- Email: [email protected]
Origin of uniparental disomy 6: presentation of a new case and review on the literature
Annales de Génétique 44 (2001) 41–45 © 2001 Éditions scientifiques et médicales Elsevier SAS. All rights reserved S0003399501010358/FLA
Original article
Origin of uniparental disomy 6: presentation of a new case and review on the literature Thomas Eggermanna*, Wolfgang Margb, Susanne Mergenthalera, Katja Eggermanna, Verena Schemmelb, Ullrich Stoffersb, Klaus Zerresa, Stephanie Sprangerc a Institut für Humangenetik, RWTH Aachen, Germany Zentralkrankenhaus St.-Jürgen-Strasse, Bremen, Germany c Zentrum für Humangenetik und Genetische Beratung, Bremen, Germany b
Received 4 September 2000; accepted 12 January 2001
Abstract – Paternal uniparental disomy (UPD) of chromosome 6 has been reported several times in patients with (transient) neonatal diabetes mellitus ((T)NDM). Here we present our short tandem repeat typing results in a new patient with NDM, revealing a paternal isodisomy (UPiD). Summarising these data with those published previously on complete paternal (n=13) and maternal (n=2) UPD6, all cases show isodisomy. In general, several modes of UPD formation have been suggested: While a meiotic origin of UPD mainly results in a uniparental heterodisomy (UPhD), UPiD is probably the result of a post-zygotic mitotic error. This mode of formation consists of a mitotic nondisjunction in a disomic zygote, followed by either a trisomic rescue or a reduplication. Endoduplication in a monosomic zygote is another possible but less probable mechanism, taking into consideration that monosomic zygotes are not viable. The exclusive finding of isodisomy in case of chromosome 6 therefore gives strong evidence that segregational errors of this chromosome are mainly influenced by postzygotic factors. This hypothesis is supported by the observation of two cases with partial paternal UPiD6 originating from mitotic recombination events. The influence of mitotic segregational errors in UPD6 formation is in agreement with the results in trisomy/UPD of other chromosomes of the C group (7 and 8), and is in remarkable contrast to the findings in studies on the origin of the frequent aneuploidies. Multiple factors ensure normal segregation and we speculate that they vary in importance for each chromosome. © 2001 Éditions scientifiques et médicales Elsevier SAS
uniparental disomy 6 / trisomy 6 / transient neonatal diabetes mellitus
1. Introduction
Uniparental Disomy (UPD) is the inheritance of two homologous chromosomes from one parent in an euploid offspring [10]. Two types of UPD can be distinguished: uniparental heterodisomy (UPhD), e.g. both homologous chromosomes are transmitted from the same parent, and uniparental isodisomy (UPiD) with two copies of the same parental chromosome being present. Depending on their maternal or paternal origin, distinct and recurrent phenotypes are well known for some chromosomes (for review: [18, 19]). These include Prader–Willi syndrome (maternal UPD15), Angelman syndrome (paternal UPD15), Beckwith–Wiedemann syndrome (paternal UPD11) and Silver–Russell syndrome (maternal UPD7). Paternal UPD6 has been described 12 times in patients with
(transient) neonatal diabetes mellitus ((T)NDM) [1, 6–8, 11, 14, 15, 21, 23, 27, 29] and in 3 further patients not suffering from NDM [4, 20, 28]. Two of these patients showed a segmental paternal UPD6 with biparental disomy of terminal 6q [20] and 6p [8], respectively. Conversely, maternal UPD6 is not associated with a specific phenotype except intrauterine growth retardation [3, 26]. The pattern of inheritance of (T)NDM and its association with UPD6 is consistent with the presence of an imprinted gene(s) on chromosome 6. Systematic screening for chromosome 6 abnormalities in (T)NDM patients allowed to delineate the region suspected of harbouring the gene(s) of interest to be 6q24; an imprinted locus associated with TNDM was identified by Gardner and coworkers [12]. Studies on the formation of UPDs allow to get insights in nondisjunction mechanisms of the respec-
* Correspondence and reprints. E-mail address: [email protected] (T. Eggermann).
