American Journal of Medical Genetics 40345-347 (1991)
Balanced Reciprocal lkanslocation Mosaicism: New Cases and a Literature Review S. A. Farrell Division of Genetics, The Credit Valley Hospital, Mississauga, Ontario, Canada Mosaicism for a balanced reciprocal translocation is uncommon. These two new cases were detected during investigation of infertility and miscarriages. Otherwise, the probands were normal. Of five previously described cases, only one was possibly syndromal. More reports of this class of chromosomal aberration are needed to assess accurately the risk of phenotypic abnormalities. KEY WORDS: chromosome mosaicism, chromosome translocation, spontaneous miscarriage INTRODUCTION Balanced reciprocal translocation mosaicism in man is rare [Fryns and Kleczkowska, 19861. Two new cases are described. Analysis of case 1was initiated due to a history of infertility. Case 2 was found during a cytogenetic study of relatives of a man with a reciprocal translocation, originally ascertained during investigation for multiple miscarriages. Published reports of human reciprocal translocation mosaicism are reviewed. Most, including these two new cases, are associated with a normal phenotype, although miscarriages, infertility, and minor anomalies have been noted. The prevalence, possible mechanisms of origin, and potential effects are discussed. CLINICAL REPORT Case 1 This couple was investigated for infertility. Their only pregnancy ended in miscarriage at 12 weeks. Ninety percent of the male partner’s lymphocytes were cytogenetically normal, but the remainder had an apparently balancedreciprocaltranslocation:t(3;6)(q13.2;q25.3)(four of 45 cells). Repeat lymphocyte analysis confirmed presence of the translocation in 6% of cells. The spouse’s
Received for publication August 24, 1990; revision received December 14, 1990. Address reprint requests to Dr. S. A. Farrell, Division of Genetics, The Credit Valley Hospital, 2200 Eglinton Avenue West, Mississauga, Ontario, Canada L5M 2N1.
0 1991 Wiley-Liss, Inc.
karyotype was normal. Further family members were not analyzed.
Case 2 This woman was studied cytogenetically as part of a family study. Her son had an apparently balanced reciprocal translocation determined during investigation of first-trimester miscarriages. His karyotype was 46,XY,t(5;18)(q35.1;q21.3). His mother was mosaic with 28% of lymphocytes (five of 18 cells) bearing the same translocation while the remainder were normal. She had three miscarriages and five children but only the one son inherited the translocation. Previous investiga-, tions elsewhere, undertaken because of a family history of mental retardation, had shown her other two sons to have the Fragile X syndrome. One daughter was determined to be a carrier of this by cytogenetic analysis. The Fragile X site was not detected in this woman’s lymphocytes. Her husband’s chromosome were normal. There were further cases of the Fragile X syndrome in her extended family. Otherwise, the family history was unremarkable. DISCUSSION Mosaicism for reciprocal translocations is uncommon [Sciorra et al., 1985; Fryns and Kleczkowska, 19861. Known cases are listed in Table I. Kleczkowska et al. [19901indicated their two cases of reciprocal translocation mosaicism were found among 245 patients with reciprocal translocations out of a total of 74,306 specimens. That of Saura et al. [19871 occurred amidst 29 reciprocal translocations from a total of 3,500 samples. Our two were among ten reciprocal translocations from 3,000 samples. Without the distribution of referral reasons, these data cannot be used to estimate prevalence of this type of mosaicism, as different laboratories have varying referral patterns. Hook and Cross [1987] found two apparently balanced mosaic reciprocal translocations in about 63,000 amniocentesis. In comparison, one mosaic Robertsonian translocation was noted. Prenatal diagnosis such as the report of Hook and Cross [19871 yields the best minimal estimate of the prevalence of reciprocal translocation mosaicism since there is no bias of ascertainment from an abnormal phenotype. Cases can be missed since analysis of 15 cells will exclude mosaicism only at the level of 15% with a confidence level of 0.90 [Hook, 19771. Obviously, reciprocal trans-
346
Farrell TABLE I. Cases of Balanced Reciprocal Translocation Mosaicism
