Letter to the Editor
Nonrandom chromosome breakpoints in 6q deletions To the Editor: Partial deletions of the long (9) arm of chromosome 6 of a constitutional nature have been known since 1975 (Milosevic & Kalicanin 1975). In this issue of Clinical Genetics, Valtat et al. (1992) report 4 new cases and provide an excellent review of the literature. Including their new cases, Valtat et al. consider a total of 37 cases with deletions of 6q. These 37 cases consist of 19 interstitial and 18 terminal deletions. Here we analyze the breakpoints. The breakpoints in these deletions are tabulated in Table 1. There were 37 breakpoints recorded in interstitial deletions and 19 breakpoints specified in terminal deletions of 6q, for a total of 56 breakpoints. Although it is possible that some of the breakpoint assignments are incorrect, we will assume that they are all correct. The interstitial deletion breakpoints are largely located in the segment of 6q running from q14 through q23. Within that segment, the breakpoints appear evenly distributed. There are 5-6 breakpoints in each of the 6 bands in the region q1-23. Thirty-six of the interstitial deletion breakpoints in 6q are in euchromatin. We measured the ISCN (1985) ideogram of chromosome 6 using calipers and a millimeter ruler to obtain a crude estimate of the relative lengths ofdark (56.6%) and light (43.4%) band contributions to 6q. Comparing the observed
distribution of 17 breakpoints in dark bands and 19 breakpoints in light bands with the theoretical expectations, the chi-square is 1.29, indicating that the breakpoints in interstitial 6q deletions are randomly distributed between dark and light bands. The terminal deletion breakpoints are all distal to 6q 16. Eleven of 19 breakpoints are clustered in band 6q25 which, as Valtat et al. (1992) point out, is a preferential location for breakpoints in 6q deletions. However, it should be emphasized that band 6q25 is not a favored site for interstitial deletion breakpoints. The favored status of band 6q25 pertains strictly to terminal deletion breakpoints. Virtually all terminal deletion breakpoints in 6q are in light bands. There are 17 breakpoints in light bands versus only 2 in dark bands. This strong skew toward light-band breakpoints is due mainly but not exclusively to the fact that q25 is a light band. Of the 8 breakpoints not in q25, 6 are in light versus 2 in dark bands, a tendency that may bear watching. The deletions of 6q are listed in Table 2. Note especially the interstitial deletions with proximal breakpoints in bands q13-16 and q22. There are 10 bands distal to q13, but both deletions with a breakpoint proximally in q13 have a distal breakpoint in ql5. There are 9 bands distal to q14, but 3 of 4 deletions with a proximal breakpoint in q14 have a distal breakpoint in q16. There are 8 bands distal to
Table 1. Breakpoints in 6q deletions
Table 2. Deletions of 6q Breakpoints Deletion
Band
GBand
Interstitial
Terminal
Total
6qll q12 q13 q14 q15 q16 q21 q22 923 q24 q25 q26 q27
Variable Dark Light Dark Light Dark Light Dark Light Dark Light Dark Light
1 1 2 5 6 5 5 5 5 1 1
0 0
0 0
11 2 1
1 1 2 5 6 5 6 5 9 1 12 2 1
37'
19"
56
Totals
'Includes one case with deletion of 6q21. "Includes one case with breaks in 6q21 and q27.
0
0 0 0 1 0 4
0
Interstitial
Terminal
qllq15 q12q14 91391 5 q13q15 91 4 4 5 qW16 q14q16 ~ 1 4 4 6 q15q21 ql5q21 ql6q22 ql6q22 $3 q21q 2 2 q21q23 q22q23 q22q23 q23q24 q23q25
q21-q27 q23qter q23qter q23qter q23qter q25qter q25qter q25qter q25qter q25qter q25qter q25qter q25qter q25qter q25-qter q25qter q26qter q26-qter
Based on data in Wtat et al. (1992).