42
T. Eggermann et al. / Ann. Génét. 44 (2001) 41–45
Table I. Results of STR marker typing in the present case with TNDM. The genetic order of the polymorphisms corresponds to that published elsewhere [6, 13]. STR
Localisation
Father
Mother
Patient
Informativity
6pter D6S260 D6S276 D6S295 D6S294 D6S1010 D6S308 D6S311 6qter
6p23 6p22.3-21.3 6p12 6p11 6q22-q24 6q22-24 6q25
1-1 1-3 1-1 1-1 2-3 2-3 2-3
2-3 1-2 1-1 2-2 1-2 1-3 1-4
1-1 3-3 1-1 1-1 2-2 2-2 2-2
Paternal UPD Paternal UPiD
tive chromosomes, since UPDs are the products of meiotic or mitotic segregation errors. Similar studies have recently been reported for UPD and trisomy of chromosomes 7 and 15 [22, 24]. Trisomy 6 is a relatively rare condition in spontaneous abortions with a frequency of 0.3 % [16]. With the exception of hematologic disorders, non-mosaic or mosaic trisomy of the complete chromosome 6 has neither been described in stillbirths nor in livebirths. This observation may be explained by the lethality of trisomy 6. To estimate the contribution of mitotic and meiotic nondisjunction to the formation of UPD6, we analysed an own case with paternal UPD6 as well as the cases published in the literature. We then draw conclusions with respect to trisomy 6 origin. 2. Patient
The female newborn presented with low birth weight, macroglossia and NDM. At the age of two months, the girl was still under insulin therapy. Molecular genetic studies were performed at the age of 1 month. Cytogenetic analysis showed a normal karyotype in the patient (46,XX). Maternal and paternal age at birth were 23 and 40 years, respectively. 3. Material and methods
DNA from the patient and her parents was extracted from peripheral blood lymphocytes by a simple salting-out procedure. Uniparental disomy of chromosome 6 was determined by short tandem repeat typing (STR) (table I). Data and PCR conditions can be obtained from Genome Database. Following electrophoresis on a denaturing sequencing gel, the alleles were visualized by silver-staining. Typing of three different markers on chromosomes other than 6 was
Paternal UPD (UPiD) Paternal UPiD Paternal UPiD
carried out to confirm normal maternal and paternal contributions. 4. Results and discussion
The results of STR analysis in our NDM patient are presented in table I. The girl showed inheritance of a single paternal allele at 6 informative loci (figure 1), STR D6S295 was not informative. Thus, the child inherited two identical copies of the same chromosome 6 from the father indicating a complete isodisomy. Complete isodisomy has been described for all the 12 paternal UPD6 patients published so far [1, 4, 6, 7, 11, 14, 15, 21, 23, 28, 29]. A further TNDM patient was carrier of a maternally derived ring chromosome 6, showing paternal UPiD6 for the tips of chromosome 6 [27]. Additionally, two patients showed segmental paternal UPiD6, with the distal part of 6q and 6p, respectively, being of biparental origin [8, 20]. The two maternal UPD6 cases were also isodisomic [3, 26]. Of course, it has to be borne in mind that undetected recombination events cannot be excluded due to the genetic distances between the analysed markers and the limited number of STRs analysed. Obviously, this might lead to a misinterpretation of the complete isodisomies. Nevertheless, it is remarkable that not a single UPhD for at least one marker has been observed in one of the 18 probands. Therefore, we assume that probably all UPD6 cases are isodisomic and suggest the following for the segregational behaviour of chromosome 6: While the first step in UPhD formation is always a meiotic nondisjunction, UPiD may either be the result of meiotic as well as of mitotic non-disjunction errors [25]. – UPiD may be caused by correction of a trisomy which had been the result of a meiosis II non-disjunction of an achiasmatic bivalent (a).
T. Eggermann et al. / Ann. Génét. 44 (2001) 41–45
43
Figure 1. Examples of STR typing in the paternal UPD6 patient presented here. Typing of both markers revealed UPD6. (Fa father, Mo mother, Pat patient)
– A mitotic nondisjunction might split a disomic zygote into two karyotypically different cell lines, a trisomic rescue may lead to UPiD in one third of all cases (b). – Alternatively, the monosomic cell line can become isodisomic by reduplication (c). – This process may also take place in a monosomic zygote, formed by the fertilization of a monosomic by a nullisomic gamete (d).