Repeat Studies Karyotype (percent of cells with (% cells with translocation in lymphocytes) Phenotvpe Ascertainment translocation) Comments Reference FH-Fragile LymphocytesFryns and Kleczkowska 46,XY/46,XY,t(1;9)(p13.l;p12.2) Normal Translocation (50%) X 50% [1986]; see also found in two Kleczkowska et al. daughters at prenatal diag[1990] nosis SynSyndromal LymphocytesSaura et al. [19871 Normal parental 46,XY/46,XY,t(8;12)(p23.2;q13.3) (55%) 55% karyotypes dromal Skin fibroblast+ 54% Normal Miscarriages LymphocytesSciorra et al. [19851 23.8% Skin fibroblasts-0 Hook and Cross [19871 Case 1 (BDI 41106) 46,XY/46,XY,t(7;16) Prenatal dx 46,XY/46,XY,t(1;3) Prenatal dx Case 2 (BDI 40209) Two miscarNormal Miscarriages 46,XY/46,XY,t(9;13)(p21;q13) Kleczkowska et al. [1990] (30%) riages This report Case 1 46,XY/46,XY,t(3;6)(q13.2;q25.3) Translocation Normal Infertility Lymphocytes(10%) 5% detected in son 46,XX/46,XX,t(5;18)(q35.lq21.3) Normal Miscarriages Not repeated Case 2 (28%) (son’s wife) FH =family history; prenatal dx = prenatal diagnosis.
location mosaicism is uncommon but the exact frequency remains uncertain. The origin of this type of mosaicism is unknown. If a post-conception exchange occurs between non-homologous chromosomes at mitosis, subsequent segregation could result in two cell lines, some with and some without the rearrangement. The zygote initially lacks the translocation. Mitotic recombination between non-homologous chromosomes has been documented in human cells, specifically from Bloom syndrome patients [Therman et al., 1981; Therman and Kuhn, 19851. An alternate model for prezygotic origin of structural mosaicism has been proposed [Cantu et al., 1985a,b,c;Cantu and Ruiz, 19861. It is analogous to Gartler and Francke’s [19751 model for mosaicism of single-base changes. In Cantu’s model, single-strand breaks occur in the two non-homologous chromosomes, followed by abnormal non-homologous rejoining of the chromatids before anaphase I1 of gamete formation. After conception, segregation of the two normal non-homologous chromosomes to one cell and the translocation chromosomes to the other cell results in structural mosaicism. This halfchromatid mutation model implies that the translocation chromosomes would be uniparental, whereas with mitotic error, the involved chromosomes could be either uniparental or biparental. Germ-line mosaicism has been proposed for several single-gene conditions [Hall, 19881. Case 2 demonstrates the presence of the translocation in germ cells, since it was transmitted to her son. Similarly, Fryns and Kleczkowska [19861detected inheritance of a transloca-
tion from a parent with translocation mosaicism. These cases suggest that balanced reciprocal translocations can originate from a mosaic parent who is likely to have germ-line mosaicism for the structural rearrangement. Table I lists the ascertainment reason for cases of reciprocal translocation mosaicism. One was associated with minor anomalies, and one had a family history of mental retardation. The others presumably had a normal phenotype but were studied due to miscarriages or infertility. Our two cases were associated with miscarriages. Stenchever et al. [19771 reported three possible cases of reciprocal translocation mosaicism in a parental study of reproductive wastage. However, Sciorra et al. [19851interpreted the chromosomes of these cases to be normal. Lippman-Hand and Vekemans [19831reviewed the literature on balanced translocations and miscarriages. The only cases of reciprocal translocation mosaicism they noted were those of Stenchever et al. [19771. Caste1 and Bernstein [19881 described patients with mosaicism for a balanced translocation studied for a history of multiple miscarriages. However, three of the seven involved breakpoints of chromosomes 7 and 14, which are frequently noted in cultured lymphocytes and could reflect artifact. In such studies, only single cultures were analyzed; thus, an in vitro event could not be ruled out. The relationship of translocation mosaicism to miscarriages and infertility is undefined. An increased risk of congenital problems is associated with de novo non-mosaic reciprocal translocations [Gardner and Sutherland, 19891, but whether this occurs with reciprocal translocation mosaicism remains to
Reciprocal Damlocation Mosaicism
be determined. Low-level mosaicism for balanced translocations in persons with and without anomalies warrants repeat analysis to attempt confirmation. The phenotype must be recorded to determine if there is any increased risk of abnormalities. At prenatal diagnosis, pseudomosaicism for structural abnormalities is not usually reported, but our cases suggest true mosaicism could be present. Further investigation of low levels of mosaicism at prenatal diagnosis should be considered after birth, yet parental anxiety might outweigh the need for more information as few cases likely represent true mosaicism. The relationship of reciprocal translocation mosaicism to the presenting histories of minor anomalies, miscarriages, and infertility is uncertain since there are so few cases. Further families and long-term follow-upof prenatally diagnosed children are necessary to determine the prevalence and possible effects of this type of structural mosaicism.
