Familial small supernumerary marker chromosomes are predominantly inherited via the maternal line

Abstract

To the Editor: We read with interest the recently published paper of Dalprà et al.1.Dalpà L. Giardino D. Finelli P. Corti C. Cytogenetic and molecular evaluation of 241 small supernumerary marker chromosomes: cooperative study of 19 Italian laboratories.10.1097/01.gim.0000182876.57766.2dGenet Med. 2005; 7: 620-625Google Scholar in this journal. They report on 241 cases with small supernumerary marker chromosomes (sSMC) studied in 19 different Italian laboratories within the last 10 years. This paper is another important contribution to the still understudied field of sSMC-research. Among other interesting conclusions, the authors also report that 16% of their sSMC cases were maternally inherited and only 7% paternally inherited.1.Dalpà L. Giardino D. Finelli P. Corti C. Cytogenetic and molecular evaluation of 241 small supernumerary marker chromosomes: cooperative study of 19 Italian laboratories.10.1097/01.gim.0000182876.57766.2dGenet Med. 2005; 7: 620-625Google Scholar In their discussion, the authors1.Dalpà L. Giardino D. Finelli P. Corti C. Cytogenetic and molecular evaluation of 241 small supernumerary marker chromosomes: cooperative study of 19 Italian laboratories.10.1097/01.gim.0000182876.57766.2dGenet Med. 2005; 7: 620-625Google Scholar allude to a similar 2:1 ratio of maternally/paternally derived sSMC in a previous paper of Crolla et al.2.Crolla J.A. Long F. Rivera H. Dennis N.R. FISH and molecular study of autosomal supernumerary marker chromosomes excluding those derived from chromosomes 15 and 22: I. Results of 26 new cases.1:STN:280:DyaK1c7ktFOntw%3D%3D10.1002/(SICI)1096-8628(19980203)75Am J Med Genet. 1998; 75 (:4<355::AID-AJMG4>3.0.CO;2-P): 355-366Google Scholar However, no correlation was described or suggested in either a recent paper of Crolla et al. reporting on 137 sSMC-carriers3.Crolla J.A. Youings S.A. Ennis S. Jacobs P.A. Supernumerary marker chromosomes in man: parental origin, mosaicism and maternal age revisited.1:CAS:528:DC%2BD2MXnt1Wmsg%3D%3D10.1038/sj.ejhg.5201311Eur J Hum Genet. 2005; 13: 154-160Google Scholar, nor in any previous paper. This led us to analyze the recently summarized data on all reported sSMC cases to see if such a correlation really exists. By January, 2006, we collected 1,885 sSMC cases on the sSMC-homepage.4.Liehr T. sSMC homepage Available at: http://mti-n.mti.uni-jena.de/∼huwww/MOL_ZYTO/sSMC/00START.htm, Accessed on: January 19, 2006.Google Scholar One thousand, one hundred eighty-two of these cases were de novo, 102 inherited, and for the remainder, no information on the parental origin was available (Table 1). The following data are derived from the 1,284 cases in which information on the parental origin was available. As known by newborn studies,4.Liehr T. sSMC homepage Available at: http://mti-n.mti.uni-jena.de/∼huwww/MOL_ZYTO/sSMC/00START.htm, Accessed on: January 19, 2006.Google Scholar, 5.Liehr T. Claussen U. Starke H. Small supernumerary marker chromosomes (sSMC) in humans.1:STN:280:DC%2BD2cvgtV2mtA%3D%3D10.1159/000079572Cytogenet Genome Res. 2004; 107: 55-67Google Scholar the incidence of familial sSMC cases is 40%. At present, only 8% of the cases were familial. Thus, this data shows that there is a bias in the available data.4.Liehr T. sSMC homepage Available at: http://mti-n.mti.uni-jena.de/∼huwww/MOL_ZYTO/sSMC/00START.htm, Accessed on: January 19, 2006.Google Scholar Interesting sSMC-cases are reported throughout the literature and sSMC which are not correlated with clinical problems are not that likely to be reported, i.e., sSMC in connection with clinical abnormalities.Table 1Parental and chromosomal origin of all reported sSMC cases However, when posing the question for the relation of maternal-to-paternal inheritance of familial sSMC there is no reason to suggest a similar bias for those 102 cases in which data are available for the parental origin of the sSMC. For those cases (Table 1), we find 72 sSMC inherited from the mother versus 30 sSMC inherited from the father, which is similar to the 2.4:1 ratio suggested in the paper by Dalprà et al.1.Dalpà L. Giardino D. Finelli P. Corti C. Cytogenetic and molecular evaluation of 241 small supernumerary marker chromosomes: cooperative study of 19 Italian laboratories.10.1097/01.gim.0000182876.57766.2dGenet Med. 2005; 7: 620-625Google Scholar for the parental origin of sSMC. As detailed in Table 1, this ratio is more expressed in sSMC derived from non-acrocentric chromosomes. The data presented here is independent of that of Dalprà et al.,1.Dalpà L. Giardino D. Finelli P. Corti C. Cytogenetic and molecular evaluation of 241 small supernumerary marker chromosomes: cooperative study of 19 Italian laboratories.10.1097/01.gim.0000182876.57766.2dGenet Med. 2005; 7: 620-625Google Scholar as there were no details available on their individual patients. Thus, the observation that familial small supernumerary marker chromosomes (sSMC) are predominantly inherited via the maternal line is substantiated by this analysis. However, an explanation still lacks. One has to suggest that a yet