Each of these four mechanisms may result in a complete isodisomy. To date, these modes of UPiD formation are indistinguishable. Trisomic rescue will inevitably lead to mosaicism. To the best of our knowledge, mosaicism has indeed never been described in UPD6 patients. Two reasons are possible: firstly, trisomy 6 might be lethal for a cell line. This may also be delineated from the rarity of this aneuploidy in abortions and its lack in later gestational stages; a mosaicism might be directly eliminated. Secondly, mosaicism is generally difficult to prove, as discussed by Dras and coworkers in a case of partial UPiD6 [8]. UPD in humans is thought to be primarily caused by meiotic nondisjunction events, followed by trisomy (a) or monosomy rescue (d). These mechanisms are compatible with the association with advanced maternal age in the majority of cases [5]. In case of paternal UPD, the initial step of formation (d) would take place in maternal meiotic nondisjunction, resulting in a nullisomic oocyte. It is uncertain whether a gamete nullisomic for a chromosome as large as chromosome 6 is viable. Mechanism (a) includes a disomic gamete as a result of a meiosis II error. Due to the lack of chiasmata formation in meiosis I,
chromosomes 6 in this gamete should be identical. However, in trisomies of other chromosomes, complete absence of recombination is very rare [5]. Therefore, mechanisms (b) and (c) based on mitotic segregational errors seem to be the most probable ones. This hypothesis is supported by the relatively high frequency of maternal isodisomy in UPD of chromosome 7. A similar formation mechanism may therefore be delineated: In trisomy 7 as well as in maternal UPD7, a large proportion of cases originate from a postzygotic segregation error (for review: [22]). Mergenthaler et al. [22] therefore suggested that rescue of a mitotically caused trisomy 7 is a frequent mode of UPD7 formation. Trisomy of chromosome 8 also shows a preponderance of postzygotic mitosis as cell stage of nondisjunction [17]. At least one out of three published UPD8 cases was also isodisomic [for review: 18]. However, the complete lack of UPhD6 might be attributed to the non-viability of a trisomy 6 zygote; thus, meiotic errors as a cause for UPD6 formation cannot finally be excluded. It is interesting to note that in UPD6 paternally missegregated chromosomes are preponderant. While meiotic errors appear to be the most frequent cause of maternally derived aberrations, the parental origin of mitotically missegregated chromosomes should be distributed equally as described for trisomy 21 [2]. However, neither in UPD7/trisomy 7, trisomy 8 [17, 22] nor in UPD6 this equal distribution is observed. For maternal UPD6, no specific phenotype is known and therefore cases are probably only found by chance, as also suggested for paternal UPD7 [22]. The
44
T. Eggermann et al. / Ann. Génét. 44 (2001) 41–45
high frequency of paternal mitotic segregation errors of chromosome 6 is remarkable in comparison to that in trisomies of chromosomes 13, 14, 15, 18, 21, and 22, the cell stage of origin of the paternally derived supernumerary chromosomes is meiosis in more than 50 % of cases [2, 5, 9, 30]. To sum up, the results of studies of parental origin in chromosomes of the C group are in remarkable contrast to the common autosomal trisomies of the D, E and G group, where the majority of cases can be delineated from errors in maternal meiosis. The data may reflect the presence of multiple factors which act to ensure normal segregation, each varying in importance for each chromosome. Furthermore, with the confirmation of a postzygotic origin of UPD6 formation a low recurrence risk for couples seeking genetic counselling may be given: a gonadal mosaicism as occasionally postulated for trisomies 13, 18 and 21, can be excluded. Additionally, the genetic finding of paternal UPD6 allows prediction of a transient rather than permanent course for diabetes mellitus and no increased recurrence risk for transient NMD in subsequent pregnancies has to be given [7].
References [1] Abramowicz M.J., Andrien M., Dupont E., et al., Isodisomy of chromosome 6 in a newborn with methylmalonic acidemia and agenesis of pancreatic beta cells causing diabetes mellitus, J. Clin. Invest. 19 (1994) 418–421. [2] Antonarakis S.E., Avramopoulos D., Blouin J.L., Talbot C.C. Jr., Schinzel A.A., Mitotic errors in somatic cells cause trisomy 21 in about 4.5 % of cases and are not associated with advanced maternal age, Nat. Genet. 13 (1993) 146–150. [3] van den Berg-Loonen E.M., Savekoul P., van Hooff H., van Eede P., Riesewijk A., Geraedts J., Uniparental maternal disomy 6 in a renal transplant patient, Hum. Immun. 45 (1996) 46–51. [4] Bittencourt M.C., Morris M.A., Chabod J., et al., Fortuitous detection of uniparental isodisomy of chromosome 6, J. Med. Genet. 34 (1997) 77–78. [5] Bugge M., Collins A., Petersen M.B., et al., Non-disjunction of chromosome 18, Hum. Mol. Genet. 7 (1998) 661–669. [6] Cave H., Polak M., Drunat S., Denamur E., Czernichow P., Refinement of the 6q chromosomal region implicated in transient neonatal diabetes, Diabetes 49 (2000) 108–111. [7] Christian S.L., Rich B.H., Loebl C., Israel J., Vasa R., Kittikamron K., Spiro R., Rosenfield R., Ledbetter D.H., Significance of genetic testing for paternal uniparental disomy of chromosome 6 in neonatal diabetes mellitus, J. Pediatr. 134 (1999) 42–46. [8] Das S., Lese C.M., Song M., Jensen J.L., Wells L.A., Barnoski B.L., Roseberry J.A., Camacho J.M., Ledbetter D.H., Schnur R.E., Partial paternal uniparental disomy of chromosome 6 in an infant with neonatal diabetes, macroglossia, and craniofacial abnormalities, Am. J. Hum. Genet. 67 (2000) 1586–1591.