REFERENCES Cantd JM, Ruiz C (1986): On a prezygotic origin of normalhalanced translocation mosaics. Ann Genet 29:221-222. Cantu JM, Rivas F, Ruiz C, Barajas LO, Moller M, Rivera H (1985a): Trisomy 7p due to a mosaic normal/dir dup(7)(p13+p22). Ann Genet 28:254-257. Cantd JM, Rivas F, Rivera H, Ruiz C (198513): The prezygotic origin of structural mosaics. Ann Genet 28:73-74. Cantd JM, Hernandez A, JimBnez-SBinz M, Moller M, Rdon A, Chromosomal aberrations in Gonzalez-Flores0, Rivera H (1985~): 334 individuals with repeated spontaneous abortions and or fetal wastage. Rev Invest Clin (Mex) 37:131-134. Castle D, Bernstein R (1988): Cytogenetic analysis of 688 couples
347
experiencing multiple spontaneous abortions. Am J Med Genet 29:549-556. Fryns JP, Kleczkowska A (1986):Letter to the Editor: Reciprocal translocation mosaicism in man. Am J Med Genet 25:175-176. Gardner RJM, Sutherland GR (1989): “Chromosome Abnormalities and Genetic Counselling.” New York: Oxford University Press, pp 198-199. Gartler SM, Francke U (1975): Half chromatid mutations: Transmission in humans? Am J Hum Genet 27:218-223. Hall JG (1988): Review and hypotheses: Somatic mosaicism: Observations related to clinical genetics. Am J Hum Genet 43:355-363. Hook EB (1977):Exclusion of chromosomal mosaicism: Tables of 9095, 95%, and 99% confidence limits and comments on use. Am J Hum Genet 29:94-97. Hook EB, Cross EK (1987): Rates of mutant and inherited structural cytogenetic abnormalities detected at amniocentesis: results on about 63,000 fetuses. Ann Hum Genet 51:27-55. Kleczkowska A, Fryns JP, Van den Berghe H (1990): On the variable effect of mosaic normalhalanced chromosomal rearrangements in man. J Med Genet 27:505-507. Lippman-Hand A, Vekemans M (1983):Balanced translocations among couples with two or more spontaneous abortions: Are males and females equally likely to be carriers? Hum Genet 63:252-257. Saura R, L o n g M, Serville F, Chokairi 0,Froute MF (1987): Letter to the Editor: Abnormal phenotype in a child with a “balanced translocation 8112 in mosaic state. Am J Med Genet 28:1021-1023. Sciorra U,Lee M, Cuccurllo G (1985): Translocation mosaicism in a woman having multiple miscarriages. Am J Med Genet 22:615-. 617. Stenchever MA, Parks KJ, Allen MA, Stenchever MR (1977): Cytogenetics of habitual abortion and other reproductive wastage. Am J Obstet Gynecol 127:143-150. Therman E, Kuhn EM (1985): Incidence and origin of symmetric and asymmetric dicentrics in Bloom’s syndrome. Cancer Genet Cytogenet 15293-301. Therman E, Otto PG, Shadidi NT (1981): Mitotic recombination and segregation of satellites in Bloom’s syndrome. Chromosoma 82:627-636.