unknown effect is driving selection via fertilization-success of sperm without an sSMC. Problems in connection with sSMC-replication arising predominantly in the more rapidly progressing sperm meiosis or a ‘weight-effect’ making sperm without more rapid than those with an sSMC, similar to the effect known from Y- versus X-chromosome carrying sperm6.Smits L.J. de Bie R.A. Essed G.G. van den Brandt P.A. Time to pregnancy and sex of offspring: cohort study.10.1136/bmj.331.7530.1437BMJ. 2005; 331: 1437-1438Google Scholar could be envisaged as possible mechanisms involved here. The next question that we had based on the available data4.Liehr T. sSMC homepage Available at: http://mti-n.mti.uni-jena.de/∼huwww/MOL_ZYTO/sSMC/00START.htm, Accessed on: January 19, 2006.Google Scholar was if there is a difference in sex ratio in the offspring coming from the parentally inherited compared to de novo sSMC cases. As summarized in Table 2, 94 familial and 535 de novo cases were available for this problem. There was not enough data to distinguish between maternally and paternally inherited ones for that question. When looking at the overall summary of Table 2 there is a 1:1 sex ratio in the offspring of de novo (266:269) and familial cases (45:49). However, splitting into acrocentric and non-acrocentric derived sSMC there is a difference in the latter familial cases (male-to-female ratio of 2:1). Though, this could easily be a bias due to low case numbers (22 cases). Moreover, it could be that single chromosomes form exceptions here, as shown for chromosome 14 in Table 2: among 11 parentally inherited sSMC (14) cases, only 20% were male offspring, while in the 20 available de novo sSMC (14) cases 70% were male. Further studies are required to clarify this point.Table 2Gender of the offspring of sSMC-cases as summarized in Table 1 As summarized in Table 3, there is a difference in the clinical outcome of familial versus de novo cases. While 76% of the familial cases are without clinical signs, 75% of the reported de novo cases show clinical abnormalities. However, for this question one, has to admit that the bias is valid, that predominantly ‘interesting’ cases are reported in the literature. As summarized on the sSMC-homepage4.Liehr T. sSMC homepage Available at: http://mti-n.mti.uni-jena.de/∼huwww/MOL_ZYTO/sSMC/00START.htm, Accessed on: January 19, 2006.Google Scholar it is known by studies performed in newborn cohorts,7.Daniel A. Malafiej P. A Series of supernumerary small ring marker autosomes identified by FISH with chromosome probe arrays and literature review excluding chromosome 15.10.1002/ajmg.a.10100Am J Med Genet. 2003; 117: A212-A222Google Scholar, 8.Warburton D. De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints.1:STN:280:DyaK38%2Fis1WjsQ%3D%3D19281051928105Am J Hum Genet. 1991; 49: 995-1013Google Scholar, 9.Crolla J.A. FISH and molecular studies of autosomal supernumerary marker chromosomes excluding those derived from chromosome 15: II. Review of the literature.1:STN:280:DyaK1c7ktFOntA%3D%3D10.1002/(SICI)1096-8628(19980203)75Am J Med Genet. 1998; 75 (:4<367::AID-AJMG5>3.0.CO;2-N): 367-381Google Scholar that de novo sSMC are associated with clinical signs only in 11–30%. Thus, the only conclusions to be drawn from this data are that a small but considerable part of familial sSMC can lead to clinical problems in the offspring. This has to be considered in genetic counseling of familial cases as well. Moreover, there was a first genotype-phenotype correlation for sSMC published recently,10.Liehr T. Mrasek K. Weise A. Dufke A. Small supernumerary marker chromosomes–progress towards a genotype-phenotype correlation.1:STN:280:DC%2BD2MrpsF2nsw%3D%3D10.1159/000087510Cytogenet Genome Res. 2006; 112: 23-34Google Scholar which can be considered in clinical cases, too.Table 3Clinical outcome of sSMC-cases as summarized in Table 1 In summary, the analysis of all in detail reported sSMC cases4.Liehr T. sSMC homepage Available at: http://mti-n.mti.uni-jena.de/∼huwww/MOL_ZYTO/sSMC/00START.htm, Accessed on: January 19, 2006.Google Scholar concerning the differentiation of maternal and paternal origin, sex ratio, and clinical signs of the offspring gave the following results. As suggested by Dalprà et al.1.Dalpà L. Giardino D. Finelli P. Corti C. Cytogenetic and molecular evaluation of 241 small supernumerary marker chromosomes: cooperative study of 19 Italian laboratories.10.1097/01.gim.0000182876.57766.2dGenet Med. 2005; 7: 620-625Google Scholar in this journal, there is a yet unexplained doubled transmittance rate of sSMC via the maternal compared to the paternal line. Apart from chromosome 14 it seems quite clear, that there is a 1:1 sex ratio in the offspring of familial and de novo sSMC cases. Finally, clinical signs in connection with an sSMC are to be expected in a subset of parentally inherited as well as de novo cases. Supported in parts by the Dr. Robert Pfleger-Stiftung, the DFG (436 RUS 17/135/03; 436 RUS 17/109/04, 436 WER 17/1/04, 436 WER 17/5/05, 436 RUS 17/22/06), the DAAD, the EU (Marie-Curie-Fellowship HPMT-CT-2001-00273), the Schering Foundation and the Evangelische Studienwerk e.V. Villigst.