[9] Eggermann T., Nöthen M.M., Eiben B., Hofmann D., Hinkel K., Fimmers R., Schwanitz G., Trisomy of human chromosome 18: molecular studies on parental origin and cell stage of nondisjunction, Hum. Genet. 97 (1996) 218–223. [10] Engel E., A new genetic concept: uniparental disomy and its potential effect, isodisomy, Am. J. Med. Genet. 6 (1980) 137–143. [11] Gardner R.J., Robinson D.O., Lamont L., Shield J.P.H., Temple I.K., Paternal uniparental disomy of chromosome 6 and transient neonatal diabetes mellitus, Clin. Genet. 54 (1998) 522–525. [12] Gardner R.J., Mackay D.J.G., Mungall A.J., et al., An imprinted locus associated with transient neonatal diabetes mellitus, Hum. Mol. Genet. 9 (2000) 589–596. [13] Gyapay G., Morissette J., Vignal A., et al., The 1993–94 Généthon human genetic linkage map, Nat. Genet. 7 (1994) 812–816. [14] Hermann R., Soltesz G., Paternal uniparental isodisomy of chromosome 6 in transient neonatal diabetes mellitus, Eur. J. Pediatr. 156 (1997) 740. [15] Israel J., Vasa R., Loeb C., Ledbetter D., Christian S., A unique case of uniparental disomy of chromosome 6 and neonatal diabetes with macroglossia, Am. J. Hum. Genet. 61S (1997) A100. [16] Jacobs P.A., Hassold T.J., Chromosome abnormalities: origin and etiology in abortions and livebirths, in: Vogel F., Sperling K. (Eds.), Human Genetics, Springer-Verlag, Heidelberg, 1989. [17] Karadima G., Bugge M., Nicolaidis P., et al., Origin of nondisjunction in trisomy 8 and trisomy 8 mosaicism, Eur. J. Hum. Genet. 6 (1998) 432–438. [18] Kotzot D., Abnormal phenotypes in uniparental disomy (UPD): fundamental aspects and a critical review with bibliography of UPD other than 15, Am. J. Med. Genet. 82 (1999) 265–274. [19] Ledbetter D.H., Engel E., Uniparental disomy in humans: development of an imprinting map and its implications for prenatal diagnosis, Hum. Mol. Genet. 4 (1995) 1757–1764. [20] Lopez-Guittierrez A.U., Riba L., Ordonez-Sanchez M.L., Ramirez-Jinmenez S., Cerrillo-Hinojosa M., Tusie-Luna M.T., Uniparental disomy for chromosome 6 results in steroid 21hydroxylase deficiency: evidence of different genetic mechanisms involved in the production of the disease, J. Med. Genet. 35 (1998) 1014–1019. [21] Marquis E., Robert J.J., Benezech C., Junien C., DiatloffZito C., Variable features of transient neonatal diabetes mellitus with paternal isodisomy of chromosome 6, Eur. J. Hum. Genet. 8 (2000) 137–140. [22] Mergenthaler S., Wollmann H.A., Burger B., et al., Formation of uniparental disomy 7 delineated from new cases and a UPD7 case after trisomy 7 rescue, Ann. Génét. 43 (2000) 15–21. [23] Palmer S.E., Christian S.L., Danney M.M., Odom M.W., Ledbetter D.H., Neonatal diabetes mellitus due to uniparental disomy of chromosome 6, Am. J. Hum. Genet. 63S (1998) A116. [24] Robinson W.P., Kuchinka B.D., Bernasconi F., et al., Maternal meiosis I non-disjunction of chromosome 15: dependence of the maternal age effect on level of recombination, Hum. Mol. Genet. 7 (1998) 1011–1019. [25] Spence J.F., Perciaccante R.G., Greig G.M., et al., Uniparental disomy as a mechanism for human genetic disease, Hum. Genet. 42 (1988) 217–226. [26] Spiro R.P., Christian S.L., Ledbetter D.H., New M.I., Wilson R.C., Roizen N., Rosenfield R.L., Intrauterine growth retardation associated with maternal uniparental disomy for chro-
T. Eggermann et al. / Ann. Génét. 44 (2001) 41–45 mosome 6 unmasked by congenital adrenal hyperplasia, Pediatr. Res. 46 (1999) 510–513. [27] Temple I.K., James R.S., Crolla J.A., Sitch F.L., Jacobs P.A., Howell W.M., Betts P., Baum D., Shield J.P.H., An imprinted gene(s) for diabetes? Nat. Genet. 9 (1995) 110–112. [28] Welch T.R., Beischel L.L.S., Choi E., Balakrishnan K., Bishop N.A., Uniparental isodisomy 6 associated with deficiency of the fourth component of complement, J. Clin. Invest. 86 (1990) 675–678.
45
[29] Whiteford M.L., Narendra A., White M.P., Cooke A., Wilkinson A.G., Robertson K.J., Tolmie J.L., Paternal uniparental disomy for chromosome 6 causes transient neonatal diabetes, J. Med. Genet. 345 (1997) 167–168. [30] Zaragoza M.V., Jacobs P.A., James R.S., Rogan P., Sherman S., Hassold T., Nondisjunction of human acrocentric chromosomes: studies of 432 trisomic fetuses and liveborns, Hum. Genet. 94 (1994) 411–417.