Balanced Reciprocal lkanslocation Mosaicism: New Cases and a Literature Review S. A. Farrell Division of Genetics, The Credit Valley Hospital, Mississauga, Ontario, Canada Mosaicism for a balanced reciprocal translocation is uncommon. These two new cases were detected during investigation of infertility and miscarriages. Otherwise, the probands were normal. Of five previously described cases, only one was possibly syndromal. More reports of this class of chromosomal aberration are needed to assess accurately the risk of phenotypic abnormalities. KEY WORDS: chromosome mosaicism, chromosome translocation, spontaneous miscarriage INTRODUCTION Balanced reciprocal translocation mosaicism in man is rare [Fryns and Kleczkowska, 19861. Two new cases are described. Analysis of case 1was initiated due to a history of infertility. Case 2 was found during a cytogenetic study of relatives of a man with a reciprocal translocation, originally ascertained during investigation for multiple miscarriages. Published reports of human reciprocal translocation mosaicism are reviewed. Most, including these two new cases, are associated with a normal phenotype, although miscarriages, infertility, and minor anomalies have been noted. The prevalence, possible mechanisms of origin, and potential effects are discussed. CLINICAL REPORT Case 1 This couple was investigated for infertility. Their only pregnancy ended in miscarriage at 12 weeks. Ninety percent of the male partner’s lymphocytes were cytogenetically normal, but the remainder had an apparently balancedreciprocaltranslocation:t(3;6)(q13.2;q25.3)(four of 45 cells). Repeat lymphocyte analysis confirmed presence of the translocation in 6% of cells. The spouse’s
Received for publication August 24, 1990; revision received December 14, 1990. Address reprint requests to Dr. S. A. Farrell, Division of Genetics, The Credit Valley Hospital, 2200 Eglinton Avenue West, Mississauga, Ontario, Canada L5M 2N1.
0 1991 Wiley-Liss, Inc.
karyotype was normal. Further family members were not analyzed.
Case 2 This woman was studied cytogenetically as part of a family study. Her son had an apparently balanced reciprocal translocation determined during investigation of first-trimester miscarriages. His karyotype was 46,XY,t(5;18)(q35.1;q21.3). His mother was mosaic with 28% of lymphocytes (five of 18 cells) bearing the same translocation while the remainder were normal. She had three miscarriages and five children but only the one son inherited the translocation. Previous investiga-, tions elsewhere, undertaken because of a family history of mental retardation, had shown her other two sons to have the Fragile X syndrome. One daughter was determined to be a carrier of this by cytogenetic analysis. The Fragile X site was not detected in this woman’s lymphocytes. Her husband’s chromosome were normal. There were further cases of the Fragile X syndrome in her extended family. Otherwise, the family history was unremarkable. DISCUSSION Mosaicism for reciprocal translocations is uncommon [Sciorra et al., 1985; Fryns and Kleczkowska, 19861. Known cases are listed in Table I. Kleczkowska et al. [19901indicated their two cases of reciprocal translocation mosaicism were found among 245 patients with reciprocal translocations out of a total of 74,306 specimens. That of Saura et al. [19871 occurred amidst 29 reciprocal translocations from a total of 3,500 samples. Our two were among ten reciprocal translocations from 3,000 samples. Without the distribution of referral reasons, these data cannot be used to estimate prevalence of this type of mosaicism, as different laboratories have varying referral patterns. Hook and Cross [1987] found two apparently balanced mosaic reciprocal translocations in about 63,000 amniocentesis. In comparison, one mosaic Robertsonian translocation was noted. Prenatal diagnosis such as the report of Hook and Cross [19871 yields the best minimal estimate of the prevalence of reciprocal translocation mosaicism since there is no bias of ascertainment from an abnormal phenotype. Cases can be missed since analysis of 15 cells will exclude mosaicism only at the level of 15% with a confidence level of 0.90 [Hook, 19771. Obviously, reciprocal trans-
346
Farrell TABLE I. Cases of Balanced Reciprocal Translocation Mosaicism