187
Letter to the Editor q15, but bothdeletions withaproximal breakinq15
have a distal breakpoint in q21. There are 7 bands distal to q16, but both deletions with a proximal break in q16 have a distal breakpoint in q22. And there are 5 bands distal to q22, but both deletions with a proximal break in q22 have a distal breakpoint in q23. The interstitial deletions of 6q are clearly nonrandom in length. Since the breakpoints are evenly distributed among bands ql-23, it appears that the length of these intersitital deletions cannot simply reflect preferential breakpoints. The length of deletion is a function of selection. A very short deletion is difficult to detect and a long deletion is usually lethal. There is selection for deletions with breakpoints separated at most by a single intervening band on 6q. The terminal deletions of 6q tend to have a breakpoint in q23 or distal to it. The terminal deletion with a breakpoint in q25 is most common and involves less than 20% of the length of 6q. Very short terminal deletions involving, for example, just the distal half of q27 are nearly impossible to identify cytogenetically. Very long terminal deletions, again, tend to be lethal. Diagnosis was made by 6 months of age in 3 of 4 cases with a breakpoint proximal to q24 versus only 2 of 13 cases with a breakpoint distal to q24. The phenotype is inferred to bemoreabnormal with long terminal deletions. This fits with the greater lethality of extensive deletions.
168
In sum,the lengths of 6q deletions are highly nonrandom. There is nonrandom pairing of breakpoints in interstitial deletions of 69. There is a breakpoint cluster band, 6q25, in terminal deletions. Selection for deletions that are detectable and yet compatible with life provides a sound explanation. Fragile sites (Sutherland & Hecht 1985) could play a role, too, but this remains unproven. Selection seems to be acting on both cytogeneticists and their subjects to produce a range of observable deletions of 6q and, for that matter, a number of autosomal arms. Refsrencss ISCN. An International System for Human Cytogenetic Nomenclature, Harnden DG, Klinger HP (eds). Birth Defects: Original Article Series, vol. 2 I , no. I . New York: March of Dimes Birth Defects Foundation, 1985. Milosevic J, Kalicanin P. Long arm deletion of chromosome 6 in amentally retardedboy with multiple physica) malformations. J Ment Defic Res 1975: 19: 139-144. Sutherland GR, Hecht F. Fragile sites on human chromosomes. New York: Oxford University Press, 1985. Valtat C, Galliano D,Mettey R, Toutain A, Moraine C. Monosomy 6q: report of four new cases. Clin Genet 1992: 41: 159-166.
Correspondence: FREDERICK HECHT BARBARA K. HECHT Molecular Medicine and Genetics The Children’s Mercy Hospital 2401 Gillham Road Kansas City. Missouri 64108, USA
Nonrandom chromosome breakpoints in 6q deletions To the Editor: Partial deletions of the long (9) arm of chromosome 6 of a constitutional nature have been known since 1975 (Milosevic & Kalicanin 1975). In this issue of Clinical Genetics, Valtat et al. (1992) report 4 new cases and provide an excellent review of the literature. Including their new cases, Valtat et al. consider a total of 37 cases with deletions of 6q. These 37 cases consist of 19 interstitial and 18 terminal deletions. Here we analyze the breakpoints. The breakpoints in these deletions are tabulated in Table 1. There were 37 breakpoints recorded in interstitial deletions and 19 breakpoints specified in terminal deletions of 6q, for a total of 56 breakpoints. Although it is possible that some of the breakpoint assignments are incorrect, we will assume that they are all correct. The interstitial deletion breakpoints are largely located in the segment of 6q running from q14 through q23. Within that segment, the breakpoints appear evenly distributed. There are 5-6 breakpoints in each of the 6 bands in the region q1-23. Thirty-six of the interstitial deletion breakpoints in 6q are in euchromatin. We measured the ISCN (1985) ideogram of chromosome 6 using calipers and a millimeter ruler to obtain a crude estimate of the relative lengths ofdark (56.6%) and light (43.4%) band contributions to 6q. Comparing the observed
distribution of 17 breakpoints in dark bands and 19 breakpoints in light bands with the theoretical expectations, the chi-square is 1.29, indicating that the breakpoints in interstitial 6q deletions are randomly distributed between dark and light bands. The terminal deletion breakpoints are all distal to 6q 16. Eleven of 19 breakpoints are clustered in band 6q25 which, as Valtat et al. (1992) point out, is a preferential location for breakpoints in 6q deletions. However, it should be emphasized that band 6q25 is not a favored site for interstitial deletion breakpoints. The favored status of band 6q25 pertains strictly to terminal deletion breakpoints. Virtually all terminal deletion breakpoints in 6q are in light bands. There are 17 breakpoints in light bands versus only 2 in dark bands. This strong skew toward light-band breakpoints is due mainly but not exclusively to the fact that q25 is a light band. Of the 8 breakpoints not in q25, 6 are in light versus 2 in dark bands, a tendency that may bear watching. The deletions of 6q are listed in Table 2. Note especially the interstitial deletions with proximal breakpoints in bands q13-16 and q22. There are 10 bands distal to q13, but both deletions with a breakpoint proximally in q13 have a distal breakpoint in ql5. There are 9 bands distal to q14, but 3 of 4 deletions with a proximal breakpoint in q14 have a distal breakpoint in q16. There are 8 bands distal to
Table 1. Breakpoints in 6q deletions
Table 2. Deletions of 6q Breakpoints Deletion
Band
GBand
Interstitial
Terminal
Total
6qll q12 q13 q14 q15 q16 q21 q22 923 q24 q25 q26 q27
Variable Dark Light Dark Light Dark Light Dark Light Dark Light Dark Light
1 1 2 5 6 5 5 5 5 1 1
0 0
0 0
11 2 1
1 1 2 5 6 5 6 5 9 1 12 2 1
37'
19"
56
Totals
'Includes one case with deletion of 6q21. "Includes one case with breaks in 6q21 and q27.