Original article
Origin of uniparental disomy 6: presentation of a new case and review on the literature Thomas Eggermanna*, Wolfgang Margb, Susanne Mergenthalera, Katja Eggermanna, Verena Schemmelb, Ullrich Stoffersb, Klaus Zerresa, Stephanie Sprangerc a Institut für Humangenetik, RWTH Aachen, Germany Zentralkrankenhaus St.-Jürgen-Strasse, Bremen, Germany c Zentrum für Humangenetik und Genetische Beratung, Bremen, Germany b
Received 4 September 2000; accepted 12 January 2001
Abstract – Paternal uniparental disomy (UPD) of chromosome 6 has been reported several times in patients with (transient) neonatal diabetes mellitus ((T)NDM). Here we present our short tandem repeat typing results in a new patient with NDM, revealing a paternal isodisomy (UPiD). Summarising these data with those published previously on complete paternal (n=13) and maternal (n=2) UPD6, all cases show isodisomy. In general, several modes of UPD formation have been suggested: While a meiotic origin of UPD mainly results in a uniparental heterodisomy (UPhD), UPiD is probably the result of a post-zygotic mitotic error. This mode of formation consists of a mitotic nondisjunction in a disomic zygote, followed by either a trisomic rescue or a reduplication. Endoduplication in a monosomic zygote is another possible but less probable mechanism, taking into consideration that monosomic zygotes are not viable. The exclusive finding of isodisomy in case of chromosome 6 therefore gives strong evidence that segregational errors of this chromosome are mainly influenced by postzygotic factors. This hypothesis is supported by the observation of two cases with partial paternal UPiD6 originating from mitotic recombination events. The influence of mitotic segregational errors in UPD6 formation is in agreement with the results in trisomy/UPD of other chromosomes of the C group (7 and 8), and is in remarkable contrast to the findings in studies on the origin of the frequent aneuploidies. Multiple factors ensure normal segregation and we speculate that they vary in importance for each chromosome. © 2001 Éditions scientifiques et médicales Elsevier SAS
uniparental disomy 6 / trisomy 6 / transient neonatal diabetes mellitus
1. Introduction
Uniparental Disomy (UPD) is the inheritance of two homologous chromosomes from one parent in an euploid offspring [10]. Two types of UPD can be distinguished: uniparental heterodisomy (UPhD), e.g. both homologous chromosomes are transmitted from the same parent, and uniparental isodisomy (UPiD) with two copies of the same parental chromosome being present. Depending on their maternal or paternal origin, distinct and recurrent phenotypes are well known for some chromosomes (for review: [18, 19]). These include Prader–Willi syndrome (maternal UPD15), Angelman syndrome (paternal UPD15), Beckwith–Wiedemann syndrome (paternal UPD11) and Silver–Russell syndrome (maternal UPD7). Paternal UPD6 has been described 12 times in patients with
(transient) neonatal diabetes mellitus ((T)NDM) [1, 6–8, 11, 14, 15, 21, 23, 27, 29] and in 3 further patients not suffering from NDM [4, 20, 28]. Two of these patients showed a segmental paternal UPD6 with biparental disomy of terminal 6q [20] and 6p [8], respectively. Conversely, maternal UPD6 is not associated with a specific phenotype except intrauterine growth retardation [3, 26]. The pattern of inheritance of (T)NDM and its association with UPD6 is consistent with the presence of an imprinted gene(s) on chromosome 6. Systematic screening for chromosome 6 abnormalities in (T)NDM patients allowed to delineate the region suspected of harbouring the gene(s) of interest to be 6q24; an imprinted locus associated with TNDM was identified by Gardner and coworkers [12]. Studies on the formation of UPDs allow to get insights in nondisjunction mechanisms of the respec-
* Correspondence and reprints. E-mail address: [email protected] (T. Eggermann).