Repeat Studies Karyotype (percent of cells with (% cells with translocation in lymphocytes) Phenotvpe Ascertainment translocation) Comments Reference FH-Fragile LymphocytesFryns and Kleczkowska 46,XY/46,XY,t(1;9)(p13.l;p12.2) Normal Translocation (50%) X 50% [1986]; see also found in two Kleczkowska et al. daughters at prenatal diag[1990] nosis SynSyndromal LymphocytesSaura et al. [19871 Normal parental 46,XY/46,XY,t(8;12)(p23.2;q13.3) (55%) 55% karyotypes dromal Skin fibroblast+ 54% Normal Miscarriages LymphocytesSciorra et al. [19851 23.8% Skin fibroblasts-0 Hook and Cross [19871 Case 1 (BDI 41106) 46,XY/46,XY,t(7;16) Prenatal dx 46,XY/46,XY,t(1;3) Prenatal dx Case 2 (BDI 40209) Two miscarNormal Miscarriages 46,XY/46,XY,t(9;13)(p21;q13) Kleczkowska et al. [1990] (30%) riages This report Case 1 46,XY/46,XY,t(3;6)(q13.2;q25.3) Translocation Normal Infertility Lymphocytes(10%) 5% detected in son 46,XX/46,XX,t(5;18)(q35.lq21.3) Normal Miscarriages Not repeated Case 2 (28%) (son’s wife) FH =family history; prenatal dx = prenatal diagnosis.
location mosaicism is uncommon but the exact frequency remains uncertain. The origin of this type of mosaicism is unknown. If a post-conception exchange occurs between non-homologous chromosomes at mitosis, subsequent segregation could result in two cell lines, some with and some without the rearrangement. The zygote initially lacks the translocation. Mitotic recombination between non-homologous chromosomes has been documented in human cells, specifically from Bloom syndrome patients [Therman et al., 1981; Therman and Kuhn, 19851. An alternate model for prezygotic origin of structural mosaicism has been proposed [Cantu et al., 1985a,b,c;Cantu and Ruiz, 19861. It is analogous to Gartler and Francke’s [19751 model for mosaicism of single-base changes. In Cantu’s model, single-strand breaks occur in the two non-homologous chromosomes, followed by abnormal non-homologous rejoining of the chromatids before anaphase I1 of gamete formation. After conception, segregation of the two normal non-homologous chromosomes to one cell and the translocation chromosomes to the other cell results in structural mosaicism. This halfchromatid mutation model implies that the translocation chromosomes would be uniparental, whereas with mitotic error, the involved chromosomes could be either uniparental or biparental. Germ-line mosaicism has been proposed for several single-gene conditions [Hall, 19881. Case 2 demonstrates the presence of the translocation in germ cells, since it was transmitted to her son. Similarly, Fryns and Kleczkowska [19861detected inheritance of a transloca-
tion from a parent with translocation mosaicism. These cases suggest that balanced reciprocal translocations can originate from a mosaic parent who is likely to have germ-line mosaicism for the structural rearrangement. Table I lists the ascertainment reason for cases of reciprocal translocation mosaicism. One was associated with minor anomalies, and one had a family history of mental retardation. The others presumably had a normal phenotype but were studied due to miscarriages or infertility. Our two cases were associated with miscarriages. Stenchever et al. [19771 reported three possible cases of reciprocal translocation mosaicism in a parental study of reproductive wastage. However, Sciorra et al. [19851interpreted the chromosomes of these cases to be normal. Lippman-Hand and Vekemans [19831reviewed the literature on balanced translocations and miscarriages. The only cases of reciprocal translocation mosaicism they noted were those of Stenchever et al. [19771. Caste1 and Bernstein [19881 described patients with mosaicism for a balanced translocation studied for a history of multiple miscarriages. However, three of the seven involved breakpoints of chromosomes 7 and 14, which are frequently noted in cultured lymphocytes and could reflect artifact. In such studies, only single cultures were analyzed; thus, an in vitro event could not be ruled out. The relationship of translocation mosaicism to miscarriages and infertility is undefined. An increased risk of congenital problems is associated with de novo non-mosaic reciprocal translocations [Gardner and Sutherland, 19891, but whether this occurs with reciprocal translocation mosaicism remains to
Reciprocal Damlocation Mosaicism
be determined. Low-level mosaicism for balanced translocations in persons with and without anomalies warrants repeat analysis to attempt confirmation. The phenotype must be recorded to determine if there is any increased risk of abnormalities. At prenatal diagnosis, pseudomosaicism for structural abnormalities is not usually reported, but our cases suggest true mosaicism could be present. Further investigation of low levels of mosaicism at prenatal diagnosis should be considered after birth, yet parental anxiety might outweigh the need for more information as few cases likely represent true mosaicism. The relationship of reciprocal translocation mosaicism to the presenting histories of minor anomalies, miscarriages, and infertility is uncertain since there are so few cases. Further families and long-term follow-upof prenatally diagnosed children are necessary to determine the prevalence and possible effects of this type of structural mosaicism.
