsequent mitoses. Such ÒneocentromereÓ sequences have, however, been described in rare cases of constitutional (Slater et al. 1999) and acquired (Gisselsson et al. 1999) ring chromosomes.
 * By fusion of dysfunctional telomeres from the same chromosome. Several in vitro and animal models have shown that shortening of telomeric DNA repeats leads to the detachment of protective proteins from the chromosome ends (Counter et al. 1992). This renders the chromosome ends prone to recombination with DNA either from other chromosomes Ð leading to formation of a dicentric Ð or with the other arm of the same chromosome Ð leading to formation of a ring.
 * Parents carrying acrocentric isochromosomes or homologous Robertsonian translocations have been known to have children with a ring chromosome apparently derived from the parental abnormality (Mears AJ cites de Almeida et al. 1983 and Neri et al. 1983)
 * Extranumerary can form when a marker chromosome breaks and ends of the monocentric fragment fuse

Constitutional ring chromosomes
Supernumary ring chromosomes
 * 1/50,000 human fetuses (Jacobs et al. 1975)
 * In most instances, these rings are formed by breakpoints in both arms, followed by fusion of the proximal ends into a ring with loss of the distal material.
 * Such rings may thus result in clinical features mimicking terminal deletion syndromes.
 * Alternatively, congenital ring chromosomes are supernumerary, i.e. they occur together with two normal homologues of the corresponding chromosome (Anderlid et al. 2001)
 * rare due to:
 * actually are rare in occurrence
 * supernumerary ring chromosomes often gradually disappear in vivo and only cells with normal karyotype are eventually observed (Michalski K et al. 1993 cited Hoo et al. 1980)
 * not very many reports makes it difficult to predict prognosis or provide empiric risk data
 * supernumerary marker chromosomes are more common than supernumerary rings occurring in 1 in 1,500 to 1 in 500 for a (Michalski K et al. 1993 extrapolated this from multiple studies from 1984-1990)
 * the consequences will be similar to partial trisomies or duplications
 * Different characteristics depending on:
 * which chromosome is involved
 * the position of breakpoints within the chromosome.
 * patients with extra rings do not only display diverse symptoms resulting from deletions or duplications
 * In a meta-study including more than two-hundred patients with congenital ring chromosomes it has been demonstrated that the majority of children with rings show a failure to thrive beyond the extent expected from their chromosomal imbalances (Kosztolanyi 1987).
 * suggested that this is due to the mitotic instability of rings, preventing somatic cells from proliferating normally.
 * hypothesis is supported by the fact that growth failure is more common among patients with large ring chromosomes, than among those with small ones (Kosztolanyi 1987).
 * This is in accordance with the BFB model of ring chromosome dynamics.
 * Statistically, large rings will undergo more sister chromatid exchanges per cell cycle than small rings and would thus have a higher propensity for breaking at anaphase.
 * In a normal cell, this provokes a physiological DNA damage response leading to either cell cycle arrest or apoptosis (Cohen-Jonathan et al. 1999).
 * a cell population carrying a ring chromosome would proliferate slower than a population without rings; the population with rings would be less fit and be at a selective disadvantage.
 * Interestingly, ring chromosome loss or size reduction is not uncommon in cases with congenital rings.
 * In particular, cases with small rings often exhibit a subclone without the ring chromosome and these patients are thus ring/monosomy mosaics (Gisselsson et al. 1999).

Ring chromosomes at cell division

 * In contrast to linear chromosomes, rings may undergo cell division in three different ways (McClintock 1938; Lejeune 1968). Which of these pathways a ring chromosome will follow depends on the number of sister chromatid exchanges (SCE) that has occurred in the ring before cell division:
 * No SCE or an even number of SCEs in the same direction will enable normal, symmetrical segregation of the chromatids.
 * An even number of SCEs in different directions will lead to the formation of interlocked rings.
 * An odd number of SCEs will lead to transformation from two parallel chromatids into one continuous ring, with the double size of the original rings (Fig. 2).