42
T. Eggermann et al. / Ann. Génét. 44 (2001) 41–45
Table I. Results of STR marker typing in the present case with TNDM. The genetic order of the polymorphisms corresponds to that published elsewhere [6, 13]. STR
Localisation
Father
Mother
Patient
Informativity
6pter D6S260 D6S276 D6S295 D6S294 D6S1010 D6S308 D6S311 6qter
6p23 6p22.3-21.3 6p12 6p11 6q22-q24 6q22-24 6q25
1-1 1-3 1-1 1-1 2-3 2-3 2-3
2-3 1-2 1-1 2-2 1-2 1-3 1-4
1-1 3-3 1-1 1-1 2-2 2-2 2-2
Paternal UPD Paternal UPiD
tive chromosomes, since UPDs are the products of meiotic or mitotic segregation errors. Similar studies have recently been reported for UPD and trisomy of chromosomes 7 and 15 [22, 24]. Trisomy 6 is a relatively rare condition in spontaneous abortions with a frequency of 0.3 % [16]. With the exception of hematologic disorders, non-mosaic or mosaic trisomy of the complete chromosome 6 has neither been described in stillbirths nor in livebirths. This observation may be explained by the lethality of trisomy 6. To estimate the contribution of mitotic and meiotic nondisjunction to the formation of UPD6, we analysed an own case with paternal UPD6 as well as the cases published in the literature. We then draw conclusions with respect to trisomy 6 origin. 2. Patient
The female newborn presented with low birth weight, macroglossia and NDM. At the age of two months, the girl was still under insulin therapy. Molecular genetic studies were performed at the age of 1 month. Cytogenetic analysis showed a normal karyotype in the patient (46,XX). Maternal and paternal age at birth were 23 and 40 years, respectively. 3. Material and methods
DNA from the patient and her parents was extracted from peripheral blood lymphocytes by a simple salting-out procedure. Uniparental disomy of chromosome 6 was determined by short tandem repeat typing (STR) (table I). Data and PCR conditions can be obtained from Genome Database. Following electrophoresis on a denaturing sequencing gel, the alleles were visualized by silver-staining. Typing of three different markers on chromosomes other than 6 was
Paternal UPD (UPiD) Paternal UPiD Paternal UPiD
carried out to confirm normal maternal and paternal contributions. 4. Results and discussion
The results of STR analysis in our NDM patient are presented in table I. The girl showed inheritance of a single paternal allele at 6 informative loci (figure 1), STR D6S295 was not informative. Thus, the child inherited two identical copies of the same chromosome 6 from the father indicating a complete isodisomy. Complete isodisomy has been described for all the 12 paternal UPD6 patients published so far [1, 4, 6, 7, 11, 14, 15, 21, 23, 28, 29]. A further TNDM patient was carrier of a maternally derived ring chromosome 6, showing paternal UPiD6 for the tips of chromosome 6 [27]. Additionally, two patients showed segmental paternal UPiD6, with the distal part of 6q and 6p, respectively, being of biparental origin [8, 20]. The two maternal UPD6 cases were also isodisomic [3, 26]. Of course, it has to be borne in mind that undetected recombination events cannot be excluded due to the genetic distances between the analysed markers and the limited number of STRs analysed. Obviously, this might lead to a misinterpretation of the complete isodisomies. Nevertheless, it is remarkable that not a single UPhD for at least one marker has been observed in one of the 18 probands. Therefore, we assume that probably all UPD6 cases are isodisomic and suggest the following for the segregational behaviour of chromosome 6: While the first step in UPhD formation is always a meiotic nondisjunction, UPiD may either be the result of meiotic as well as of mitotic non-disjunction errors [25]. – UPiD may be caused by correction of a trisomy which had been the result of a meiosis II non-disjunction of an achiasmatic bivalent (a).
T. Eggermann et al. / Ann. Génét. 44 (2001) 41–45
43
Figure 1. Examples of STR typing in the paternal UPD6 patient presented here. Typing of both markers revealed UPD6. (Fa father, Mo mother, Pat patient)
– A mitotic nondisjunction might split a disomic zygote into two karyotypically different cell lines, a trisomic rescue may lead to UPiD in one third of all cases (b). – Alternatively, the monosomic cell line can become isodisomic by reduplication (c). – This process may also take place in a monosomic zygote, formed by the fertilization of a monosomic by a nullisomic gamete (d).