REFERENCES Cantd JM, Ruiz C (1986): On a prezygotic origin of normalhalanced translocation mosaics. Ann Genet 29:221-222. Cantu JM, Rivas F, Ruiz C, Barajas LO, Moller M, Rivera H (1985a): Trisomy 7p due to a mosaic normal/dir dup(7)(p13+p22). Ann Genet 28:254-257. Cantd JM, Rivas F, Rivera H, Ruiz C (198513): The prezygotic origin of structural mosaics. Ann Genet 28:73-74. Cantd JM, Hernandez A, JimBnez-SBinz M, Moller M, Rdon A, Chromosomal aberrations in Gonzalez-Flores0, Rivera H (1985~): 334 individuals with repeated spontaneous abortions and or fetal wastage. Rev Invest Clin (Mex) 37:131-134. Castle D, Bernstein R (1988): Cytogenetic analysis of 688 couples
347
experiencing multiple spontaneous abortions. Am J Med Genet 29:549-556. Fryns JP, Kleczkowska A (1986):Letter to the Editor: Reciprocal translocation mosaicism in man. Am J Med Genet 25:175-176. Gardner RJM, Sutherland GR (1989): “Chromosome Abnormalities and Genetic Counselling.” New York: Oxford University Press, pp 198-199. Gartler SM, Francke U (1975): Half chromatid mutations: Transmission in humans? Am J Hum Genet 27:218-223. Hall JG (1988): Review and hypotheses: Somatic mosaicism: Observations related to clinical genetics. Am J Hum Genet 43:355-363. Hook EB (1977):Exclusion of chromosomal mosaicism: Tables of 9095, 95%, and 99% confidence limits and comments on use. Am J Hum Genet 29:94-97. Hook EB, Cross EK (1987): Rates of mutant and inherited structural cytogenetic abnormalities detected at amniocentesis: results on about 63,000 fetuses. Ann Hum Genet 51:27-55. Kleczkowska A, Fryns JP, Van den Berghe H (1990): On the variable effect of mosaic normalhalanced chromosomal rearrangements in man. J Med Genet 27:505-507. Lippman-Hand A, Vekemans M (1983):Balanced translocations among couples with two or more spontaneous abortions: Are males and females equally likely to be carriers? Hum Genet 63:252-257. Saura R, L o n g M, Serville F, Chokairi 0,Froute MF (1987): Letter to the Editor: Abnormal phenotype in a child with a “balanced translocation 8112 in mosaic state. Am J Med Genet 28:1021-1023. Sciorra U,Lee M, Cuccurllo G (1985): Translocation mosaicism in a woman having multiple miscarriages. Am J Med Genet 22:615-. 617. Stenchever MA, Parks KJ, Allen MA, Stenchever MR (1977): Cytogenetics of habitual abortion and other reproductive wastage. Am J Obstet Gynecol 127:143-150. Therman E, Kuhn EM (1985): Incidence and origin of symmetric and asymmetric dicentrics in Bloom’s syndrome. Cancer Genet Cytogenet 15293-301. Therman E, Otto PG, Shadidi NT (1981): Mitotic recombination and segregation of satellites in Bloom’s syndrome. Chromosoma 82:627-636.