0
0 0 0 1 0 4
0
Interstitial
Terminal
qllq15 q12q14 91391 5 q13q15 91 4 4 5 qW16 q14q16 ~ 1 4 4 6 q15q21 ql5q21 ql6q22 ql6q22 $3 q21q 2 2 q21q23 q22q23 q22q23 q23q24 q23q25
q21-q27 q23qter q23qter q23qter q23qter q25qter q25qter q25qter q25qter q25qter q25qter q25qter q25qter q25qter q25-qter q25qter q26qter q26-qter
Based on data in Wtat et al. (1992).
187
Letter to the Editor q15, but bothdeletions withaproximal breakinq15
have a distal breakpoint in q21. There are 7 bands distal to q16, but both deletions with a proximal break in q16 have a distal breakpoint in q22. And there are 5 bands distal to q22, but both deletions with a proximal break in q22 have a distal breakpoint in q23. The interstitial deletions of 6q are clearly nonrandom in length. Since the breakpoints are evenly distributed among bands ql-23, it appears that the length of these intersitital deletions cannot simply reflect preferential breakpoints. The length of deletion is a function of selection. A very short deletion is difficult to detect and a long deletion is usually lethal. There is selection for deletions with breakpoints separated at most by a single intervening band on 6q. The terminal deletions of 6q tend to have a breakpoint in q23 or distal to it. The terminal deletion with a breakpoint in q25 is most common and involves less than 20% of the length of 6q. Very short terminal deletions involving, for example, just the distal half of q27 are nearly impossible to identify cytogenetically. Very long terminal deletions, again, tend to be lethal. Diagnosis was made by 6 months of age in 3 of 4 cases with a breakpoint proximal to q24 versus only 2 of 13 cases with a breakpoint distal to q24. The phenotype is inferred to bemoreabnormal with long terminal deletions. This fits with the greater lethality of extensive deletions.
168
In sum,the lengths of 6q deletions are highly nonrandom. There is nonrandom pairing of breakpoints in interstitial deletions of 69. There is a breakpoint cluster band, 6q25, in terminal deletions. Selection for deletions that are detectable and yet compatible with life provides a sound explanation. Fragile sites (Sutherland & Hecht 1985) could play a role, too, but this remains unproven. Selection seems to be acting on both cytogeneticists and their subjects to produce a range of observable deletions of 6q and, for that matter, a number of autosomal arms. Refsrencss ISCN. An International System for Human Cytogenetic Nomenclature, Harnden DG, Klinger HP (eds). Birth Defects: Original Article Series, vol. 2 I , no. I . New York: March of Dimes Birth Defects Foundation, 1985. Milosevic J, Kalicanin P. Long arm deletion of chromosome 6 in amentally retardedboy with multiple physica) malformations. J Ment Defic Res 1975: 19: 139-144. Sutherland GR, Hecht F. Fragile sites on human chromosomes. New York: Oxford University Press, 1985. Valtat C, Galliano D,Mettey R, Toutain A, Moraine C. Monosomy 6q: report of four new cases. Clin Genet 1992: 41: 159-166.
Correspondence: FREDERICK HECHT BARBARA K. HECHT Molecular Medicine and Genetics The Children’s Mercy Hospital 2401 Gillham Road Kansas City. Missouri 64108, USA