Each of these four mechanisms may result in a complete isodisomy. To date, these modes of UPiD formation are indistinguishable. Trisomic rescue will inevitably lead to mosaicism. To the best of our knowledge, mosaicism has indeed never been described in UPD6 patients. Two reasons are possible: firstly, trisomy 6 might be lethal for a cell line. This may also be delineated from the rarity of this aneuploidy in abortions and its lack in later gestational stages; a mosaicism might be directly eliminated. Secondly, mosaicism is generally difficult to prove, as discussed by Dras and coworkers in a case of partial UPiD6 [8]. UPD in humans is thought to be primarily caused by meiotic nondisjunction events, followed by trisomy (a) or monosomy rescue (d). These mechanisms are compatible with the association with advanced maternal age in the majority of cases [5]. In case of paternal UPD, the initial step of formation (d) would take place in maternal meiotic nondisjunction, resulting in a nullisomic oocyte. It is uncertain whether a gamete nullisomic for a chromosome as large as chromosome 6 is viable. Mechanism (a) includes a disomic gamete as a result of a meiosis II error. Due to the lack of chiasmata formation in meiosis I,
chromosomes 6 in this gamete should be identical. However, in trisomies of other chromosomes, complete absence of recombination is very rare [5]. Therefore, mechanisms (b) and (c) based on mitotic segregational errors seem to be the most probable ones. This hypothesis is supported by the relatively high frequency of maternal isodisomy in UPD of chromosome 7. A similar formation mechanism may therefore be delineated: In trisomy 7 as well as in maternal UPD7, a large proportion of cases originate from a postzygotic segregation error (for review: [22]). Mergenthaler et al. [22] therefore suggested that rescue of a mitotically caused trisomy 7 is a frequent mode of UPD7 formation. Trisomy of chromosome 8 also shows a preponderance of postzygotic mitosis as cell stage of nondisjunction [17]. At least one out of three published UPD8 cases was also isodisomic [for review: 18]. However, the complete lack of UPhD6 might be attributed to the non-viability of a trisomy 6 zygote; thus, meiotic errors as a cause for UPD6 formation cannot finally be excluded. It is interesting to note that in UPD6 paternally missegregated chromosomes are preponderant. While meiotic errors appear to be the most frequent cause of maternally derived aberrations, the parental origin of mitotically missegregated chromosomes should be distributed equally as described for trisomy 21 [2]. However, neither in UPD7/trisomy 7, trisomy 8 [17, 22] nor in UPD6 this equal distribution is observed. For maternal UPD6, no specific phenotype is known and therefore cases are probably only found by chance, as also suggested for paternal UPD7 [22]. The
44
T. Eggermann et al. / Ann. Génét. 44 (2001) 41–45
high frequency of paternal mitotic segregation errors of chromosome 6 is remarkable in comparison to that in trisomies of chromosomes 13, 14, 15, 18, 21, and 22, the cell stage of origin of the paternally derived supernumerary chromosomes is meiosis in more than 50 % of cases [2, 5, 9, 30]. To sum up, the results of studies of parental origin in chromosomes of the C group are in remarkable contrast to the common autosomal trisomies of the D, E and G group, where the majority of cases can be delineated from errors in maternal meiosis. The data may reflect the presence of multiple factors which act to ensure normal segregation, each varying in importance for each chromosome. Furthermore, with the confirmation of a postzygotic origin of UPD6 formation a low recurrence risk for couples seeking genetic counselling may be given: a gonadal mosaicism as occasionally postulated for trisomies 13, 18 and 21, can be excluded. Additionally, the genetic finding of paternal UPD6 allows prediction of a transient rather than permanent course for diabetes mellitus and no increased recurrence risk for transient NMD in subsequent pregnancies has to be given [7].
References [1] Abramowicz M.J., Andrien M., Dupont E., et al., Isodisomy of chromosome 6 in a newborn with methylmalonic acidemia and agenesis of pancreatic beta cells causing diabetes mellitus, J. Clin. Invest. 19 (1994) 418–421. [2] Antonarakis S.E., Avramopoulos D., Blouin J.L., Talbot C.C. Jr., Schinzel A.A., Mitotic errors in somatic cells cause trisomy 21 in about 4.5 % of cases and are not associated with advanced maternal age, Nat. Genet. 13 (1993) 146–150. [3] van den Berg-Loonen E.M., Savekoul P., van Hooff H., van Eede P., Riesewijk A., Geraedts J., Uniparental maternal disomy 6 in a renal transplant patient, Hum. Immun. 45 (1996) 46–51. [4] Bittencourt M.C., Morris M.A., Chabod J., et al., Fortuitous detection of uniparental isodisomy of chromosome 6, J. Med. Genet. 34 (1997) 77–78. [5] Bugge M., Collins A., Petersen M.B., et al., Non-disjunction of chromosome 18, Hum. Mol. Genet. 7 (1998) 661–669. [6] Cave H., Polak M., Drunat S., Denamur E., Czernichow P., Refinement of the 6q chromosomal region implicated in transient neonatal diabetes, Diabetes 49 (2000) 108–111. [7] Christian S.L., Rich B.H., Loebl C., Israel J., Vasa R., Kittikamron K., Spiro R., Rosenfield R., Ledbetter D.H., Significance of genetic testing for paternal uniparental disomy of chromosome 6 in neonatal diabetes mellitus, J. Pediatr. 134 (1999) 42–46. [8] Das S., Lese C.M., Song M., Jensen J.L., Wells L.A., Barnoski B.L., Roseberry J.A., Camacho J.M., Ledbetter D.H., Schnur R.E., Partial paternal uniparental disomy of chromosome 6 in an infant with neonatal diabetes, macroglossia, and craniofacial abnormalities, Am. J. Hum. Genet. 67 (2000) 1586–1591.
[9] Eggermann T., Nöthen M.M., Eiben B., Hofmann D., Hinkel K., Fimmers R., Schwanitz G., Trisomy of human chromosome 18: molecular studies on parental origin and cell stage of nondisjunction, Hum. Genet. 97 (1996) 218–223. [10] Engel E., A new genetic concept: uniparental disomy and its potential effect, isodisomy, Am. J. Med. Genet. 6 (1980) 137–143. [11] Gardner R.J., Robinson D.O., Lamont L., Shield J.P.H., Temple I.K., Paternal uniparental disomy of chromosome 6 and transient neonatal diabetes mellitus, Clin. Genet. 54 (1998) 522–525. [12] Gardner R.J., Mackay D.J.G., Mungall A.J., et al., An imprinted locus associated with transient neonatal diabetes mellitus, Hum. Mol. Genet. 9 (2000) 589–596. [13] Gyapay G., Morissette J., Vignal A., et al., The 1993–94 Généthon human genetic linkage map, Nat. Genet. 7 (1994) 812–816. [14] Hermann R., Soltesz G., Paternal uniparental isodisomy of chromosome 6 in transient neonatal diabetes mellitus, Eur. J. Pediatr. 156 (1997) 740. [15] Israel J., Vasa R., Loeb C., Ledbetter D., Christian S., A unique case of uniparental disomy of chromosome 6 and neonatal diabetes with macroglossia, Am. J. Hum. Genet. 61S (1997) A100. [16] Jacobs P.A., Hassold T.J., Chromosome abnormalities: origin and etiology in abortions and livebirths, in: Vogel F., Sperling K. (Eds.), Human Genetics, Springer-Verlag, Heidelberg, 1989. [17] Karadima G., Bugge M., Nicolaidis P., et al., Origin of nondisjunction in trisomy 8 and trisomy 8 mosaicism, Eur. J. Hum. Genet. 6 (1998) 432–438. [18] Kotzot D., Abnormal phenotypes in uniparental disomy (UPD): fundamental aspects and a critical review with bibliography of UPD other than 15, Am. J. Med. Genet. 82 (1999) 265–274. [19] Ledbetter D.H., Engel E., Uniparental disomy in humans: development of an imprinting map and its implications for prenatal diagnosis, Hum. Mol. Genet. 4 (1995) 1757–1764. [20] Lopez-Guittierrez A.U., Riba L., Ordonez-Sanchez M.L., Ramirez-Jinmenez S., Cerrillo-Hinojosa M., Tusie-Luna M.T., Uniparental disomy for chromosome 6 results in steroid 21hydroxylase deficiency: evidence of different genetic mechanisms involved in the production of the disease, J. Med. Genet. 35 (1998) 1014–1019. [21] Marquis E., Robert J.J., Benezech C., Junien C., DiatloffZito C., Variable features of transient neonatal diabetes mellitus with paternal isodisomy of chromosome 6, Eur. J. Hum. Genet. 8 (2000) 137–140. [22] Mergenthaler S., Wollmann H.A., Burger B., et al., Formation of uniparental disomy 7 delineated from new cases and a UPD7 case after trisomy 7 rescue, Ann. Génét. 43 (2000) 15–21. [23] Palmer S.E., Christian S.L., Danney M.M., Odom M.W., Ledbetter D.H., Neonatal diabetes mellitus due to uniparental disomy of chromosome 6, Am. J. Hum. Genet. 63S (1998) A116. [24] Robinson W.P., Kuchinka B.D., Bernasconi F., et al., Maternal meiosis I non-disjunction of chromosome 15: dependence of the maternal age effect on level of recombination, Hum. Mol. Genet. 7 (1998) 1011–1019. [25] Spence J.F., Perciaccante R.G., Greig G.M., et al., Uniparental disomy as a mechanism for human genetic disease, Hum. Genet. 42 (1988) 217–226. [26] Spiro R.P., Christian S.L., Ledbetter D.H., New M.I., Wilson R.C., Roizen N., Rosenfield R.L., Intrauterine growth retardation associated with maternal uniparental disomy for chro-
T. Eggermann et al. / Ann. Génét. 44 (2001) 41–45 mosome 6 unmasked by congenital adrenal hyperplasia, Pediatr. Res. 46 (1999) 510–513. [27] Temple I.K., James R.S., Crolla J.A., Sitch F.L., Jacobs P.A., Howell W.M., Betts P., Baum D., Shield J.P.H., An imprinted gene(s) for diabetes? Nat. Genet. 9 (1995) 110–112. [28] Welch T.R., Beischel L.L.S., Choi E., Balakrishnan K., Bishop N.A., Uniparental isodisomy 6 associated with deficiency of the fourth component of complement, J. Clin. Invest. 86 (1990) 675–678.
45
[29] Whiteford M.L., Narendra A., White M.P., Cooke A., Wilkinson A.G., Robertson K.J., Tolmie J.L., Paternal uniparental disomy for chromosome 6 causes transient neonatal diabetes, J. Med. Genet. 345 (1997) 167–168. [30] Zaragoza M.V., Jacobs P.A., James R.S., Rogan P., Sherman S., Hassold T., Nondisjunction of human acrocentric chromosomes: studies of 432 trisomic fetuses and liveborns, Hum. Genet. 94 (1994) 411–417.